Nanoengineered Biomaterials for Advanced Drug Delivery (Woodhead Publishing Series in Biomaterials) [1 ed.] 0081029853, 9780081029855

Table of contents :
Cover
Nanoengineered
Biomaterials for
Advanced Drug Delivery
Copyright
Contributors
Preface
Acknowledgment
Part One: Principles of nanotechnology-based drug delivery
1
Principles of nanotechnology-based drug delivery
Principles of nanosized drug delivery systems
Introduction
What are nanosized drug delivery systems and why they are useful?
Different types of nanodelivery systems
Polymeric nanoparticles
Liposomes
Niosomes
Solid lipid nanoparticles
Micro- and nanoemulsions
Polymeric micelles
Dendrimers
Inorganic nanoparticles and quantum dots
Nanocrystals
Protein-based and natural biopolymer-based nanoparticles
Particle properties and related biobarrier interactions of nanosystems
Opsonization and phagocytosis
Particle size
Shape
Surface charge
Hydrophilic/hydrophobic character
Other factors
Nanoparticles in medicines
Lipid nanotechnology
Nanoparticle nanotechnology
Conclusions
References
2
Controlled/localized release and nanotechnology
Introduction
The evolution of drug delivery systems
Nanostructures from dimension viewpoint
Zero-dimensional nanostructures
One-dimensional nanostructures
Two-dimensional nanostructures
Three-dimensional nanostructures
Bionanostructures
Micro- and nanomotors
Conclusion
References
3
Stimuli-sensitive drug delivery systems
Introduction
pH-sensitive drug delivery systems
Redox-sensitive drug delivery systems
Thermosensitive drug delivery systems
Magnetically sensitive drug delivery systems
Ultrasound-sensitive drug delivery systems
Photosensitive drug delivery systems
Electrosensitive drug delivery systems
Intrinsically conducting polymers
Hydrogels
Enzyme-sensitive drug delivery systems
Dual- and multisensitive drug delivery systems
Conclusions
References
4
Sustainable drug delivery systems through green nanotechnology
Nanotechnology
Green nanotechnology
Green nanotechnology in drug delivery
Classification of nanoparticles
Liposomes
Polymeric nanoparticles
Dendrimer
Quantum dots
Silica nanoparticles
Magnetic nanoparticles
Metal-organic frameworks
Green methods for synthesis of MOFs
Mechanochemistry
Sonochemistry
Microwave
Synthesis of MOFs by using bioactive molecules
Summary
References
Further reading
5
Recent advances in multifunctional nanoengineered biomaterials
Introduction
Recent advances in imaging techniques
Optical imaging
Photoacoustic imaging
Multimodality imaging
Recent advances in biomedical applications
Cancer theranostics
Optogenetics
Bacterial infections
Conclusions
References
Part Two: Nanoengineered biomaterials for drug delivery
6
Nanoengineered biomaterials for drug delivery
Nanoengineered polymeric biomaterials for drug delivery system
Introduction
Nanoengineering in drug delivery
Nanoengineered biomaterials for drug delivery
Polymers in drug delivery
Advantages and disadvantage of polymeric biomaterials
Advantages of natural polymers
Disadvantages
Natural polymeric nanomaterials
Nanopolymer of cellulose
Drug delivery application
Chitosan nanoparticles
Drug delivery application
Starch nanoparticle
Drug delivery application
Nanoparticles of chondroitin sulfate
Drug delivery application
Alginate nanoparticles
Drug delivery application
Gelatin nanoparticles
Drug delivery application
Silk fibroin nanoparticles
Drug delivery application
Hyaluronic acid nanoparticles
Drug delivery application
Synthetic nanopolymer and drug delivery application
Poly(lactic-co-glycolic acid) nanoparticles
Drug delivery application
Poly(ethylene-co-vinyl acetate) nanocomposites
Drug delivery application
Poly(methyl methacrylate) nanoparticles
Drug delivery application
Poly (d,l-lactic acid) nanoparticles
Drug delivery application
Polyanhydrides nanoparticles
Drug delivery application
Conclusion
Acknowledgment
References
7
Protein and peptide-based delivery systems
Introduction
Self-assembly in peptides and proteins
DDS based on peptides
Cell-penetrating peptides
Receptor-targeting peptides
Delivery systems based on proteins
Conclusion
References
8
Lipid vesicles: Potentials as drug delivery systems
Introduction
Lipid vesicles in drug delivery
Liposomes
Emulsomes
Transfersomes
Enzymosomes
Ethosomes
Cubosomes
Sphingosomes
Pharmacosomes
Virosomes
Ufasomes
Conclusions
References
9
Block copolymers for nanoscale drug and gene delivery
Introduction
Block copolymers and self-assembly
Block copolymer as a carrier
Rational design of block copolymer
Temperature-responsive nanoscale block copolymer
pH-responsive nanoscale block copolymer
Redox-responsive nanoscale block copolymer
Light-responsive nanoscale block copolymer
Conclusion
References
10
Dendrimers for drug delivery purposes
Introduction
Types of dendrimers
PAMAM dendrimers
PPI dendrimers
PLL dendrimers
Carbosilane dendrimers
Generation of dendrimers
Synthesis of dendrimers
Divergent approach
Convergent approach
Dendrimer-drug interaction in drug delivery
Delivery of small molecules
Delivery of nucleic acids
Routes of dendrimer delivery
Transdermal drug delivery with dendrimers
Intravenous delivery with dendrimers
Pulmonary delivery
Challenges for dendrimer-based drug delivery
Dendrimer-based drug delivery for cancer treatment
Delivery with nonmodified dendrimers
Delivery with modified dendrimers
Surface-shielded dendrimers
Covalent drug-dendrimer conjugates
Stimulus-sensitive dendrimer conjugates
Tumor-targeting delivery with dendrimers
Dendrimer-based codelivery system
Dendrimers for codelivery of small molecule drugs
Dendrimers for codelivery of small molecule drugs and nucleic acids
Dendrimer-based drug delivery for antimicrobial treatment
Antibacterial activity
Antifungal activity
Antiparasitic activity
Dendrimer-based drug delivery for anti-HIV treatment
Dendrimer-based drug delivery for osteoarthritis treatment
Conclusion
References
11
Reversible cross-linked polymeric micelles for drug delivery
Introduction
Design of reversibly cross-linked polymeric nanocarriers with single or multiple responsive properties
Hydrolyzable reversibly cross-linked polymeric nanocarriers for drug delivery
Redox-sensitive reversibly cross-linked polymeric nanocarriers for drug delivery
Redox-sensitive reversibly cross-linked nanocarriers assembled from thiol-containing monomers
Redox-sensitive reversibly cross-linked nanocarriers via incorporation of disulfide bond-containing cross-li ...
pH-sensitive reversibly cross-linked polymeric nanocarriers for delivery purposes
Multiresponsive reversibly cross-linked polymeric nanocarriers for delivery purposes
pH and sugar dual-responsive reversibly cross-linked polymeric nanocarriers
pH and reductive dual-responsive reversibly cross-linked polymeric nanocarriers
pH and temperature dual-responsive reversibly cross-linked polymeric nanocarriers
Temperature and reductive dual-responsive reversibly cross-linked polymeric nanocarriers
Summary
References
12
Polymeric micelles as delivery systems
Introduction
Polymeric micelles
Classification of polymer micelles
Block polymer micelles
Graft copolymer micelles
Polyelectrolyte copolymer micelles
Noncovalently connected micelles
The preparation method of PM
Direct dissolution method
Dialysis method
Characteristics and advantages of PM system
PM for drug and gene delivery
pH-responsive PM delivery systems
Reduction-responsive PM delivery systems
ROS-responsive PM delivery systems
Dual-responsive PM delivery systems
PM for fluorescent dye delivery
Conclusion
Acknowledgments
References
13
Metallic nanoparticulate delivery systems
Introduction
Nanotechnology
Metallic nanoparticlates
Fabrication of metallic nanoparticulates
Thermal decomposition
Sonochemical synthesis
Microemulsion
Chemical reduction
Laser ablation
Polyol method
Microwave-assisted method
Green synthesis
Application of metallic nanoparticulates in drug delivery and theranostics
Gold nanoparticles
AuNPs in drug delivery
AuNPs in gene delivery
Silver nanoparticles
AgNPs in drug delivery
AuNPs in gene delivery
Magnetic nanoparticles
MNS in drug delivery
Metallic nanotoxicity
Conclusion
References
14
Gold nanoparticles in delivery applications
Introduction
Gold nanoparticles and drug delivery applications
Preparation of gold nanoparticles
Gold nanoparticle as a tool in cancer diagnostics and treatment
Theranostic application of gold nanoparticles
Gold nanoparticles in cancer immunotherapy
Attenuation of TLR9/IL-1 β and TGF- β 1 pathways
Application of optical properties of gold nanoparticles to stimulate immune response
Gene therapy
Gold nanoparticles as a tool in gene silencing for cancer therapy
Gold nanoparticles in type 1 diabetes
Gold nanoparticles in delivery of antimicrobials and their potential to improve drug resistance
Concluding remarks
References
Further reading
15
Silver nanoparticles for delivery purposes
Synthesis of silver nanoparticles
Applications of silver nanoparticles
AgNPs as delivery systems in cancer therapy
AgNPs as antiviral agents
AgNPs as antimicrobial agents
Concluding remarks and future outlook
References
Further reading
16
Iron oxide nanoparticles for delivery purposes
Introduction
Synthesis and surface modification of IONPs
Synthesis methods
Coprecipitation
Thermal decomposition
Microemulsion
Sol-gel
Miscellaneous methods
Surface modification
Molecular monolayers and polymeric coatings
Bioconjugation
Biocompatibility of IONPs
IONPs for delivery of therapeutic agents
IONPs in drug delivery
IONPs in gene delivery
Radiolabeled magnetic drug delivery systems
Conclusions
References
17
Molecular and nanoscale engineering of porous silica particles for drug delivery
Introduction
Engineering of porous silica materials
Nonporous silica nanoparticles
Mesoporous silica nanoparticles
Surface functionalization of silica nanomaterials
Core@shell nanocomposites
Drug loading and release
Drug loading methods
Sustained and controlled release mechanisms
Applications of porous silica nanoparticles in cellular drug delivery
Intracellular drug delivery
Delivery of biomolecules
Peptides and proteins
Nucleic acids
Gated MSNs and advanced carrier designs
Gated MSNs for controlled drug release
Advanced designs on surface-drug interactions
Bioadhesive molecules on pore walls for enhanced retention of hydrophilic drugs
Mesoporous nanoparticles with pore walls of polydopamine for drug loading and release
Dosage form design encompassing porous silica nanoparticles
MSNs in printed formulations
MSNs in orodispersible films
MSNs in lyophilized tablet formulation
Conclusions
References
18
Carbon family nanomaterials for drug delivery applications
Introduction
Carbon-based nanomaterials
Mesoporous carbon nanoparticles
Surface modification of MCNs
Drug delivery with MCNs: Immediate release systems
Drug delivery with MCNs: Sustained release systems
Controlled/targeted drug delivery systems
Fullerenes
Fullerene as drug delivery carrier
Carbon nanotubes
Single-walled carbon nanotubes
Multiwalled carbon nanotubes
Growth mechanism of carbon nanotubes
Properties of carbon nanotubes
Carbon nanotubes in drug delivery
Graphene family
Members of the graphene family
Graphene in drug delivery
Nanodiamonds
Properties of nanodiamonds
Nanodiamonds in drug delivery
Functionalization of CNMs
Drug-loading methods
Concluding remarks and future perspectives
References
Part Three: Delivery routes of nanoengineered biomaterials
19
Delivery routes of nanoengineered biomaterials
Potential nanocarriers for the delivery of drugs to the brain
Introduction
Drug delivery to brain: Various approaches
Receptor-mediated transport systems
Transferrin receptor
Insulin receptor
Low-density lipoprotein receptor
Diphtheria toxin receptor
Transporter-mediated transport systems
Amino acid transporters
Monocarboxylate transporters
Hexose transporters
Glutathione transporters
Choline transporter
Adsorptive-mediated transport systems
Nanocarriers used in the delivery of drugs to the brain
Polymeric nanoparticles
Solid lipid nanoparticles
Liposomes
Micelles
Dendrimers
Miscellaneous
Conclusion
References
20
Nanotechnology for oral drug delivery and targeting
Introduction
Oral route: Boon and obstacles
Systems targeted to the stomach/duodenum
Polymer-lipid hybrid systems
Mucoadhesive dendrimers
System targeted to the small intestine/lymphatics
Lipid-based drug delivery systems
Self-emulsifying drug delivery systems
Mechanism of self-emulsification
Nanoemulsions
Nanostructured lipid carriers
Solid lipid nanoparticles
Liposomes
Exosomes
Polymeric systems
Nanocapsules
Polymeric carriers
Systems targeted to the colon/large intestine
Current oral nanodrug delivery system–based approaches to inflamed colon
Active targeting–based strategies for oral nanodrug delivery
Miscellaneous nanocarriers for oral drug delivery
Nanocrystals
Carbon nanotubes
Metallic nanocarriers
Conclusion and future prospects
References
21
Nanotechnology for ocular and optic drug delivery and targeting
Introduction
Nanotechnology in drug delivery and targeting
Nanotechnology and ophthalmology
The eye with specific anatomy and physiology as a target organ for DDSs
Strategies and routes for ocular targeted drug delivery
Topical drug delivery
Periocular drug delivery
Intravitreal drug delivery
Systemic drug delivery
Nanosystems for ocular drug delivery and targeting
Polymeric nanoparticles
Chitosan-based NPs
PLGA-based NPs
Polymeric micelles
Dendrimers
Vesicular systems: Liposomes
Solid lipid nanoparticles
Conclusions and final remarks
References
22
Nanoparticulate systems for dental drug delivery
Introduction
Oral cavity complication
Dental caries
Nanotechnology for treatment and prevention of dental caries
Periodontal disease
Nanoparticles for periodontal treatment
Liposome
Nanofibers
Nanoparticles for diagnosis, prevention, and treatment of oral diseases
Liposomes
Prevention of demineralization
Facilitating remineralization
Immunization with liposomes
Physical protection by liposomes
Polymeric micelles
Polymeric nanoparticles
Carbon-based nanoparticles
Carbon nanotube
Graphene
Nanohydroxyapatite
Iron oxide
Zirconia
Silica
Silver (Ag) nanoparticles
Oral cancer: An overview
Etiopathogenesis of oral cancer
Presenting signs and symptoms
Treatment
Diagnosis
Nanobased ultrasensitive biomarker detection
Cancer treatment by nanoparticles
Liposomes in oral cancer treatment
Gold nanoparticles for anticarcinogenic drug delivery
Hydrogels
Liquid crystals
Cyclodextrin
PDT using nanoparticles
Polymeric nanoparticles
Conclusion
References
23
Nanotechnology for pulmonary and nasal drug delivery
Introduction
Fate of nanomedicines in the lungs
Lung anatomy and drug delivery methods
Respiratory diseases
Asthma
Pneumonia
Lung cancer
Systemic drug delivery through the pulmonary system
Diabetes
Gene therapy
Antibody
Nucleic acid
The role of nanotechnology in nasal drug delivery
Antibiotic
Diabetes
Brain-related diseases
Conclusion
References
24
Nanoemulsions for intravenous drug delivery
Introduction
Nanoemulsion formation
Stability of nanoemulsion
Nanoemulsion for intravenous drug delivery
Formulation for poorly soluble drugs
Improvement of pharmacokinetics
Targeting
Multifunctionality
Conclusion
References
Further reading
25
Nanoparticles for mucosal vaccine delivery
Introduction
Organization of the mucosal immune system
Routes of mucosal vaccination
Barriers to mucosal vaccine delivery
Nanotechnology-based solutions for mucosal vaccination
Physicochemical properties that influence the biological performance of nanoparticles
Nanoparticle-based delivery systems for mucosal vaccines
Lipid-based nanoparticles
Nanoparticles based on natural polymers
Nanoparticles based on synthetic polymers
Lipid-polymer hybrid nanoparticles
Virus-like particles and virosomes
Gas-filled microbubbles
Nanoparticulate pulmonary mucosal vaccination
Conclusions and future perspectives
Acknowledgments
References
26
Nanotechnology for vaginal drug delivery and targeting
Introduction
Vaginal drug delivery
Advantages offered by the vaginal route
Anatomy and physiology of the vagina
Vaginal secretions
Vaginal pH
Microflora
Enzyme activity
Menstrual cycle
Nanostructures for vaginal drug delivery
Nanoparticles
Factors influencing vaginal drug delivery
Particle size
Formulation components
Surface charge
Surface modification
Surface functionalization
Vaginal dosage forms for nanoparticles
Vaginal gels
Solid vaginal dosage forms
pH-sensitive nanoparticles
Liposomes
Nanoemulsions
Dendrimers
Cyclodextrins
Conclusions
Conflict of interest
References
27
Nanotechnology for intracellular delivery and targeting
An overview on drug delivery systems
Routes of administration
Oral route
Ocular route
Intranasal route
Intra-/transdermal route
Intramuscular route
Intravenous route
Intratumoral route
Intrathecal route
Clearance and toxicity
Challenges faced by clinical translation of drug delivery systems
Conclusions and future perspectives
References
Part Four: Applications of nanoengineered biomaterials in drug delivery
28
Nanoengineered biomaterials for infectious diseases
Introduction
Bacterial cell wall
Mechanism of nanopatterned self-cleaning biomaterials to prevent infectious disease
Antibacterial nanoparticles
Conclusion
References
29
Nanoengineered biomaterials for neurodegenerative disorders
Introduction
Nanobiomaterials
Alzheimer’s disease
Approved therapies and recent research in AD
Nanobiomaterials in AD
Nanobiomaterials targeting BBB penetration
Amyloid plaque reduction by nanobiomaterials
Nanobiomaterials targeting other AD symptoms
Parkinson’s disease
Approved therapies and recent research in PD
Nanobiomaterials in PD
Huntington’s disease
Approved therapies and recent research in HD
Nanobiomaterials in HD
Early diagnostic detection using nanobiomaterials
Challenges
Conclusion
Acknowledgments
References
30
Nanoengineered biomaterials for diabetes
Introduction
Transmucosal insulin delivery
Glucose monitoring by external body secretions
Glucose monitoring in sweat
Glucose monitoring in saliva
Glucose measurement in tears
Transmucosal delivery of insulin
Oral insulin delivery
Nasal insulin delivery
Pulmonary insulin delivery
Transdermal delivery of insulin
Nanoengineering for transdermal monitoring of glucose
Follicular monitoring
Smart tattoo monitoring
Carbon nanotubes for glucose monitoring
Nanoengineering for transdermal delivery of insulin
Insulin microneedle patch
Conclusion
References
31
Nanoengineered biomaterials for cardiovascular disease
Introduction
Approaches to improve the hemocompatibility
Nanostructured surfaces
Methods for fabrication of nanostructured surfaces
Anodization
Chemical etching
Electron beam physical vapor deposition
Nanoparticles
Conclusion
References
32
Nanotechnology-based biosensors in drug delivery
Introduction
Terminology of biosensors
Nanotechnology-based biosensor
Nanomaterial-based biosensors
Inorganic nanomaterials
Organic nanomaterials
Nanostructured biosensors based on biological moieties
Nanofabricated biosensors
Smart nanocarriers simulating biosensors
Nanostructured biosensors in drug delivery
Conclusion
References
Index
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Citation preview

Nanoengineered Biomaterials for Advanced Drug Delivery

Woodhead Publishing Series in Biomaterials

Nanoengineered Biomaterials for Advanced Drug Delivery

Edited by

Masoud Mozafari

Elsevier Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States © 2020 Elsevier Ltd. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/ permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-08-102985-5 For information on all Elsevier publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Matthew Deans Acquisitions Editor: Sabrina Webber Editorial Project Manager: Charlotte Rowley Production Project Manager: Surya Narayanan Jayachandran Cover Designer: Mark Rogers Typeset by SPi Global, India

Contributors

Basel A. Abdel-Wahab Department of Pharmacology, College of Medicine, Assiut University, Assiut, Egypt; Department of Pharmacology, College of Pharmacy, Najran University, Najran, Kingdom of Saudi Arabia Adewale Adewuyi Department of Chemical Sciences, Redeemer’s University, Ede, Osun, Nigeria Anne Adebukola Adeyanju  Department of Biological Sciences, McPherson University, Seriki-Sotayo, Ogun, Nigeria Oluyomi Stephen Adeyemi Medicinal Biochemistry, Nanomedicine and Toxicology Laboratory, Department of Biochemistry, Landmark University, Omu-Aran, Kwara, Nigeria Abbas Afkhami Department of Analytical Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran Javed Ahmad Department of Pharmaceutics, College of Pharmacy, Najran University, Najran, Kingdom of Saudi Arabia Mohammad Zaki Ahmad  Department of Pharmaceutics, College of Pharmacy, Najran University, Najran, Kingdom of Saudi Arabia Mazaher Ahmadi Department of Analytical Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran Sohail Akhter  Center for Molecular Biophysics (CBM), CNRS UPR4301; LE STUDIUM Loire Valley Institute for Advanced Studies, Orleans, France; Nanomedicine Research Lab, Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, New Delhi, India Rafieh Alizadeh ENT and Head & Neck Research Center and Department, The Five Senses Institute, Hazrat Rasoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran

xivContributors

José L. Arias Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy; Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM); Biosanitary Research Institute of Granada (ibs. GRANADA), Andalusian Health Service (SAS)—University of Granada, Granada, Spain Sajjad Ashraf  Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada Sara Aly Attia  Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, United States Oluwakemi Josephine Awakan  Medicinal Biochemistry, Nanomedicine and Toxicology Laboratory, Department of Biochemistry, Landmark University, OmuAran, Kwara, Nigeria Babak Bagheri  Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea Amir Hossein Bahmanpour Biomaterial Group, Faculty of Biomedical Engineering (Center of Excellence), Amirkabir University of Technology, Tehran, Iran Shuang Bai  School of Materials and Energy, Southwest University, Chongqing, People’s Republic of China Satheeswaran Balasubramanian Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore, India Liliana Bernardino  Health Sciences Research Centre (CICS-UBI), University of Beira Interior, Covilhã, Portugal D. Cristea Transilvania University of Brasov, Material Science Department, Brasov, Romania Mazen M. El-Hammadi Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Seville, Seville, Spain Mehdi Farokhi National Cell Bank of Iran, Pasteur Institute of Iran, Tehran, Iran Marziyeh Fathi  Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran Raquel Ferreira Health Sciences Research Centre (CICS-UBI), University of Beira Interior, Covilhã, Portugal

Contributorsxv

Nina Filipczak  Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, United States; Laboratory of Lipids and Liposomes, Department of Biotechnology, University of Wroclaw, Wroclaw, Poland Camilla Foged Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Mohammad Reza Ganjali  Center of Excellence in Electrochemistry, School of Chemistry, College of Science, University of Tehran; Biosensor Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran Yong-E Gao  School of Materials and Energy, Southwest University, Chongqing, People’s Republic of China Yuan Gao  School of Materials and Energy, Southwest University, Chongqing, People’s Republic of China Laxmikant Gautam  Drug Delivery and Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar, M.P., India Maryam Ghaffari Biomaterial Group, Faculty of Biomedical Engineering (Center of Excellence), Amirkabir University of Technology, Tehran, Iran Maryam Ghavami  Department of pharmacy, Faculty of pharmacy, Eastern Mediterranean University, Famagusta, Turkey I. Ghiuță Transilvania University of Brasov, Material Science Department, Brasov, Romania Arash Ghoorchian Department of Analytical Chemistry, Faculty of Chemistry, BuAli Sina University, Hamedan, Iran Jouni Hirvonen  Division of Pharmaceutical Chemistry and Technology, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland Yuan Hu State Key Laboratory of Fire Science, University of Science and Technology of China, Hefei, People’s Republic of China Anamika Jain Drug Delivery and Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar, M.P., India Fatemeh Kabirian  Bioengineering Research Group, Nanotechnology & Advanced Materials Department, Materials & Energy Research Center (MERC), Tehran, Iran

xviContributors

Mahdie Kamalabadi Department of Analytical Chemistry, Faculty of Chemistry, BuAli Sina University, Hamedan, Iran Yeu Chun Kim  Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea Maryam Koopaie  Department of Oral Medicine, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran Kit S. Lam Department of Biochemistry and Molecular Medicine, UC Davis NCIdesignated Comprehensive Cancer Center, University of California Davis, Sacramento, CA, United States Ling Li State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China Yuanpei Li Department of Biochemistry and Molecular Medicine, UC Davis NCIdesignated Comprehensive Cancer Center, University of California Davis, Sacramento, CA, United States Xiaoqian Ma  School of Materials and Energy, Southwest University, Chongqing, People’s Republic of China Tayyebeh Madrakian  Department of Analytical Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran Akhilesh Kumar Maurya Applied Science Division, Indian Institute of Information Technology, Allahabad, Uttar Pradesh, India Anamika Mishra  Applied Science Division, Indian Institute of Information Technology, Allahabad, Uttar Pradesh, India Nidhi Mishra Applied Science Division, Indian Institute of Information Technology, Allahabad, Uttar Pradesh, India Nishi Mody Drug Delivery and Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar, M.P., India Fatemeh Mottaghitalab  Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran Masoud Mozafari  Department of Tissue Engineering & Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada

Contributorsxvii

Hafezeh Nabipour State Key Laboratory of Fire Science, University of Science and Technology of China, Hefei, People’s Republic of China Parisa Norouzi Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran Yadollah Omidi  Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran David Adeiza Otohinoyi  All Saints University, College of Medicine, Belair, Saint Vincent and the Grenadines Chiagoziem Anariochi Otuechere  Department of Biochemistry, Redeemer’s University, Ede, Osun, Nigeria Yousef Pakzad  Bioengineering Research Group, Nanotechnology and Advanced Materials Department, Materials and Energy Research Center (MERC), Tehran; Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran Jiayi Pan Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, United States Satyanarayan Pattnaik Talla Padmavathi College of Pharmacy, Warangal, India Leena Peltonen  Division of Pharmaceutical Chemistry and Technology, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland Ekambaram Perumal  Molecular Toxicology Laboratory, Biotechnology, Bharathiar University, Coimbatore, India

Department

of

Azhwar Raghunath Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore, India Joshua D. Ramsey  School of Chemical Engineering, Oklahoma State University, Stillwater, OK, United States J. Venkateshwar Rao Talla Padmavathi College of Pharmacy, Warangal, India Ali Rastegari Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran Jessica M. Rosenholm Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland

xviiiContributors

Mohammad Reza Saeb  Department of Resin and Additives, Institute for Color Science and Technology, Tehran, Iran Rajeev Sharma  Drug Delivery and Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar, M.P., India Priya Shrivastava  Drug Delivery and Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar, M.P., India Satya Prakash Singh Faculty of Pharmacy, Integral University, Lucknow, India Mayank Singhal  Division of Pharmaceutical Chemistry and Technology, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland Anup Kumar Sirbaiya Faculty of Pharmacy, Integral University, Lucknow, India Y. Surendra Talla Padmavathi College of Pharmacy, Warangal, India Kalpana Swain Talla Padmavathi College of Pharmacy, Warangal, India Aneesh Thakur Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Vladimir P. Torchilin Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, United States Nila Mary Varghese Department of Pharmaceutics, JSS College of Pharmacy, Ooty; St. Johns College of Pharmaceutical Sciences and Research, Idukki, India Senthil Venkatachalam  Department of Pharmaceutics, JSS College of Pharmacy, Ooty, India Nikhar Vishwakarma  Drug Delivery and Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar, M.P., India Sonal Vyas Department of Pathology, Index Medical College, Hospital and Research Centre, Indore, M.P., India Suresh P. Vyas Drug Delivery and Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar, M.P., India Yajun Wang  School of Materials and Energy, Southwest University, Chongqing, People’s Republic of China

Contributorsxix

Musarrat Husain Warsi Department of Pharmaceutics, College of Pharmacy, Taif University, Taif, Kingdom of Saudi Arabia Xia-Wei Wei  State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China Hao Wu  Department of Biochemistry and Molecular Medicine, UC Davis NCIdesignated Comprehensive Cancer Center, University of California Davis, Sacramento, CA, United States Zhigang Xu  School of Materials and Energy, Southwest University, Chongqing, People’s Republic of China Mohsen Khodadadi Yazdi School of Chemical Engineering, College of Engineering, University of Tehran, Tehran, Iran Ali Zamanian  Bioengineering Research Group, Nanotechnology and Advanced Materials Department, Materials and Energy Research Center (MERC), Tehran, Iran Payam Zarrintaj Polymer Engineering Department, Faculty of Engineering, Urmia University, Urmia, Iran; School of Chemical Engineering, Oklahoma State University, Stillwater, OK, United States Jixi Zhang Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China Lu Zhang  Department of Biochemistry and Molecular Medicine, UC Davis NCIdesignated Comprehensive Cancer Center, University of California Davis, Sacramento, CA, United States Tian Zhang  School of Materials and Energy, Southwest University, Chongqing, People’s Republic of China

Preface

The field of biomaterials science and engineering has been significantly evolved after finding an integrated dialogue between biomaterials and nanotechnology. The market for this class of biomaterials is growing fast, and it is anticipated to reach around $350 billion USD by 2025. The role of biomaterials is going to be highlighted more than ever especially for the development of innovative drugs and vaccines. For instance the drug developer Moderna recently spiked almost 30% in a few trading hours in the US stock market, beating out the competition by going through the first coronavirus vaccine testing on human body. This newly developed company offers a wide range of innovative delivery systems. It is interesting that the biomaterial’s pioneer “Robert Langer” is among the coinvestors as one of the largest individual shareholders in the company. The development of such advanced nanotechnology-based drug delivery systems recommended fewer side effects and higher efficacy for many diseases, suggesting the high potential of this field for future advancements in pharmaceutics. The benefits of nanoengineered biomaterials are not only limited to the drug delivery systems but also beneficial as contrast reagents for diagnosis and monitoring of the effects of drugs on unprecedented short timescales. I believe that there are many opportunities when working on nanoengineered biomaterials for advanced drug delivery applications. It is now the time to reinforce the interdisciplinary collaborations to find solutions for global problems. The extensive set of chapters in this book represents the recent developments in the field of nanoengineered biomaterials for advanced drug delivery. The book starts with the fundamentals and principles of n­ anotechnology-based drug delivery. Then, it explains the developments of different classes of nanoengineered biomaterials for drug delivery, ranging from polymeric to metallic and even ceramic-based systems. In the third part, it highlights the specific characteristics of different delivery routes of nanoengineered biomaterials. In the last part of the book, it deals with the emerging applications of nanoengineered biomaterials in advanced drug delivery. Although many developments and improvements happened so far, knowledge gaps regarding the new eras of research and their implications must be continuously addressed and actively researched. The dynamic, practical, and socially responsible research will promote the critical role of biomaterials in public health in the 21st century. Masoud Mozafari  University of Toronto, Toronto, ON, Canada

Acknowledgment

I am grateful to all of those with whom I have had the pleasure to work, specially the contributing authors for their professional cooperation during the various stages of this project. I would like to thank the editorial team at Elsevier involved in this project, Simon Holt, Leticia M. Lima, Sheela Bernardine B. Josy, Charlotte Rowley, and Surya Narayanan Jayachandran for the continuous support. I am also grateful to our graphic designer Catherin Aldana Ortiz for brilliant opinions during the idea development and design of the cover image artwork. I would like to extend my appreciation to our editorial assistant, Tara Tariverdian, for leading a team who did most of the work and deserve the props. Of course, this would not be possible without their effort and support.

Principles of nanosized drug delivery systems

1

Leena Peltonen, Mayank Singhal, Jouni Hirvonen Division of Pharmaceutical Chemistry and Technology, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland

1.1 Introduction For pharmaceutical and medical purposes, different nanosized drug delivery systems for various administration routes have been developed (Fig. 1.1) [1]. Since the 1970s polymeric drug nanoparticles have been widely studied [2]. Later, nanosized systems like solid lipid nanoparticles [3], nanoemulsions [4], liposomes [5], niosomes [6], nanocrystals [7], viral and nonviral vectors [8], and dendrimers [9] have been under intensive research. These nanosized drug delivery systems have been developed to improve physicochemical properties of the drug, mostly solubility and dissolution rate, which often mean improved pharmacokinetic/pharmacodynamic profiles and higher efficacy of the drug in vivo [10]. Functionalization or adding of targeting moieties to the nanodrugs can further improve the bioavailability and safety [11]. In 2017, when comparing the total market share of nanodrugs in US dollars, polymeric nanoparticles and drug nanocrystals covered, with equal share, a little bit less than 80% of all the market [12]. Year after year the number of submissions of nanomaterial containing drug products to the US FDA has shown increasing trends [13–15]. But still, more than half of these submissions are based on either liposomes or nanocrystals, and it seems that the relative amount of these two dosage forms among nanoformulations is even increasing: When analyzing the number of submissions from year 1973 to 2009, 33% of the applications was liposome based and 20% nanocrystal based, while the corresponding numbers in 2010–15 were 35% and 29%, respectively. The liposomal cancer therapeutics were the largest single class among these applications. And, for drug nanocrystals, over 60% of the submission was for oral administration [14]. From all the nanomaterials containing applications, 65% was investigational new drugs, 18% abbreviated new drug applications, and 17% new drug applications. Typical particle size, in 80% of the applications, was below 300 nm. When comparing the number of publications during the years, the aforementioned numbers are at a quite low level. The very limited passage of nanosized drug delivery systems and other nanomedical applications from laboratory to commercialized products, despite the intensive research input in that area, is partly due to the complexity of the products. This is also seen in the considerably high relative amount of ­nanocrystal-based formulations among the nanomaterials containing drug products for US FDA: they are considerably simple in structure and easy to produce in a repeatable way, even the scale-up/scale-down changes are quite easy to perform [7, 14, 16]. Nanoengineered Biomaterials for Advanced Drug Delivery. https://doi.org/10.1016/B978-0-08-102985-5.00001-2 © 2020 Elsevier Ltd. All rights reserved.

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Fig. 1.1  Examples of some common nanocarrier structures. Reproduced from S. Hossen, M.K. Hossain, M.K. Basher, M.N.H. Mia, M.T. Rahman, M.J. Uddin, Smart nanocarrier-based drug delivery systems for cancer therapy and toxicity studies: a review, J. Adv. Res. 15 (2019) 1–18, with permission from Elsevier.

Challenges considering technical and regulatory aspects are demanding in chemistry, manufacturing, and controls (CMC) of the nanosized systems. Quality by design (QbD) approach utilizing risk-based analysis to help identify the critical quality attributes (CQAs) of the final product and the critical process parameters (CPPs) for reaching the CQAs are required for developing the quality inside these products and for reaching profound process, product, and platform understanding [17, 18]. In this chapter, first, the determinations of nanosized drug delivery systems and their most important properties/characteristics are presented. Then, different types of nanosystems/nanovehicles are discussed, followed by cell and barrier interactions and particle properties important to these interactions. Finally, utilization of nanosized materials in medical applications, including diagnostic and theranostic applications, is shortly described.

1.2 What are nanosized drug delivery systems and why they are useful? Nanosciences do study materials at atomic, molecular, and macromolecular level; in this size fraction the physical material properties are significantly altered from material properties at a larger scale. Nanotechnologies control the size and shape at nanometer scale for different applications. Drug authority determinates nanoscale product to be a system having at least one dimension in the size range of approximately 1–100 nm [19, 20]. Further, US FDA determines materials to be nanomaterial containing, if a material or end product has size-related properties or phenomena (physical, chemical, or biological) up to 1 μm (1000 nm) [19].

Principles of nanosized drug delivery systems5

The International Organization for Standardization (ISO) determines nanomaterials being materials where any external dimensions or internal or surface structures are in nanoscale [21]. Drug nanosystems can have many benefits. They can be used, for example, to improve the solubility profiles, for controlled and targeted drug delivery purposes; to provide maximum pharmacological effect with minimum systemic side effects; to decrease the frequency of administration, for increased metabolic/enzymatic stability; or to protect and stabilize the drug material toward uncontrolled degradation during the storage and in vivo. It has also been shown that nanoparticles as such can be taken up by the cells [22]. Depending on the material and the design of nanosystems, the safety and toxicity issues related to the nanosize can vary considerably, but with all the nanosystems, the potential exposure and toxicity of the nanosystems need to be considered carefully (Fig. 1.2) [23, 24]. With nanosized materials, not only the material toxicity matters, but also the small size nanotoxicity requires consideration [25, 26]. Nanomaterials can induce oxidative stress, inflammation reactions, cytotoxicity, and genotoxicity in vivo [25]. Especially, safety of nondegradable and slowly biodegradable nanosystems should be analyzed with extra care [23, 24]. Here, it is important to remember that the molecular weight of the polymer affects the degradation rate, higher-molecular weight fraction of the polymer degrading slower and also releasing the drug slower, which can affect the toxicological profiles of these systems [27]. On the other hand, with nanosystems, it is possible to reach better therapeutic activity and clinical outcomes and reduced toxicity profiles of the in vivo soluble nanosystems, like drug nanocrystals, which are often related to the increased bioavailability: the therapeutic dose needs to be determined separately for these nanosystems.

Fig. 1.2  Suggested nanotoxicological classification system (NCS), which is based on biodegradability and size of the nanoparticles. Reproduced from R.H. Müller, S. Gohla, C.M. Keck, State of the art of nanocrystals— special features, production, nanotoxicology aspects and intracellular delivery, Eur. J. Pharm. Biopharm. 78 (2011) 1–9, with permission from Elsevier.

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Nanoengineered Biomaterials for Advanced Drug Delivery

1.3 Different types of nanodelivery systems A lot of different types of nanodrug systems exist. In some cases the system consists of a pure drug substance covered only with some excipients (drug nanocrystals), but in most applications the drug is encapsulated inside of some kind of carrier, for example, polymeric nanoparticles, liposomes, micelles, or porous particles like porous silica/ silicon (Fig.  1.3). Next, different types of drug nanodelivery systems are presented shortly in more detail.

1.3.1 Polymeric nanoparticles Polymeric nanoparticles are solid and spherical (in most cases) structures prepared from natural or synthetic polymers. Drug delivery is known to be one of the most important biomedical applications of polymeric nanomaterials. Polymeric nanoparticles have been tested to deliver wide range of drugs, such as small hydrophilic and hydrophobic drugs, vaccines, peptides, and biological macromolecules, via several routes of administration [28]. Different grades of poly(lactide-co-glycolide) and

Macroscale

Tennis ball 100,000,000 nm

Microscale

Head of a pin 10,00,000 nm

Bee 10,00,000 nm

10–1 Decimeter

Red blood cell 10,000 nm

10–3

10–4

Millimeter

Virus 100 nm

10–5

10–6

5 Silicon atoms 1 nm

DNA diameter 2.5 nm

Bacteria 1000 nm

Human hair diameter 150,000 nm

10–2

Nanoscale

10–7

Micrometer

10–8

Hydrogen atom 0.1 nm

10–9

10–10

Nanometer

Centimeter

Liposomes 80–300 nm

Silica; magnetic nanoparticles 10–300 nm

Solid lipid nanoparticles; nanoemulsions 80–300 nm

Carbon Polymeric Dendrimers nanoparticles nanoparticles 1–10 nm 1–5 nm diameter 10–100 nm

Nanoparticles as a drug delivery systems

Fig. 1.3  Selected examples of nanosized drug delivery systems and their relative sizes as compared with some other structures. Reproduced from A.Z. Wilczewska, K. Niemirowicz, K.H. Markiewicz, H. Car, Nanoparticles as drug delivery systems, Pharmacol. Rep. 54(5) (2012) 1020–1037, with permission from Elsevier.

Principles of nanosized drug delivery systems7

poly(­lactide) copolymers are the most successfully used biodegradable polymers to prepare polymeric nanoparticles [29]. Most important advantages offered by the polymeric nanoparticles include the following: (1) provide controlled release to the desired site, (2) provide stability to labile molecules (e.g., proteins), and (3) provide ability to modify surfaces with ligands for stealth and targeted drug delivery purposes [30].

1.3.2 Liposomes Liposomes are among the most studied nanodelivery systems for applications in the pharmaceutical and cosmetic industry for diverse molecules. They are spherical vesicles composed of phospholipid bilayers, especially phosphatidylcholines, surrounding an aqueous core, and they are usually in the 50–450 nm size range [31]. Cholesterol is added to the lipid bilayer of liposomes to reduce their permeability and increase in vivo and in vitro stability of the bilayer systems. This kind of structure enables the delivery of both the hydrophilic (dissolved in aqueous core) and hydrophobic drugs (entrapped in the lipid bilayer) (Fig. 1.4). Given that their membrane, enclosing actives, is analogous to the cell membranes in vivo, they are considered good drug delivery vehicles due to their biocompatible and biodegradable nature [31].

Fig. 1.4  Schematic description of formation and fate in vivo of liposome-based anticancer drug delivery system. Reproduced from S. Hossen, M.K. Hossain, M.K. Basher, M.N.H. Mia, M.T. Rahman, M.J. Uddin, Smart nanocarrier-based drug delivery systems for cancer therapy and toxicity studies: a review, J. Adv. Res. 15 (2019) 1–18, with permission from Elsevier.

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Nanoengineered Biomaterials for Advanced Drug Delivery

1.3.3 Niosomes Similar to liposomes, niosomes are also spherical vesicles having a bilayer structure, but they are formed by self-association of nonionic surfactants and cholesterol in an aqueous phase instead of lipids. Niosomes are known to be biocompatible, biodegradable, and nonimmunogenic. They also exhibit better stability and have long shelf life in vivo, which enables the efficient delivery of drugs to the target site [32]. Several types of nonionic surfactants have been explored to form stable niosomes to entrap a large number of drugs [33–35]. Critical parameters, such as drug loading, niosome size, number of lamellae, and surface charge, can be optimized to make them interesting drug delivery systems.

1.3.4 Solid lipid nanoparticles Solid lipid nanoparticles (SLNs) comprise about 0.1%–30% (w/w) of solid fat, which is suspended in an aqueous phase. The lipid components are solid at both body and ambient temperatures. The free energy of the hydrophobic surfaces is reduced by adding surfactants (0.5%–5% (w/w)) or by functionalizing the surfaces using some hydrophilic elements [36]. Selection of lipids and surfactants can be used to control the particle size, shelf life, drug loading, and release behavior [36]. Commonly used lipids used to prepare SLNs include fatty acids, steroids, waxes, monoglycerides, diglycerides, and triglycerides.

1.3.5 Micro- and nanoemulsions Microemulsion- or nanoemulsion-based colloidal delivery systems have been studied largely in the last decade for applications in the food and pharmaceutical industries to encapsulate, protect, and deliver lipophilic bioactive components due to the simplicity of the manufacturing process, good stability, and easy industrial scaling up [37]. Such colloidal systems tremendously increase drug solubility and bioavailability due to the presence of oil and surfactant in the composition. Microemulsions are known to be thermodynamically stable but kinetically unstable systems, while nanoemulsions are thermodynamically unstable but kinetically stable systems [38].

1.3.6 Polymeric micelles Nanostructured polymeric micelles are made of amphiphilic block copolymers that self-assemble to form a core-shell structure (single layer) in the aqueous solution. The copolymers undergo micelle formation after reaching the critical concentration. In an aqueous environment, hydrophobic chains form the core, and hydrophilic moieties form the shell, which make the whole system to be solubilized in water. Such a delivery system is primarily suited for hydrophobic drugs [39]. During formulation development, hydrophobic drug partitions in the hydrophobic core of the micelles. Stability of micelles depends very much on the drug-to-copolymer ratio. Polymeric micelles are in size below 100 nm, and they have a narrow size distribution. Due to the hydrophilic polymeric shell, the nonspecific interactions with biological components are restrained [40].

Principles of nanosized drug delivery systems9

1.3.7 Dendrimers Dendrimers are polymeric macromolecules. They have a well-defined structure with a core at the center (composed of an atom or a molecule) and several repeated branches symmetrically emerging from the core, generally adopting a spherical three-dimensional globular structure [41, 42]. The properties of dendrimers are dominated by the functional groups on the molecular surface. The most studied dendrimers for biomedical applications are polyamidoamine (PAMAM) and poly(propyleneimine) (PPI). Dendrimers are limited in their clinical applications, because of the presence of amine groups. These groups are positively charged or cationic, which makes them toxic; hence, dendrimers are usually modified to reduce the toxicity issues or to totally eliminate them. Drug loading into dendrimers can be performed via one of the following mechanisms: simple encapsulation, electrostatic interaction, or covalent conjugation [43].

1.3.8 Inorganic nanoparticles and quantum dots Inorganic nanoparticles consist of materials like silver, gold, iron oxide, silicon, and silica. Silver and gold nanoparticles have particular applications in surface plasmon resonance (SPR) analysis, which other nanocarriers, such as liposomes, dendrimers, and micelles, do not possess. After surface functionalization, these materials show good biocompatibility and versatility. Surface of gold nanoparticles can be conjugated with drugs via physical absorption and ionic or covalent bonding, where the delivery and release to the target site can be controlled by biological or external stimuli [44]. Silver nanoparticles exhibit antimicrobial activity, but very few studies have been carried out for drug delivery [45]. Porous silicon and silica nanoparticles are getting increasing attention from the scientific biomedical community. Nanostructured porous silicon has successfully been demonstrated to have potential applications in drug delivery, diagnostics, and therapy. Good in vivo biocompatibility and biodegradability have led many researchers to study applications of these materials for oral, transdermal, and parenteral delivery of therapeutic agents [46]. Quantum dots are very small (a few nanometers in size) metallic particles. They consist of semiconductor atoms, like CdS, CdSe, CdTe, ZnS, ZnSe, ZnO, GaAs, InAs, or InP. Their photostability can be increased by combining two semiconductor materials: one in the core and the other having larger spectral bandgap as a covering layer. Quantum dots have specific optical properties, and due to that, they can be utilized in biomedical imaging and diagnostics [47].

1.3.9 Nanocrystals Nanocrystallization is an important tool in improving the solubility and dissolution of poorly soluble active pharmaceutical ingredients, which is a great challenge for the pharmaceutical industry [7]. Nanocrystals are pure solid drug particles having sizes below 1 μm. Nanocrystals can be produced by (1) top-down, (2) bottom-up, or (3) combination of top-down and bottom-up approaches. Top-down approach represents breaking large drug particles into smaller sizes, and bottom-up approach means

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Nanoengineered Biomaterials for Advanced Drug Delivery

p­ recipitation of drug from supersaturated solution. Depending on the technique employed, the process parameters should be critically controlled to obtain physically stable formulations capable of conserving particle size during the shelf life of the product [48]. To prevent aggregation and crystal growth, the nanocrystals are usually stabilized by covering the solid drug particles with polymeric steric stabilizers or surfactants. After oral administration, nanocrystals support drug absorption by enhancing solubility, fast dissolution, and ability to adhere firmly in the intestinal wall [49].

1.3.10 Protein-based and natural biopolymer-based nanoparticles Natural biopolymers include proteins and polysaccharides extracted from biological sources, such as plants, animals, and microorganisms. Protein-based nanoparticles, like bovine and human serum albumin, are generally decomposable and metabolizable, and they are easily functionalized by attaching specific drugs and other targeting ligands [50]. Functionalization of protein-based nanoparticles with a ligand enables identification of exact cells and tissues to promote and augment their targeting mechanism(s) [51]. Chitosan is a polysaccharide that exhibits mucoadhesive properties, and it can be used to act in the tight epithelial junctions. Therefore chitosan nanomaterials are extensively studied for controlled drug delivery across epithelia, including buccal [52], intestinal [53], nasal [54], ocular [55], and pulmonary [56] drug delivery routes.

1.4 Particle properties and related biobarrier interactions of nanosystems When summarizing the research performed between the years 2005 and 2015, with regard to different types of nanosystems and different solid tumor models, the overall finding was with all the types of nanocarriers that only approximately 1% of the injected dose did reach the desired site of action [57]. This emphasizes the importance of understanding the properties of biological membranes and their impact on the permeation and interactions with nanocarriers. The interactions between the biological barriers and nanosystems are dependent on the physicochemical properties of the nanocarriers. To reach maximum bioavailability, understanding properly the in vivo fate of the nanosized drug delivery systems and thorough physicochemical analysis of the nanomaterials are required. The physicochemical characteristics of sustained drug release nanocarrier systems, like size, shape, surface charge, hydrophobicity/hydrophilicity, porosity, morphology, and elasticity, affect their bioproperties [58].

1.4.1 Opsonization and phagocytosis For intravenous administration the biological barriers for permeation include mononuclear phagocyte system (MPS), hemodynamics and site-specific extravasation, and cellular level cell membrane trafficking and endosomal compartmentalization (Fig. 1.5) [11].

Intracellular barriers

Nanocarriers Endocytosis

Mononuclear phagocyte system Liver

Endosomal entrapment

Site-specific extravasation

Size

Spleen

Porosity

Shape Nanocarrier efficacy

Kupffer cells

Splenic macrophages

Elasticity

Surface chemistry

Tissue

Physiological hemodynamics

Cell free layer

Fig. 1.5  Biological barriers for permeation after intravenous administration. Reproduced from Z. Zhao, A. Ukidve, V. Krishnan, S. Mitragotri,Effect of physicochemical and surface properties on in vivo fate of drug nanocarrriers, Adv. Drug Deliv. Rev. (2019), doi:10.1016/j.addr.2019.01.002, with permission from Elsevier.

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After intravenous administration of nanosystems, opsonization may take place in blood circulation, for example, plasma proteins start to absorb onto particle surfaces forming a corona. This protein corona determines the particle fate in  vivo. Opsonization is dependent on the size, shape, zeta potential, level of hydrophobicity and hydrophilicity, and surface-functionalizing groups (targeting ligands) of the particles. For example, large surface-to-volume ratio with small particles means higher protein binding. In phagocytosis, protein corona binds to the receptors on phagocytes, followed by particle internalization. Opsonization can also mask the active targeting ligands and hence hinder their action [59]. Further, hydrophobic particle surfaces are opsonized, but hydrophilic polymers, like poly(ethylene glycols) (PEGs), create a polymeric chain layer on particle surfaces, which make the particles stealth against plasma proteins. It should be noticed that MPS can also in some cases be used as an aimed target: in inflammation and diseases like cancer or atherosclerosis, for example, macrophage targeting can be the aim [60].

1.4.2 Particle size With particle systems, particle size is inversely proportional to particle surface area, which can interact with the bio membranes. Also, enhanced permeation and retention (EPR) mechanism (Fig. 1.6), which is often responsible for accumulating the nanoparticles to the tumor area, depending on particle- and tumor-type properties, is generally most efficient for particle sizes from 10 to 200 nm [61, 62]. An example of the particle

Fig. 1.6  EPR effects: normal cells (up) and tumor cells (down). Nanoparticles can penetrate tumor cells via leaky endothelial cells in blood vessel walls. Reproduced from X. Yu, I. Trase, M. Ren, K. Duval, X. Guo, Z. Chen, Design of nanoparticlebased carriers for targeted drug delivery, J. Nanomater. 2016 (2016) 1087250, under the Creative Commons Attribution License.

Principles of nanosized drug delivery systems13

size effect is drug-loaded polymeric micelles with different micelle sizes [63]. When tumors with high permeability were studied, different-sized polymeric micelles (30, 50, 70, and 100 nm) accumulated similarly into the tumors having also similar antitumor efficiencies. But, when poorly permeable tumors were studied, only the smallest micelles (30 nm) penetrated the tumors and exerted an antitumor efficiency. Passive targeting via the EPR effect is based on the fact that, contrary to normal blood vessels, in tumors, the blood vessels are more complex, unorganized, and leaky, meaning for different blood flow properties. But, due to the tumor heterogeneity, the leakiness of vasculature in the tumor can differentiate throughout the tumor structure [64]. In tumors the well-organized lymphatic network is missing, and together with unregulated cancer cell proliferation, widespread fibrosis and dense extracellular matrix may prevail, which means that the interstitial fluid pressure is higher. Though EPR increases the passive accumulation of nanocarriers to the tumor site, the increased interstitial fluid pressure can delay or lower the therapeutic effect of these drugs. Nanosized particles are mainly taken up by the cells via pinocytosis (micropinocytosis or macropinocytosis) or phagocytosis (Fig. 1.7) [65, 66]. Further, Swanson and Watts [67] showed that particles larger than 200 nm were entering the cells via phagocytosis or micropinocytosis, while particles smaller than 200 nm were internalized via micropinocytosis (either clathrin-mediated, caveola-mediated or lipid raft-mediated, or clathrin- or caveola-independent mechanisms) [27].

Phagocytosis and endocytosis as f(size) Large microparticles

Cell

Macrophage Submicron particles 100 nm < d < 1000 nm Nanoparticles d < 100 nm

Fig. 1.7  Particle interactions with cells, when the particle size is changed. Reproduced from R.H. Müller, S. Gohla, C.M. Keck, State of the art of nanocrystals— special features, production, nanotoxicology aspects and intracellular delivery, Eur. J. Pharm. Biopharm. 78 (2011) 1–9, with permission from Elsevier.

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The effect of particle size on tissue distribution was shown with two differently sized oridonin nanosuspensions [68]. With 100-nm nanocrystals, tissue distribution after intravenous administration was similar to drug solution (particles dissolved very fast), while 900-nm drug particles were taken up by the reticuloendothelial system (RES) organs showing totally different biodistribution. In the bloodstream, flow dynamics should be taken into account with small particle systems. Size and shape of nanocarriers affect the flow dynamics in blood vessels and also, for example, the particle adhesion properties in the endothelial walls.

1.4.3 Shape In nanocarriers, besides size, particle shape is an important physicochemical property affecting in vivo fate of the systems. Shape impacts not only blood flow and hence binding to vessel walls but also other bio processes like cell uptake and biodistribution of nanosystems. When the aim of the drug delivery is vascular endothelium, nonspherical shapes, like discoidal and rod shapes, have been noticed to be more efficient as compared with spherical particles [69]. Adhesion of elongated nonspherical particles is better due to the typically higher surface area for adhesion, and they show reduced drag and are more resistant for tumbling and rolling in blood flow due to the flow pressure in the vessels. The hydrodynamic force is increased with increasing particle size, and also, ligand density on the surface of the nanocarriers and the receptors on the cell surfaces affects the adhesion. The interaction area for adhesion between the particle and cell interface increases with particle size meaning stronger binding. When the adhesive strengths were compared with the same adhesive force, nonspherical particles have better therapeutic and imaging efficiency: nonspherical particles were able to carry higher amounts of drugs and contrast agents as compared with spherical particles [70]. Also in macrophage cell-uptake studies, particle shape, more specifically the particle shape at the point of cell contact, not the overall particle shape, was shown to play the most important role [71]. Local particle shape determines the complexity of actin structure, which is required to initiate phagocytosis, and hence determines in  vivo whether the phagocytosis or interactions with cell membranes are taken place. Besides shape, also aspect ratio is important for organ distribution. When rod-shaped mesoporous silica nanoparticles were studied, longer particles (aspect ratio 5) accumulated to spleen, while shorter particles (aspect ratio 1.5) accumulated mostly in the liver [72]. Accordingly, shape is related to blood circulation time of drug nanocarriers not only via the effect on phagocytosis but also via impacting the hydrodynamics. In cell uptake, particle shape can affect the uptake kinetics and mechanisms, level of uptake, and intracellular particle distribution, which are related to cytotoxicity. For example, nonspherical particle shape has been noticed to increase the therapeutic efficacy of anticancer agents [73]. During endocytosis, nanocarrier shape (spherical vs rod) altered membrane bending energies, which affected cell internalization [74]. Differences in cell uptake of star-, rod-, and triangle-shaped gold nanoparticles were also noticed in a study by Xie et al. [75], when RAW264.7

Principles of nanosized drug delivery systems15

cells i­nternalized triangle-shaped nanoparticles most efficiently and star shaped the worst. The ­uptake ­mechanisms were also shape related: clathrin-mediated mechanisms for triangle-shaped particles and caveola- and clathrin-mediated mechanisms for rod-shaped particles. Clathrin-mediated endocytosis can be followed by particle exocytosis [76], but in the caveola-mediated cell uptake, there are different exocytosis routes, which were speculated to be the cause for the lower cell uptake of rod-shaped nanoparticles. Nanoparticle shape has also been shown to affect drug bioavailability in pulmonary drug delivery and in brain endothelium [77]. In pulmonary drug delivery, one benefit of nanocarrier systems is that they can avoid mucociliary and macrophage clearance and hence have longer residence times in the site of action before degradation or translocation by epithelial cells is taken place.

1.4.4 Surface charge Surface charge is important for the in vivo fate of nanosystems, and it is important to notice that both the net absolute charge and charge density count. When taking into account opsonization, higher surface charge density means more adsorption of proteins and faster clearance from bloodstream, but neutral charged particles have longer blood circulation times [78, 79]. Cationic nanosystems tend to have shorter residence time in blood circulation and accumulate faster to liver and spleen than anionic nanosystems. Neutral and negatively charged nanocarriers remain in blood circulation longer, which can result in higher accumulation to tumors. But, when the negative charge density is increased, again higher accumulation to liver from the blood circulations has been noticed [79]. Positive surface charge promotes interactions between particles and cells, and it can increase particle internalization. Impact of surface charge on antitumor efficacy of docetaxel-loaded PEGylated polymeric nanoparticles with different surface charges was studied with different cancer cell lines [80]. Particle size was 100 nm, and surface charge was tailored by lipids. Positively charged nanocarrriers were the most effective in inhibiting tumor growth in all the tumor models studied. The higher efficiency was due to the 2.5-fold higher cellular uptake and better tumor penetration of the cationic nanosystems; there was, however, shorter circulation time of cationic nanoparticles in blood circulation. When the importance of surface charge on tumor targeting and accumulation was realized, even switchable surface charge nanocarriers have been developed to improve the therapeutic effect [81]. Here, it is important to understand that the effect of charge is not simple; in different stages during drug delivery, different charges can be beneficial, and the final bioavailability is often a compromise of charge and other particle properties. In tumor targeting, acidic microenvironmental pH associated to cancer metabolism needs also be taken into account. This reduces the permeation of weakly basic drugs like doxorubicin: in the acidic environment, they are in a charged form, which hinders permeation. When doxorubicin was administered with sodium ­bicarbonate-loaded liposomes, having a size of 100 nm, the uptake and anticancer activity were improved due to the changes in the tumor microenvironmental pH: the measured intratumor

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pH value after the administration was approximately 7.4 [82]. When the uptake ­mechanism of negatively charged nanoparticles was studied in 4T1 cancer cell line, ­anionic 10-hydroxycamptothecin nanoparticles (130 nm particle size) were internalized mainly by clathrin-dependent endocytosis [83].

1.4.5 Hydrophilic/hydrophobic character Surface hydrophilic/hydrophobic character affects, besides opsonization, also the pharmacokinetics and biodistribution of nanosized drug delivery systems. As already mentioned, surface hydrophobicity increases the absorption of plasma proteins. This is followed by fast particle clearance from blood circulation and their capture by the RES. Surface properties can be changed by attaching not only hydrophilic polymers, mostly PEGs, but also some others like poloxamers to particle surfaces, and with this the RES clearance has been successfully reduced [84, 85]. The most effective PEGs in masking the nanosystem surfaces and reaching longer retention times in the blood circulation are relatively long-chained PEGs having high chain densities [86]. Also, biological membranes or peptide derivatives can be attached to particle surfaces to mask the particles and for reaching added functionality or efficient targeting [87, 88].

1.4.6 Other factors Most of the cells in  vivo are flexible and deformable, and they have mechanoreceptors on their surfaces. These receptors help them to react toward the rigidity of different materials. In the same way, it has been thought that the elasticity of the nanocarriers is an important factor for the in vivo fate of nanosystems. So far the elasticity factor has not been studied very widely, but some studies can be found, where, for example, it has been shown that elasticity is affecting particle endocytosis; the higher accumulation of softer nanoparticles in tumor tissues was shown in studies with silica nanocapsules and lipid-coated PLGA particles [89, 90]. Higher therapeutic efficiency of the softer nanoparticles was probably due to their capability to deform and also their better resistance against the blood flow, which accumulated them more to the leaky vasculatures in tumors. Also, porosity has been suggested to be an important factor, but there are a very low number of studies related to the porosity. It is also often difficult to separate the different properties, and often the final fate in vivo of the drug nanocarriers is the combination of more than one physicochemical factor. However, to produce efficient drug nanocarriers, careful determination of critical quality attributes (CQAs), which are based on in-depth understanding of empirically determined in vivo relations, is crucial. For example, different cells may have different uptake mechanisms, and it is important to understand that the uptake processes are complicated, and more than one factor is affecting the final result. Accordingly, more systematic research is needed in this area. It is also vital to understand the potential toxic effects in vivo, in relation to the aforementioned physicochemical properties of these nanosystems. All this can have negative consequences on the translation

Principles of nanosized drug delivery systems17

of nanocarrier systems from laboratory to human use, when taking into account ­manufacturing, costs, toxicity, and therapeutic efficacy. In the following chapter, successful nanotherapeutics are discussed more in detail.

1.5 Nanoparticles in medicines Nanoparticles and other nanometer-sized therapeutics, nanomedicines, denote the medical applications of nanotechnology, which are typically called also as nanoparticles, nanosystems, nanocarriers, nanotherapeutics, etc. [91, 92]. Nanomedicines cover a wide range of medical applications of nanomaterials and biological devices, including nanoelectronic biosensors, and even more futuristic approaches toward molecular nanotechnology, including biological machines and robotic systems [93, 94]. Current major problems for nanomedicines are oftentimes focused on unresolved issues related to potential toxicity and environmental impact questions of the nanoscale materials [95, 96]. Medical and pharmaceutical application areas of these nanosystems cover widely, and in some cases concomitantly, the therapeutics, diagnostics, and imaging (which are together called as theranostics) purposes of the nanomedicines [97]. As stated previously in this introductory chapter, the currently developed and commercialized nanomedicines have evolved into various dosage forms, for example, nanocrystals, nanoemulsions, liposomes, solid lipid nanoparticles, micelles, and polymeric and inorganic/metallic nanoparticles. The highlighted benefits of these nanomedicines over conventional medicines include one or several superior characteristics like efficacy, safety, physicochemical properties, and pharmacokinetic/pharmacodynamic profiles of the active pharmaceutical ingredients (APIs) [61]. Especially, various kinetic characteristics and targeting behavior of the nanomedicines in the body are further influenced by their dosage forms [98]. Both US Food and Drug Administration (US FDA) and European Medicines Agency (EMA) have given specific instructions and requests for the development and specific characteristics of nanomedicines. For example, EMA pays a special attention to nanomedicines´ properties in patient context [99]. These European Medicines Agency's scientific guidelines on nanomedicines have been implemented to help medicine developers prepare marketing authorization applications for human medicines. These guidelines include specific chapters about (1) data requirements for intravenous iron-based nanocolloidal products developed with reference to an innovator medicinal product, (2) data requirements for intravenous liposomal products developed with reference to an innovator liposomal product, (3) development of block copolymer micelle medicinal products, and (4) guidance on surface coatings, general issues for consideration regarding parenteral administration of coated nanomedicine products. Nanoscale materials defined by the US FDA include nanomaterials (materials used in the manufacture of nanomedicine, additives, etc.) and final products (nanomedicine) [100]. The particle size of such materials is typically 1–100 nm, and this category of nanomedicines oftentimes results in increased bioavailability, decreased therapeutical dose, improved drug efficacy, and decreased drug toxicity. Improvements in physical properties through effective drug formulation design often lead to improved

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solubility, dissolution rate, oral bioavailability, drug targeting to specific organs or cells, and/or improved/convenient dosage regimens that all may contribute to reduced drug dosing and, thereby, lower incidence of adverse reactions due to the smaller concentrations/amounts of the active pharmaceutical ingredients (API) or excipients (e.g., surfactants).

1.5.1 Lipid nanotechnology Advances in lipid nanotechnology was instrumental in the first steps of engineering medical nanodevices and novel drug delivery systems and in developing sensing applications [101]. The most successful nanotechnology-based drugs that are commercially available include Doxil and Abraxane, both approved early on by the US Food and Drug Administration (FDA). Doxil, the first FDA-approved nanodrug in 1995, has its efficacy based on prolonged blood circulation time and avoidance of the reticuloendothelial system (RES) due to the use of PEGylated nanoliposomes [102]. High and stable loading of doxorubicin is driven by a transmembrane ammonium sulfate gradient, which also allows for an enhanced drug release at the tumor site. Doxil is based on a cancer drug doxorubicin, which was originally approved by the FDA for the use on HIV-related Kaposi's sarcoma. However, it is now being used to treat also ovarian cancer and multiple myeloma [102]. The drug is encapsulated in liposomes, which helps to extend the life-span and circulation time of the drug, that is, drug distribution. Doxorubicin-containing liposomes are self-assembling, spherical, and closed colloidal structures that are composed of lipid bilayers that surround an aqueous core. The liposomal formulation also helps to increase the functionality, and especially in the case of heart muscle toxic drug like doxorubicin, the nanoformulation decreases the damage (cardiomyopathy) of the free drug in the heart [103].

1.5.2 Nanoparticle nanotechnology Another highly successful pioneer in the nanomedicine field is the Abraxane formulation that consists of albumin protein-bound paclitaxel in a nanoparticle form to treat breast cancer, nonsmall cell lung cancer (NSCLC) and pancreatic cancer [104]. Due to its low water solubility, paclitaxel is typically formulated in a mixture of Cremophor EL and dehydrated ethanol (50:50, v/v), which forms a combination known as Taxol [105]. However, Taxol exerts severe side effects for patients, which are related to the Cremophor EL and ethanol. Encapsulation of paclitaxel in a biodegradable and nontoxic nanodelivery systems provides a way to protect the drug from degradation during the blood circulation and to protect the body from the toxic side effects of paclitaxel that, thereby, lowers the toxicity, increases the circulation half-life, improves the pharmacokinetic profiles, and results in better patient compliance [105]. The ­nanoparticle-based delivery systems can take advantage of the earlier mentioned enhanced permeability and retention (EPR) effect for passive tumor targeting, thus providing a promising and ready for commercialization nanocarrier to improve the therapeutic index and to decrease the side effects of paclitaxel.

Principles of nanosized drug delivery systems19

Choi and Han [106] have very recently published a distinguished review article on the commercially available nanomedicines. All in all the US FDA had approved 51 nanomedicines by the year 2016, which could be classified into polymeric nanomedicines, micellar nanomedicines, liposomes, antibody drug conjugates, protein nanoparticles, inorganic nanoparticles, hydrophilic polymers, and nanocrystals. Among these different formulation strategies, the polymeric nanoparticles are regarded as the simplest forms of nanomedicines, which contain soft materials to increase the solubility, biocompatibility, half-life, and bioavailability of the drug and to control the release of active pharmaceutical ingredients (APIs) in the body [106]. Especially, poly(ethylene glycol) (PEG) is a frequently used surface-coating polymer in nanomedicines, resulting in increased half-life and bioavailability of the drug in vivo. Numerous commercially available nanocrystal products (most frequently via the oral administration route and based on dissolution enhancement) have been introduced in the beginning of this chapter. Micelles and liposomes are typically used in the controlled release formulations of lipophilic drugs, as liposomes typically reduce the toxicity and increase the bioavailability of drugs. Antibody drug conjugates have been used to reduce drug cytotoxicity and to improve solubility and targeting properties of the drugs. These conjugates are stable in blood and within the often targeted cancer cells and are expected to be released into the intracellular or paracellular compartments after drug/particle uptake. For a more comprehensive review of the commercially available nanomedicines, the interested reader is referred to the article by Choi and Han [106].

1.6 Conclusions Research interest in the area of nanosized drug delivery systems is all the time increasing, but the number of marketed nanomaterial-based products is still rather low. Numerous different kinds of nanocarriers have been studied for biomedical application purposes, but often the bioavailability level reached with the nanosized drug delivery systems, especially in intravenous administration, is quite low as compared with the total drug amount in these systems. Deep understanding of the physicochemical properties of these nanocarriers together with detailed understanding of biomembranes and their functioning are the basic requirements for developing more successful drug nanocarrier systems in the future.

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Controlled/localized release and nanotechnology

2

Mohsen Khodadadi Yazdia, Payam Zarrintajb, Fatemeh Mottaghitalabc, Mehdi Farokhid, Joshua D. Ramseye, Mohammad Reza Saebf a School of Chemical Engineering, College of Engineering, University of Tehran, Tehran, Iran, bPolymer Engineering Department, Faculty of Engineering, Urmia University, Urmia, Iran, cNanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran, dNational Cell Bank of Iran, Pasteur Institute of Iran, Tehran, Iran, e School of Chemical Engineering, Oklahoma State University, Stillwater, OK, United States, f Department of Resin and Additives, Institute for Color Science and Technology, Tehran, Iran

2.1 Introduction During last decades, nanotechnology has revolutionized many fields of science and engineering. Nanotechnology deals with utilization of materials, creation of structures, and fabrication of devices in which at least one dimension is in nanoscale [1]. The basic concept of this technology is grounded on manipulation of matter in atomic or molecular scale to produce materials or devices with extraordinary structures and/ or properties compared with the commonly available materials. The nanotechnology deals with material with dimensions as low as 100 nm or beneath, where the surface/ bulk atom (or molecules) ratio becomes considerable while the ratio is nearly zero for ordinary materials. Atoms placed on the surface experience different interactions compared with those in the bulk of matter that ends in a different electron density (or electronic structure) of these atoms. On the other hand the properties of a macroscopic system emanate from its electronic structure [2]. Consequently the properties of the surface-positioned atoms are noticeably different from those in the bulk. This may result in different or even peculiar properties at nanoscale materials. For example, melting temperature of gallium nitride (GaN) nanoparticles (NPs) significantly varies with the size and the shape of GaN [3]. As another example, the existence of an exotic bandgap of zero for pristine monolayer graphene as a gapless semiconductor has been confirmed [4]. In biomedical field, nanotechnology and nanomaterials have taken a very particular position individually and also in a complementary manner [5]. For example, they have been used in diverse medical imaging modalities (e.g., MRI, CT, and PET), drug and gene delivery [6–8]. Furthermore, many nanoscale vesicles have been developed in biological systems. Exosomes, which are extracellular vesicles of endocytic origin, are generally 30–100 nm in diameter [9]. In fact, nanotechnology has effectively been used in manufacturing controlled and targeted delivery systems [10, 11]. Hollow nanostructures like polymersomes can be used as a reservoir for both hydrophilic and lipophilic drugs. Hydrophilic drugs can be encapsulated in the aqueous core, while Nanoengineered Biomaterials for Advanced Drug Delivery. https://doi.org/10.1016/B978-0-08-102985-5.00002-4 © 2020 Elsevier Ltd. All rights reserved.

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lipophilic drugs can be easily integrated in the membrane. Furthermore, adsorption of drugs onto the nanostructures through diverse covalent and noncovalent interactions is possible. The nanobased strategies can further help designing modified nanocarriers for targeted delivery of anticancer drugs that specifically bind to the cancerous cells. On the other hand, due to small size, it is possible for nanocarriers to cross the biological barriers for better delivery of therapeutics. For example, nanoparticles can be used to pass through blood-brain barrier (BBB) to deliver drugs to the CNS [12]. Such delivery systems can also be used for delivery of other biological therapeutics such as gene, RNA, proteins, and monoclonal antibodies. For example, lipid-­ polymer hybrid nanoparticles have shown promising features for small interfering RNA (siRNA) delivery in the treatment of prostate cancer [13]. Some nanocarriers may carry more than one therapeutic agent. Furthermore, nanocarriers that carry both therapeutic and diagnostic agents simultaneously are known as theranostic platforms. These nanocarriers are gaining much interest in designing novel platforms for multimodal therapy [14–16]. In this chapter, different nanocarriers used for delivery of different therapeutic and/or diagnostic agent are summarized.

2.2 The evolution of drug delivery systems The evolution of drug delivery is illustrated in Fig. 2.1. Before mid-20th, drugs were generally used in the form of tablets and capsules, which were administered using different routes such as oral, nasal, and intravenous route. However, the problems associated with such methods, such as abrupt initial burst after administration, encouraged researchers to develop sustained release formulations. A great deal of effort was dedicated to the development of specific drug delivery carriers using biological-derived

Fig. 2.1  The evolution of drug delivery systems from mid-20th to current days. From M. Medina-Sánchez, H. Xu, O.G. Schmidt, Micro-and nano-motors: the new generation of drug carriers, Ther. Deliv. 9 (4) (2018) 303–316. Reproduced with permission from Therapeutic Delivery as agreed by Newlands Press Ltd.

Controlled/localized release and nanotechnology29

vesicles and different nanoparticles in the next decades. However, the majority of the aforementioned nanocarriers could rely on blood circulation and flow of other biological fluids to travel through the human body. Later, three types of nanomotors have been discovered in biological systems [18]. Inspired by these nanomotors, much effort has been made to manufacture self-moving or self-propelled micro-/nanoparticles known as nanomotors [19]. These NPs are able to convert different types of energy to the movement. In fact, these micro-/nanoscale motors can be considered as novel nanocarriers for manufacturing the next-generation drug carriers [17]. Furthermore the advent of micro- and nanorobot in the field of biomedicine is expected to grow in coming years [20].

2.3 Nanostructures from dimension viewpoint 2.3.1 Zero-dimensional nanostructures Spherical or semispherical nanoparticles are usually considered as zero-dimensional (0D) nanomaterials. Nanoparticle-based drug delivery (NDD) has been widely applied in drug delivery applications [21]. Hollow nanosphere can act as reservoir for drugs, while drugs may be adsorbed onto the surface of solid nanoparticles or distributed into them [22, 23]. For example, polymer nanoparticles have been widely used in delivery systems such as anticancer drugs [24]. Besides, particular attention has been paid to the gold nanoscale particles (AuNPs) in biomedical applications, specially drug delivery, because of biocompatibility, nontoxic nature, light-absorbing properties, and the ability to facile functionalization with various biomolecules [25]. For example, AuNPs have been successfully utilized as nanocarriers for delivery chemotherapeutic agents [26]. Furthermore, magnetic nanoparticles (MNPs) have gained special attentions in the field of oncology for targeting the cancer cells [27].

2.3.2 One-dimensional nanostructures Nanotubes, nanorods, and nanowires are the known one-dimensional (1D) nanostructures. Carbon nanotubes (CNTs) are the most famous member of this family, which can be found either in the form of single-walled carbon nanotubes (SWCNTs) or multiwalled carbon nanotubes (MWCNTs). These nanotubes have widely been used in designing delivery nanocarriers. For example, it was found that pristine SWCNTs can effectively penetrate across the BBB [28]. Besides the CNTs can absorb the light such that it is known as an intriguing photosensitizer for photodynamic therapy (PDT) [29]. Furthermore, their high surface area makes easy adsorption of chemical moieties and drugs. Thanks to this feature, CNTs have been utilized in drug delivery for cancer therapy and the CNS diseases [30]. Internalization of CNTs is possible by the cells via several mechanisms such as endocytosis. Doxorubicin (DOX) can be attached to the SWCNTs surface in basic medium, while in acidic tumor microenvironment, it can be released to kill the cancer cells more effectively with respect to the free DOX [31]. On the other hand, there were many other organic and inorganic nanotubes utilized

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in loading drugs. For example, cyclic peptide-polymer conjugates have been utilized to make organic nanotubes. Moreover, organic nanotubes based on cyclic peptide-­ conjugated poly(N-(2-hydroxypropyl) methacrylamide) (pHPMA) have been used for delivery of anticancer drugs [32]. Furthermore, nanofibers are other alternatives for developing 1D drug carriers. Both natural and synthetic polymeric nanofibers have also been used for drug delivery [33, 34].

2.3.3 Two-dimensional nanostructures High surface area enable two-dimensional (2D) nanostructures to conjugate with molecules such as drugs or biological moieties. For example, DOX can be attached onto graphene oxide (GO) nanoplatelets via π-π conjugation accompanied by hydrogen bonding. Zhang et al. conjugated cell apoptosis peptide onto GO via disulfide bonds and DOX anticancer drug via noncovalent interactions and coated it with bovine serum albumin (BSA) [35]. The obtained nanocarriers can penetrate cells where they deliver both DOX and apoptosis peptide highly interesting for synergetic cancer therapy. In recent years a new 2D architectural nanoplatelets have emerged, known as Xene. Xenes (X = Si, Ge, Sn, and so on), such as silicene, germanene, and stanene, indicate the two-dimensional monoelemental materials [36]. The graphene is also a member of Xene family. Xenes possess extraordinary physiochemical and optoelectronic properties such that they have been used in biomedical applications such as biosensors, bioimaging, and therapeutic and theranostic platforms [37]. On the other hand, 2D nanostructures with two or more elements in their chemical structure may also be used. Biotite or black mica minerals are types of sheet phyllosilicate. The presence of iron and magnesium cations in these nanoplatelets makes them promising to be utilized as theranostic applications for cancer diagnosis/therapy [38]. Furthermore, 2D organic nanostructure with more versatile chemistry may also be used in controlled/localized delivery applications [39].

2.3.4 Three-dimensional nanostructures This family can be much broader then 1D and 2D nanostructures because various changes in the third dimension provide the nanostructure more degree of freedom. Nanospheres, core-shell nanostructures, dendrimers, polyplexes, polymersomes, zeolites, and bottlebrush polymers are just several members of this broad group that are discussed here. Dendrimers are nanoscale 3D macromolecules with a highly branched structure [40]. They can entrap or conjugate with both hydrophilic and hydrophilic moieties such as drugs, genes, and antibodies such that they have been widely used in targeting and delivery applications [41]. Polyplexes, which are complexes of polymers (usually cationic) and DNA, are promising synthetic vectors in gene delivery. Similarly, lipoplex is complex of cationic lipids, and DNA and lipopolyplex are complex of polycations and cationic lipids with DNA. These nanostructures have gained attraction in the delivery of

Controlled/localized release and nanotechnology31 Cationic segment Optimization of polycations Crosslinking between polycations Biodegradable polycations

PEG

Hydrophilic PEG shell Hydrophobic barriers

Cholesterol moiety Targeting ligand

Thermoresponsive polymer Block copolymer

Targeting ligand pDNA

mRNA

Stabilization of core containing nucleic acids

Polyplex micelles

Fig. 2.2  Various technologies utilized to enhance the functionality of polyplex nanocarriers. Reproduced with permission from S. Uchida, K. Kataoka, Design concepts of polyplex micelles for in vivo therapeutic delivery of plasmid DNA and messenger RNA, J. Biomed. Mater. Res. A 107 (5) (2019) 978–990.

biological macromolecules such as gene delivery [42, 43]. For example, in nonviral methods, plasmid (p)DNA or messenger (m)RNA is usually encapsulated into polyplexes or lipoplexes to prevent degradation by nuclease activities before reaching cells [44] (Fig. 2.2). Cyclodextrins (CyDs) primarily denote the cyclic oligosaccharides, which are produced through enzymatic conversion of the starch. CyDs are also attractive in the pharmaceuticals because they enhance the stability of drugs [45]. Supramolecular systems based on CyDs have gained much attentions in drug delivery [46]. On the other hand, different cross-linkers, such as epichlorohydrin, may be used to synthesize cyclodextrin-based polymers, which show higher drug-carrying capacity compared with neat CyDs [47]. These amphiphilic compounds show excellent biocompatibility, which makes them promising in drug delivery applications specially for poorly soluble drugs [48]. For example, polymeric NPs based on cyclodextrins were utilized as a carrier for sorafenib (poorly water-soluble drug) [49]. Furthermore, nanosponges based on cyclodextrin have been utilized to make nanocarriers for drug delivery [50]. These nanosponges are 3D nanostructures conjugate to both hydrophilic/lipophilic molecules through complexation. Zeolites are highly crystalline porous structures of hydrated aluminosilicates. They can be both natural or synthetic in origin. The pores and channels in zeolites have various shapes, size, and electrical charges. Due to high porosity, adsorption capacity, and ion exchange capabilities, nanostructured zeolites have been used as carriers in many controlled release applications [51]. Polymersomes are synthetic counterparts of liposomes, which are fabricated using amphiphilic block copolymers. The aqueous core of these nanostructures can be utilized to encapsulate various hydrophilic therapeutic agents, while hydrophobic drugs may be integrated into hydrophobic membrane of the polymersome [52]. These nanostructures have high stability and benefit from relatively long blood

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circulation times. Tailor-made polymersomes have been developed for many diagnosis and therapy purposes [53]. Nanostructures based on bottlebrush polymers are another fascinating nanostructures for drug delivery applications [54].

2.4 Bionanostructures On the other hand, nanocarriers may be manufactured using nonstructural moieties of biological systems. For example, liposomes can be manufactured through disruption of biological membranes such as cell membranes with the aid of sonication. Liposomes and lipid nanoparticles (LNPs) are promising bioinspired platforms for delivery of different therapeutic agent such as drugs, gene, and RNA [55, 56] (Fig. 2.3). Besides, other biological vectors originated from extracellular vesicles can be also used as delivery platforms [57].

Conventional liposome

Theranostic liposome

Hydrophobic drug

Targeting ligand

Positively charged lipid Negatively charged lipid

(A)

Hydrophilic drug

(D)

Functionalized imaging agent

Polyethylene glycol (PEG)

PEG Small molecule Carbohydrate Peptide Protein Antibody

(B) PEGylated liposome

(C)

Ligand-targeted liposome

Fig. 2.3  Liposome with various functionalities for controlled/localized delivery: (A) conventional liposomes, (B) PEGylated liposomes to improve pharmacodynamic properties of drugs, (C) liposomes modified with targeting ligands for specific targeting of special cells, and (D) theranostic liposomes including targeting ligands, imaging agents, and nanoparticles. Reproduced with permission from L. Sercombe, T. Veerati, F. Moheimani, S.Y. Wu, A.K. Sood, S. Hua, Advances and challenges of liposome assisted drug delivery, Front. Pharmacol. 6 (2015) 286.

Controlled/localized release and nanotechnology33

2.5 Micro- and nanomotors Most of the aforementioned carriers rely only on the blood circulation or the flow of biological fluids to move throughout the body. However, what if we would be able to design self-moving vehicles for delivery of drug payload to certain tissue? In other words, if the carrier is able to move forward, independent of body fluids, it means that it can somehow exert a force on the surrounding fluid. This concept and inspiration by motility in living systems is the basis for designing micro-/nanoscale motors. The micro- and nanomotors are emerging concepts in the field of drug delivery. These biocompatible platforms are believed that are able to deliver therapeutic agents more rapidly under a controlled condition; furthermore, they can penetrate deep into the tissue while they benefit from biocompatibility and also preserving payloads safe [17]. They can be directed through external sources such as light, magnetic field, and electromagnetic fields, or they may be fueled by biological moieties such as glucose, urea, and H2O2. In 2010 Kagan et al. manufactured the first nanowire nanomotors, which decompose hydrogen peroxide as fuel, for delivery of DOX with high speed [58]. They utilized catalytic microshuttles as nanomotors that carry biocompatible and biodegradable PLGA particles loaded with drug. These motors may be synthetic, biological, or hybrid nanomotors. Furthermore, Lee et al. manufactured Janus nanoparticles (JNPs), with c.30 nm in diameter, based on Pt-Au that can successfully catalyze H2O2 decomposition [59]. Biological nanomotors are classified, based on mechanism, into linear, rotation, and revolution nanomotors [18]. However, the movement in more complicated living organism is through more sophisticated mechanism. For example, bacterial flagella provide motility in some kinds of bacteria. The concept may be developed to make more elaborate nanocarriers for controlled delivery. However, the presence of moving parts can make the manufacturing of nanocarriers really complex. On the other hand, no moving parts are seen in some man-made spacecrafts. For example, let us take a look at cube satellites (also known as CubeSat), in which a micropropulsion system (also known as microthruster) provides them with enough thrust to move and/or change direction. Inspired by these microthrusters, we may be able to design self-propelling carriers for delivery of different payloads in human body. These strategies would enable engineers to design new micro-/nanoscale carriers for utilization in human body. The robotic science will further help to increase the functionalities of these nanocarriers. In fact, bionanorobots that are more sophisticated nanocarriers can be used for diagnosis and therapy of cancer [60]. These nanocarriers integrate sensing, intelligence, and actuation in one package. Diagnosis using nanosensors, data analysis and decision-making, and actuation to release a drug can be all integrated in individual bionanorobots, which can decide to attack single cancerous cells. Furthermore the realm of micro-/nanorobots has further expanded to other biomedical applications such as surgery and detoxification [20].

2.6 Conclusion Controlled and localized delivery of therapeutic and diagnostic agents is a hot topic of research, which is further empowered by the nanotechnology. The power of

34

Nanoengineered Biomaterials for Advanced Drug Delivery

n­ anotechnology in designing well-structured nanocarriers along with biomaterials science has provided researcher to design and manufacture more effective delivery carriers for diverse payloads. Different nanostructures have exhibited very promising results for controlled and/or targeted delivery of drugs for treatment of various diseases specially cancer. On the other hand, more sophisticated micro-/nanomotors and bionanorobots have emerged as platforms with multiple functions in diagnosis and therapy of various fetal diseases. Furthermore, incorporation of wireless communication into the nanocarriers can further improve the power of smart carriers in controlled/ localized release. Data analysis and decision-making can be carried out by a processor outside patient body, while sensing and actuation are done by the nanocarriers.

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Stimuli-sensitive drug delivery systems

3

Mazaher Ahmadi, Tayyebeh Madrakian, Arash Ghoorchian, Mahdie Kamalabadi, Abbas Afkhami Department of Analytical Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran

Abbreviations AMF AuNPs CAB DDS DOPC DOX ELPs EPR ESDSs GSH GSSG ICPs IONPs LCST MMPs MNPs MPS MSNs NHMA NIR PDT PEG PEG-PCL PEO-PPO-PEO PNIPAM PNIPAM PoP PVA rGO RSDSs SDS TSDSs UCST UV

alternating magnetic field gold nanoparticles 4-cholesterocarbonyl-4′-(N,N,N-triethylamine butyloxyl bromide) azobenzene drug delivery systems dioleoylphosphatidylcholine doxorubicin elastin-like polypeptides enhanced permeability and retention effect electrosensitive delivery systems glutathione GSH/glutathione disulfide intrinsically conducting polymers iron oxide nanoparticles lower critical solubility temperature matrix metalloproteinases magnetic nanoparticles mononuclear phagocyte system mesoporous silica nanoparticles N-(hydroxymethyl)acrylamide near-infrared photodynamic therapy polyethylene glycol alginate poly(ethylene glycol)-b-poly(caprolactone) copolymer PEG-b-poly(propylene oxide)-b-poly(ethylene oxide) triblock copolymers poly(N-isopropyl acrylamide) poly(N-isopropyl amide) porphyrin-phospholipid polyvinyl alcohol reduced graphene oxide redox-sensitive delivery systems sodium dodecyl sulfate thermosensitive delivery systems upper critical solution temperature ultraviolet

Nanoengineered Biomaterials for Advanced Drug Delivery. https://doi.org/10.1016/B978-0-08-102985-5.00003-6 © 2020 Elsevier Ltd. All rights reserved.

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Nanoengineered Biomaterials for Advanced Drug Delivery

3.1 Introduction Recent advances in materials science and especially advances in nanotechnology have a significant impact on medicine in terms of therapy and diagnostics. Certain diseases such as cancer are associated with abnormal physiological conditions such as pH, redox species concentration, reactive oxygen species, and enzyme concentration. There have been many types of cancers that affect various organs and areas such as breast, lung, and liver [1]. Unfortunately, efforts such as chemotherapy, radiotherapy, immunotherapy, and aggressive surgeries only can extend the patient’s survival period and rarely can cure cancer completely. This is maybe because of lack of proper diagnostics, poor understanding of the mechanism of various cancer causes and actions, and lack of effective treatments. Although there are some anticancer drugs available in the global market approved by different healthcare agencies, the efficacy of these drugs is limited due to probably poor bioavailability and low selectivity in action. The poor bioavailability of certain drugs comes from their poor solubility in biological fluids, poor water solubility, and also the untargeted distribution of the drug molecules inside the host body. The low selectivity of some drugs leads to damaging healthy surrounding cells and toxic side effects [2]. By far, various strategies have been followed to enhance drugs’ effectiveness such as synthesis of derivatives with higher water solubility, reduction of particle size, adduct compounds, and the use of mixed solvents and surfactants. These strategies always face some drawbacks such as the associated toxicity of the materials used to prepare higher water-soluble drug formulations and nonspecific delivery, which subsequently leads to a nonspecific distribution of the drug [3]. One of the most interesting strategies that have been utilized to enhance the bioavailability of drugs is to use nano-/microformulations. To enhance the overall bioavailability, the drug molecules can be effectively encapsulated inside biocompatible/biodegradable carriers or be adsorbed on them and be attached to the carrier through covalent bond formation. These formulations can extend the drug circulation time and overcome biological barriers [4–7]. Furthermore, to enable selectivity in delivery and subsequently to improve the therapeutic efficacy, targeted delivery of anticancer drugs using special carriers have been considered. In this approach the drug is loaded on a carrier that can selectively deliver the drug to the desired tissue. Usually the general structure of this class of carriers involves a targeting moiety linked to a therapeutic payload via a spacer that often contains stimuli-cleavable bonds. The targeting moiety can be a protein, antibody, peptide, carbohydrate, small molecule, etc. with the ability of selective binding to a specific receptor on targeted cells. In the case of different cancerous diseases, the targeting moiety is designed to selectively bind to different overexpressed receptors [8]. After tagging the receptors the carrier can enter the cell by different processes such as most commonly endocytosis. The carrier should be able to selectivity release the encapsulated drug inside or close to the cells. To this end the used spacer should contain certain bonds sensitive to the specific physiological condition of targeted cells. In the case of cancerous cells, the abnormal physiological conditions of the tumors such as pH, redox species concentration, ROS, and enzymes have been used to design different carriers [9–12].

Stimuli-sensitive drug delivery systems39

Therefore the drug carrier can be specifically designed to respond to a certain stimulus. The stimuli can be divided into intrinsic (internal) stimuli and external stimuli [13]. The intrinsic stimuli are characteristics of affected/pathological tissues and areas that make the condition of tissues different from healthy tissues. Some of these intrinsic stimuli are different pH, redox conditions, temperature, and the overexpression of certain biologically/enzymatically active molecules in the pathological tissues. On the other hand the external stimuli can be applied from outside the body such as heat, light, ultrasound, and magnetic field. This chapter will present an overview of stimuli-sensitive drug delivery systems (DDS). Each section will deal with certain stimuli-sensitive DDS in terms of fundamentals and applications. Applications of different intrinsic (internal) stimuli and external stimuli in DDS such as pH, redox conditions, temperature, heat, light, ultrasound, magnetic field, electric field, and enzyme with a focus on cancer therapy will be discussed.

3.2 pH-sensitive drug delivery systems The pH of the human body has a wide distribution. For example, the normal physiological pH is 7.4 (blood and directly in contact areas), in the stomach is around 1–2.5, and in the small intestine and colon is around 7.2–7.5 and 7.9–8.5, respectively. Furthermore, all eukaryotic cells during the endocytosis process build special vesicle-like endosomes and lysosomes. It has been proven that these vesicles have lower pH than the physiological pH (i.e., 5–6.5 and 4 in endosomes and lysosomes, respectively) [14]. In recent years, pH-sensitive polymers have been widely used in DDS as smart drug carriers for cancer therapy purposes [15]. The extracellular environment of tumor tissues usually is more acidic (pH 5–6.8) compared with normal tissues due to the accumulation of acidic compounds such as lactic acid and some acidic metabolites [16, 17]. It has been reported that cancer cells consume 40 times higher amounts of glucose compared with normal cells. Therefore lactic acid can be produced and accumulated at higher rates as a result of anaerobic glycolysis of glucose due to the hypoxic conditions of the tumor tissues. Usually, pH-sensitive polymers contain pH-sensitive cleavable bonds or basic and acidic functional groups. When these polymers are utilized for the synthesis of drug carriers, the resulting product can respond to the pH change of the environment through different mechanisms including pH-cleavable bonds, ionic interactions, and change in the swelling degree of the network of hydrogels. Simply, for the synthesis of a pH-responsive carrier for cancer therapy purposes, pH-cleavable bonds such as acetal and hydrazone can be improvised in the composition of the carrier. This action can be carried out by using a linker or cross-linker containing such bonds. Therefore, the final structure can respond to a drop in the pH environment by degradation/losing its primary structural network. Furthermore the desired anticancer drug molecule can be attached to the carrier using pH-­ sensitive linker, so the drug can be released as a response to the pH change of the environment.

40

Nanoengineered Biomaterials for Advanced Drug Delivery

Another mechanism that is utilized for the synthesis of pH-responsive carriers is the use of ionic interaction as the cross-linking method of the hydrogels. When a polymeric precursor contains acidic or basic groups such as alginate and chitosan, respectively, it can be cross-linked using ionic interactions. The product would be sensitive to the environment pH since it contains functional groups that undergo protonation/deprotonation process as a result of pH change. Therefore, when a hydrogel synthesized from acidic polymeric precursors is subjected to an appropriate acidic pH, the acidic functional groups would be protonated, and the ionic interaction between the polymeric chains and the ionic cross-linker is lost. Then the hydrogel would lose its primary structure leading to the release of the encapsulated/loaded anticancer drug molecules. Among the evaluated mechanisms, change in the swelling degree of the hydrogel network is the most evaluated one. To this end the hydrogel network should contain basic functional groups (such as chitosan) that can be protonated at low pH values. As a result, when the hydrogel functional groups are protonated, osmotic pressure is produced in the hydrogel network due to the electrostatic repulsion forces between positively charged functional groups resulting in an expansion, which affect the swelling degree of the hydrogel. In addition, when the polymer contains both acidic and basic functional groups in its backbone such as carboxylic and amine functional groups, a pH change of the environment causes a change of the degree of protonation/ deprotonation of groups leading to an expansion or contraction of the hydrogel network depending of the pH value and the nature of the polymeric precursor(s) [18].

3.3 Redox-sensitive drug delivery systems Redox-sensitive delivery systems (RSDSs) take advantage of distinct differences in redox potentials between normal and tumor cells. The redox states of NADPH/NADP+ and GSH/glutathione disulfide (GSSG) control the reducing environment of tumor tissues. GSH, the main reducing agent in biological cells, facilitates the thiol-disulfide exchange reaction [19, 20]. The concentration of GSH in the mitochondrion, nucleus, and cytosol reaches 2–10 mM, while the blood concentration of that ranges from 2 to 20 μM [21, 22]. In addition, the concentration of GSH in cancerous cells is dramatically higher than in normal cells [23], and then, this GSH concentration gradient across the cellular membrane can be targeted for the design and fabrication of RSDSs. To prepare the RSDSs, disulfide bonds can be employed as intermediate linkers in the carrier structure. Attachment of drug to polymer chains through a disulfide linker results in a redox-sensitive delivery system for drug delivery. When these carriers are exposed to tumor tissue with a high concentration of GSH, the disulfide bonds are cleaved leading to chemical degradation of the carrier structure. Thus the encapsulated anticancer drug is released from the degraded polymer network [24]. Regardless of their high redox potential, cancerous cells also have a lowered pH, which has been exploited by pH-sensitive delivery systems. RSDSs have many advantages over pH-sensitive delivery systems, in the sense that they offer excellent stability against hydrolytic degradation and controllable drug delivery [13].

Stimuli-sensitive drug delivery systems41

In biomedical applications, micelles such as poly(ethylene glycol)-b-poly (caprolactone) (PEG-PCL) block copolymer networks have attracted much consideration for redox-sensitive drug release. An effective biodegradable micelle-based PEG-SS-PCL block copolymers have been developed to efficient intracellular release of doxorubicin (DOX) (Fig. 3.1) through the selective detachment of PEG block from the carrier under the action of GSH on S-S bonds between two polymeric blocks [25]. In addition, mesoporous silica nanoparticles (MSNs) are very popular for the preparation nanocarriers in cancer therapy, because of their tunable pore sizes, excellent biocompatibility, and large surface. For example, collagen-capped MSNs have been used as a redox-sensitive nanocarrier for the controlled release of fluorescein isothiocyanate as a model drug by cleavage of the disulfide linkers [26].

Self-assembly in water

Reduction-sensitive shell-sheddable biodegradable micelles

PEG-SS-PCL + DOX

SH

SH

SH

Endocytosis

SH SH

SH

SH

Cytoplasm GSH

n

SH

+ SH

SH

SH

HS

SH

HS

GSH

GSH

SH

HS

SH

HS

n+m

SH

+ SH

Nucleus

Fig. 3.1  GSH-triggered release of DOX from biodegradable micelle-based PEG-SS-PCL block copolymers. From H. Sun, B. Guo, R. Cheng, F. Meng, H. Liu, Z. Zhong, Biodegradable micelles with sheddable poly(ethylene glycol) shells for triggered intracellular release of doxorubicin, Biomaterials, 30 (2009) 6358–6366.

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Nanoengineered Biomaterials for Advanced Drug Delivery

3.4 Thermosensitive drug delivery systems Thermosensitive delivery systems (TSDSs) have been considered as an attractive class of stimuli-sensitive drug delivery systems associated with their simplicity, low cost, fast response, and ready availability [27, 28]. Over the past few years, “swellable hydrogels” have emerged as one of the most interesting materials for the design of drug delivery systems [29, 30]. The swelling behavior of these hydrogels may be dependent on environmental changes including temperature, ionic strength, and pH. Thermosensitive hydrogel networks are attractive three-dimensional polymers that reversibly swell to the original form or collapse into a compact shape in response to temperature changes [31, 32]. The performance of thermosensitive swellable hydrogels is dependent on hydrophobic and hydrogen bonding interactions [33]. Water molecules around the hydrogel are hydrogen bonded to hydrophobic polymer chain at low temperatures, and as a result the hydrogel network swells. In contrast, at high temperatures, the hydrophobic interactions remarkably increased, that is, the hydrogen bonds weaken. Therefore the polymer chains collapse in aqueous media at high temperatures [34]. In other words the solubility of these hydrogels decreases during heating as a result of the change of their hydrophobicity. During heating a hydrogel a well-defined reversible phase transition from swollen to collapsed form of the polymeric network was obtained at a critical temperature. The temperature at which this phase transition occurs is referred to as the “lower critical solubility temperature” (LCST), which can be adjusted by changing the hydrophobicity of the hydrogel chains [35]. Unlike LCST-based hydrogels the solubility of another type of swellable hydrogels increases upon heating. These thermosensitive hydrogels have an “upper critical solution temperature” (UCST), which below that the hydrogel network becomes insoluble [30]. However, LCST hydrogels are more applicable to the fabrication of TSDSs than UCST hydrogels. TSDSs based on these polymers can release or deliver drugs in two different mechanisms [32]: ●

●

Mechanism A: the release of the anticancer drug from a swollen polymeric network at T  LCST.

In Mechanism A the hydrogel network is below its LCST, and active agent or drug is released by a Fickian diffusion process. For example, methylene blue can be released from poly N-isopropyl acrylamide at T 137 >58 >43 >66

0.40 0.72 0.81 0.82 1.71

>250 >139 >123 >122 >58

1.02 1.17 1.40 0.72 1.60

>98 >85 >71 >139 >63

a Concentration required to reduced the degree of HIV infection by 50% in peripheral blood mononuclear cells (i.e., primary cells). b Concentration required to reduced cell viability by 50%/concentration required to reduced the degree of HIV infection by 50%. c 1 µg/mL = 61 nM.

(A)

NaO3S

R NH

SO3Na

H R N O

O O

NH R

NH

HN

O

NaO3S

O

O H N

NH

R NH

N H

R

O

O N H

HN

H N O

O

R

NH NH R

HN

O

N H

O

O N H

HN

H N O

O

SO3Na

O

O

R N H

(B)

SO3Na

SO3Na

O

NH R

SO3Na NaO3S

Fig. 10.11  Dendrimers for anti-HIV purposes. (A) The anti-HIV activity of three different dendrimers: poly-l-lysine, PPI, and PAMAM dendrimers. Each presents 32 sodium 1-(carboxymethoxy)naphthalene-3,6-disulfonate surface groups linked by an amide bond; (B) The chemical structure of SPL7013, the dendrimer-based antiviral in VivaGel. Reproduced from T.D. McCarthy, et al., Dendrimers as drugs: discovery and preclinical and clinical development of dendrimer-based microbicides for HIV and STI prevention, Mol. Pharm. 2(4) (2005) 312–318, Copyright © 2005, American Chemical Society.

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Fig. 10.12  Molecular mechanisms of dendrimer-based anti-HIV therapies. (A) The life cycle begins when HIV binds to a CD4 receptor and coreceptors (CXCR4 and/or CCR5) on the surface of the CD4 cell through gp120. After fusion, HIV releases RNA into the host cell, and the reverse transcriptase converts the single-stranded HIV RNA to double-stranded HIV DNA to follow the replication. (B) A combination of two compounds acting at the beginning steps is the key to control the HIV replication cycle. Combinations of different dendrimers as entry inhibitors or a dendrimer with a CCR5 antagonistic (MRV) or with a nucleotide HIV reverse transcriptase inhibitor (TFV) enhance the antiviral activity compared with the compounds alone. Reproduced from D. Sepulveda-Crespo, et al., Synergistic activity profile of carbosilane dendrimer G2-STE16 in combination with other dendrimers and antiretrovirals as topical antiHIV-1 microbicide, Nanomedicine 10(3) (2014) 609–618, Copyright © 2014, with permission from Elsevier.

required high concentrations of siRNA, making them unfavorable for in vivo a­ nti-HIV applications. Further studies are necessary to design ideal delivery platforms that can be efficiently applied for genetic interference in potential HIV host cells. In addition to the application of polyanionic carbosilane dendrimers as a microbicide, carbosilane dendrimers can also be modified with cationic surface groups for gene

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Table 10.5  Application of dendrimer-based nanosystems for delivery of anti-HIV therapeutics. Polymer

Generation

Modification

Target

Ref.

Polyester dendrimer PLL

G4

G2-S16

G2

G2-NN16

G2

PAMAM

G5

HIV-1 reverse transcriptase gp120/CD4 interaction gp120/CD4 interaction Nef downregulation TNPO3, Tat/rev

[147]

G4

Cationic amino acid modified Surface napthyl disulfonated Surface napthyl disulfonated Surface quaternized Combinatorial delivery

[141] [148] [149] [150]

Fig. 10.13  Chemical structures of the carbosilane dendrimers with different cores and surface functional groups (A) G2-STE16; (B) G2-S24P; (C) G2-S16. Reproduced from D. Sepulveda-Crespo, et al., Synergistic activity profile of carbosilane dendrimer G2-STE16 in combination with other dendrimers and antiretrovirals as topical anti-HIV-1 microbicide, Nanomedicine 10(3) (2014) 609–618, Copyright © 2014, with permission from Elsevier.

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delivery. For example, two second-generation carbosilane dendrimers (G2-NN16, G203NN24) with the same quaternized terminal amine groups but different cores were investigated for their safety and efficiency in transfecting CD4 + T cells with siNef [149] (Fig. 10.14). The expression of the auxiliary gene Nef enhances viral replication and spreads by increasing the virus titers. Though both dendrimers transfected the CD4 + T cells and enhanced the inhibition of HIV-1 infection, they differed in their efficacy. The difference indicated that the rigidity affected the transfection efficacy of dendrimers. G2-03NN24 dendrimer derived from the polyphenolic core was more rigid, while G2-NN16 with the Si atom core was more flexible, resulting in an increased cellular uptake in CD4 + T cells. This was similar to that seen in PAMAM dendrimers where transfection efficiency increased as their flexibility increased [159]. On the other hand a higher inhibitory effect was observed in CD4 + T cells exposed to G2-03NN24 dendrimer, which underwent a slower Si-O bonds hydrolysis in water. Most importantly, both dendrimers have shown the ability to decrease macrophage phagocytosis, which is one of the well-known pathways for spread of HIV-1 virus. Thus the dendrimers could prevent the virus from residing in macrophages and improve the efficacy of antiretroviral therapy [159]. Other types of cationic dendrimers were also used to genetically interfere with HIV-1 infection. Generation 5 PAMAM dendrimers with the triethanolamine core and 96 terminal amine groups were used to deliver a combination of siRNAs for CD4, TNPO3, and tat/rev proteins to inhibit the HIV infection [150]. CD4 and ­transportin-3 (TNPO3) are HIV-1 host dependency factors that play key roles in HIV-1 infection. As described previously the CD4 on T cells is the primary receptor for HIV-1 [145, 146]. The transient knockdown of this receptor blocks HIV-1 and T-cell fusion [160]. TNPO3 is a cellular factor that is involved in facilitation of cytoplasmic trafficking of the HIV-1 preintegration complex. Downregulation of this factor interferes the

Fig. 10.14  Chemical structures of the cationic carbosilane dendrimers for siNef transfection in anti-HIV therapy (A) G2-NN16; (B) G2-03NN24 in CD4 + T cells. Reproduced from A.J. Perise-Barrios, et al., Carbosilane dendrimers as gene delivery agents for the treatment of HIV infection, J. Control. Release 184 (2014) 51–57, Copyright © 2014, with permission from Elsevier.

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r­eplication of HIV-1 in host cells [161]. Additionally, HIV tat/rev proteins are viral regulatory molecules that are essential in the HIV life cycle [162]. The PAMAM dendrimers were capable of systemic delivery of a combination of functional siRNA targeting both viral and cellular transcripts. The in  vivo treatment of HIV-1 infected, viremic, humanized mice resulted in efficacious protection against HIV-1 mediated T-cell depletion without a show of apparent toxicity. Overall, delivery of gene therapy with dendrimer-based delivery systems may provide a novel strategy that could be applied as a stand-alone therapy or as an adjuvant to the current antiretroviral therapy in clinical use for the treatment of HIV-1 infection.

10.5 Dendrimer-based drug delivery for osteoarthritis treatment Osteoarthritis (OA) is a debilitating disease of individual joints resulted from the degeneration of articular cartilage that is composed of chondrocytes, collagen, proteoglycans, and other noncollagenous proteins and glycoproteins. Currently, there is a huge unmet need for clinical therapies. Various classes of drugs, including antiinflammatory small molecules, cytokine receptor antagonists, anabolic growth factors, and targeted inhibitors of catabolic enzymes, have failed in clinical development. The rapid clearance rate of administered molecules from the joint space and the dense avascular nature of cartilage tissue constitute two considerable biological barriers to drug delivery to chondrocytes [163] (Fig. 10.15). Recent studies have shown that cationic carriers with a diameter lower than 15 nm can overcome the biological barriers of the joints [164]. Because of the anionic joint cartilage’s tissues, cationic nanoparticles can bind and keep them concentrated in the cartilage rather than swept away through v­ enules and lymphatic vessels

Fig. 10.15  Dendrimer-based drug delivery for antiosteoarthritis therapy. Cationic dendrimerbased drug delivery systems are capable of penetrating cartilage tissues and delivering the drug to the chondrocytes due to the electrostatic interaction. These systems also prevent the drug from being cleared out through venules or lymphatic vessels.

Dendrimers for drug delivery purposes233

(Fig. 10.15). Cationic dendrimers, such as G4-6 PAMAM, fit all design criteria. Beyond the small size and tunable surface charges, the scalable synthesis, robust characterization, and flexibility in accommodating different classes of therapeutic cargos make them translatable cartilage penetrating nanocarriers for treatment of OA [165]. To reduce the toxicity to normal tissues resulting from the cationic surface of PAMAM, surface primary amines can be modified with PEG chains to optimize charge. The PEGylated PAMAM dendrimers can be further conjugated with therapeutic candidates to enhance their uptake and residence time. It has been reported that G4 PAMAM with 35% of surface functional groups PEGylated and G6 PAMAM with 45% surface functional groups PEGylated increased uptake with negligible acute or chronic histotoxicity [165]. When conjugated to insulin-like growth factor 1 (IGF1), an anabolic growth factor that promotes chondrocyte survival, proliferation, and biosynthesis of cartilage matrix macromolecules, the dendrimers penetrated bovine cartilage of human thickness within 2 days and enhanced therapeutic IGF-1 joint residence time in rat knees for up to 30 days [165, 166]. In addition, high generations of PAMAM have a greater hydrodynamic radius, which prevent the excretion of PAMAM dendrimers by the kidneys. Thus the G6 45% PEGylated dendrimer-IGF-1 conjugate provided significant reduction in the degenerated cartilage area, width, and total osteophyte volume [165]. Another strategy to treat OA is to induce chondrogenic differentiation of mesenchymal stem cells (MSC) using a dendrimer-based nanocarrier. MSCs are multipotent nonhematopoietic cells capable of self-renewal. Some MSCs exist in normal synovial fluids and increase in early OA [167]. They have the capacity to differentiate into multiple lineages, including the osteogenic, chondrogenic, myogenic, and adipogenic lineages; thus they are key importance for tissue regeneration and engineering [168]. In 2012 it was found that kartogenin (KGN) binds to filamin A, an actin-binding protein, and inhibits its interaction with core-binding factor beta. Through this interaction, this hydrophobic molecule induces cartilage differentiation and potently induces human mesenchymal stem cells into chondrocytes [169]. Conjugation of KGN with a G4 PEGylated PAMAM dendrimer not only solved the solubility problem but also prevented the rapid clearance and increased the retention time of KGN in the synovial cavity after intraarticular injection [170]. PEGylated PAMAM-KGN conjugate improved the chondrogenic differentiation of KGN and its retention time in the joint. In addition, genetic therapy targeting of MSCs can also be delivered in G4 PAMAMbased nanocarriers. Both strategies suggest that dendrimer-based delivery systems are promising candidates to enhance the efficacy of therapy for OA [171].

10.6 Conclusion This chapter presented an overview on the characteristics, synthesis, different generations, and possible modifications on dendrimers for drug delivery purposes. These nanometric three-dimensional polymeric structures provide unique properties in drug delivery. During the last decade, dendrimer-based delivery systems have been used in a broad range of applications. They have provided novel therapeutic strategies in

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a­ntimicrobial, antiinflammatory, anti-HIV, antiosteoarthritis, and anticancer fields. However, dendrimers, like other nanomaterials, also encountered limitations during development, such as rapid clearance through the reticuloendothelial system and toxicity due to the interaction of the amine-terminated group with the cell membrane. To achieve the optimal therapeutic outcome, a balance between generation of dendrimers and their toxicity should be taken into consideration. Surface modification of dendrimers can significantly improve their abilities and compensate the pitfalls in clinical applications. As discussed in the context, various modifications of dendrimer have been established like surface shielding, lipid decoration, nucleic acid complexation, and protein conjugation. These modifications increase the biocompatibility, enable ligand-based target delivery, and optimize release behavior based on stimulus reactivity. Therefore the obtained multifunctionalized dendrimer-based drug delivery systems may serve as promising strategies for next-generation therapies in multiple types of diseases.

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Reversible cross-linked polymeric micelles for drug delivery

11

Lu Zhanga, Hao Wua, Yuanpei Li, Kit S. Lam Department of Biochemistry and Molecular Medicine, UC Davis NCI-designated Comprehensive Cancer Center, University of California Davis, Sacramento, CA, United States

11.1 Introduction Biocompatible polymeric nanocarriers offer great potential as efficient and efficacious delivery system for conventional anticancer cytotoxic drugs. These nanocarriers often improve the solubility of the drug, prolong the in vivo drug circulation time, and allow preferential accumulation of drug at the tumor sites via the enhanced permeability and retention effect [1–5]. However, the in vitro and in vivo stability of nanocarriers remains a challenge, due to the dynamic nature of these self-assembled nanosystems, which often leads to premature drug release and nonspecific biodistribution in vivo [6–8]. Prochaska and Baloch were the first to utilize cross-linking strategy to stabilize polymeric micelles [9]. Many have followed on using this approach to solve the in vivo stability problems of nanodelivery systems [10, 11]. Recently, reversibly cross-linked polymeric nanocarriers have been developed to maintain stability during blood circulation. Increased stability allows nanoparticles to accumulate at tumor sites efficiently via passive and/or active tumor targeting. Cleavage of the cross-linkages via endogenous stimuli or exogenously added cleavage agents at the tumor sites or inside the tumor cells facilitate drug release for maximal therapeutic effects while minimizing adverse side effects. This chapter briefly summarizes the development of reversibly cross-linked polymeric nanocarriers for on-demand drug release in response to single or multiple stimuli at the tumor microenvironment.

11.2 Design of reversibly cross-linked polymeric nanocarriers with single or multiple responsive properties The cross-linkage can be introduced at the hydrophilic shell [12, 13], hydrophobic core [6, 14], or core-shell interface [15, 16] of the polymeric nanoparticles via chemical crosslink, photo cross-link, or polymerization. One or two types of cross-linkable pendants are introduced to the assembly units so that intraparticle cross-links can occur spontaneously during drug loading and nanocarrier formation [17, 18]. To make the crosslinked nanoparticles responsive to tumor local microenvironments, the polymer chain or the cross-linkers with intrinsic responsive properties to pH, temperature, or redox conditions have been used to develop reversibly cross-linked polymeric nanoparticles. a

L. Zhang and H. Wu contributed equally to this work.

Nanoengineered Biomaterials for Advanced Drug Delivery. https://doi.org/10.1016/B978-0-08-102985-5.00011-5 © 2020 Elsevier Ltd. All rights reserved.

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11.2.1 Hydrolyzable reversibly cross-linked polymeric nanocarriers for drug delivery Hydrolyzable polymers are commonly used material for biomedical, agricultural, and industrial applications. These materials often incorporate ester, anhydride [19–22], acetal [23, 24], ketal [25], or imine [26] in their backbones as hydrolyzable bonds. Biodegradable polymers, such as polylactate (PLA) and polycaprolactone (PCL), have been used to develop hydrolyzable cross-linked nanocarriers for drug delivery. Talelli et al. reported the development of a core cross-linked polymeric micelles with doxorubicin (DOX) covalently loaded in the core [27]. The micellar nanoparticle was composed of methacrylated mPEG-b-p((HPMAm-Lac1)-co-(HPMAm-Lac2)). DOX, in the form of 6-methacrylamidohexanohydrazide-DOX, was covalently loaded in the micellar core via free radical polymerization; up to 30%–40% w/w of DOX could be loaded (Fig. 11.1). The entire DOX payload was released within 24-h incubation at pH 5 and 37°C, whereas only around 5% was released at pH 7.4. This nanoformulation was found to be efficacious in a B16F10 melanoma model. In another nanosystem, Lee et al. [28] created a biocompatible polymeric micelle with pH-hydrolyzable shell cross-links for the intracellular delivery of DOX. The micelle was self-assembled from triblock copolymer of poly(ethylene glycol)-poly(l-­ aspartic acid)-poly(l-phenylalanine) (PEG48-PAsp8-PPhe19). The resulting nanocarrier had three distinct domains: the PEG outer corona, the PAsp middle shell, and the PPhe inner core. In the middle shell the PAsp residues were cross-linked by ketal-containing linkers (Fig. 11.2). Such pH-hydrolyzable ketal cross-linked nanocarrier was able to release DOX rapidly at endosomal pH, resulted in enhanced in vitro cytotoxic activity against MCF-7 breast cancer cells. For the delivery of leuprolide, a gonadotropin-releasing hormone peptide analogue, Hu et al covalently linked the peptide to core cross-linked polymeric micelles (CCLPMs) via two different hydrolyzable ester linkages (Fig.  11.3) to achieve tunable drug release [29]. Compared with the soluble unconjugated peptide, the leuprolide-­ entrapped CCL-PMs had a prolonged circulation half-life and a 100-fold higher area under the plasma concentration-time curve (AUC) value. Due to the hydrolyzable ester linkages, the released peptide remained biologically active as demonstrated by increased and long-lasting plasma testosterone levels. Through these esterase-­sensitive bonds, CCL-PMs not only allow sustained release of therapeutic peptides in blood but also can facilitate targeted delivery of anticancer and antiinflammatory peptides to tumors and inflammatory sites, respectively.

Fig. 11.1  DOX-MA was loaded in the micelles and then copolymerized with the methacrylate groups of the thermosensitive block of mPEG-b-p((HPMAm-Lac1)-co-(HPMAm-Lac2)), resulting in core cross-linked micelles with covalently linked DOX.

Fig. 11.2  Illustration of shell cross-linking of DOX-loaded polymer micelles with a pH-labile ketal cross-linker and intracellular release of DOX triggered by endosomal pH. O H3C

O

O CN O

O

p

m

NH O

NH

O

O O

O

n

n

H

O

Block copolymer

Leuprolide

Linker

Leuprolide derivative

Formation of leuprolide-loaded PMS

Leuprolide-entrapped CCL-PMs

Release of leuprolide

Degradation of block copolymer and CCL-PMs

Fig. 11.3  Synthesis scheme of leuprolide-entrapped CCL-PMs.

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Dynamic hindered urea bonds (HUBs) [22] are hydrolyzable cross-linkages that have been applied to prepare hydrogel and can potentially be introduced to nanocarriers. The HUBs have been shown to be able to reversibly dissociate into bulky amines and isocyanates, the latter of which can be further hydrolyzed, driving the equilibrium to facilitate the degradation of polyureas (Fig. 11.4). Under mild conditions the HUB cross-links can be completely degraded by water.

11.2.2 Redox-sensitive reversibly cross-linked polymeric nanocarriers for drug delivery Redox potential is regarded as a significant property that distinguishes tumor from normal tissues and intracellular microenvironment from extracellular microenvironment. Based on this physiological differentiation, various reduction-sensitive polymeric nanocarriers have been designed, such that they are stable during blood circulation, but drug release can be rapidly and effectively triggered at the tumor sites or inside the tumor cells. Disulfide bond (S-S) is commonly used in such redox-sensitive nanocarriers [30, 31]. Two common approaches have been used to introduce disulfide bonds to the drug delivery system. The first approach is to introduce thiol groups into the polymer and then convert the thiol groups into disulfides via oxidation after the micelles have been formed. The second approach is to use disulfide containing bifunctional linker to establish intramicellar cross-links. In the succeeding text are some examples of reduction-sensitive polymeric nanocarriers for drug delivery.

11.2.2.1 Redox-sensitive reversibly cross-linked nanocarriers assembled from thiol-containing monomers To minimize premature release during blood circulation, we developed redox-sensitive disulfide cross-linked micelles (DCMs) to deliver paclitaxel (PTX), which could be triggered to be released by the endogenous glutathione (GSH) at the tumor [18]. The 50-nm disulfide cross-linked micelles (DCMs), self-assembled from telodendrimer (PEG5kCys4-L8-CA8), were composed of linear PEG and dendrimer of eight cholic acids and four cysteines (Fig.  11.5). Intramicellar disulfide bond cross-linking would occur via O2-mediated oxidization of the thiol groups. In this work, we also introduced the concept

Fig. 11.4  Illustration of hydrolysis mechanism of HUBs.

Fig. 11.5  Schematic representation of the disulfide cross-linked micelles formed by oxidization of thiolated telodendrimer PEG5k-Cys4L8-CA8 after self-assembly.

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of using N-acetylcysteine, an FDA-approved drug, as an exogenous reducing agent to be administered for on-demand drug release from such disulfide cross-linked nanocarriers. Doura et al. [32] recently reported the synthesis of three kinds of thiol-­organosilica hybrid nanoparticles (95–230 nm) composed of 3-mercaptopropyltrimethoxysilane (MPMS) and 3-mercaptopropyl(dimethoxy)methylsilane (MPDMS) (Fig.  11.6). Rhodamine B was used as model payload to characterize the GSH degradability and drug release profile of these nanocarriers. Applications of such nanocarriers for drug delivery, however, remained to be studied.

11.2.2.2 Redox-sensitive reversibly cross-linked nanocarriers via incorporation of disulfide bond-containing cross-linkers Vries et al. [33] designed novel self-assembled and redox-sensitive polymer nanocontainers (PSVss), composed of a cyclodextrin vesicle (PSV) core and a thin reductively cleavable polymer shell anchored through host-guest recognition on the surface of the vesicle (Fig. 11.7). To generate PSVss, cyclodextrin vesicle (CDV) was first prepared through self-assembly of amphiphilic β-cyclodextrin, followed by the introduction of a polymer shell composed of adamantane-functionalized acrylic acid (Ad-PAA). The polymer shell was then further stabilized with disulfide-containing cystamine crosslinker. Live cell fluorescent microscopy studies confirmed cellular uptake of nanocontainers and redox-responsive release of encapsulated hydrophilic payloads such as the pH-probe pyranine and the fungal toxin phalloidin in the cytoplasm. Kim et al. [34] reported a different kind of redox-sensitive polymer micelles with disulfide bond containing ionic core. Block ionomer complexes (BIC) of DOXderivatized poly(ethylene oxide)-b-poly(methacylic acid) (PEO-b-PMA) and divalent metal cations (Ca2 +) were used as templates to prepare the micelles. To introduce disulfide cross-links at the ionic core, ethylcarbodiimide (EDC) followed by cystamine was added (Fig. 11.8). The resulting redox-sensitive cross-linked micelles exhibited

O O

O

SH

Si

SH

Si O

MPMS

O

MPDMS

Thiol O

SH

Si O O

HS

O Si

S

S

Disulfide bond

MPMS-MPDMS hybridNPs

Fig. 11.6  Fabrication of thiol-organosilica NPs, which have disulfide bonds.

O

O

Si O Si

O

Reversible cross-linked polymeric micelles for drug delivery249

Fig. 11.7  Stepwise preparation of a redox-responsive nanocontainer and the redox-triggered release of a hydrophilic payload.

high capacity of DOX loading (50% w/w) and better cytotoxic effects against A2780 ovarian cancer cells, compared with similar micelles with irreversible cross-links. Pandey et al. reported an amphiphilic glycopeptide star copolymer-based disulfide cross-linked nanocarriers that are responsive to redox and enzyme (esterase) stimuli (Fig. 11.9) [35]. This 130–160-nm micellar nanocarrier was formed by self-assembly of an amphiphilic biocompatible miktoarm star copolymer ((PCL50)2 − b-Pr-gly6 − b-GP40), which was composed of two hydrophobic poly(ε-caprolactone) (PCL) blocks, a short

Fig. 11.8  Synthesis of PEO-b-PMA cl-micelles/Cys.

(A)

OH HO

O

O

O

O

Uncrosslinked (UCL) micelles

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(B)

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Uncontrolled release

Targeted drug delivery

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ASGPR receptor

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Interface crosslinked (Icl) micelles

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O

O n

Alkyne group for crosslinking

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Self-assembly

O

O H

Hydrophilic galactose Glycopolypeptied OH O for targeting O NH OH H O N p O H H N m NH

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Fig. 11.9  Synthesized amphiphilic star coglycopolypeptides and their self-assembly into uncross-linked (UCL) and interface cross-linked (ICL) micelles for targeted and controlled drug delivery. (A) Polymer design, self-assembly and crosslinking of amphiphilic star glycopolypeptide copolymer. (B) Receptor mediated and dual stimuli-responsive intracellular drug delivery through ICL micelles.

Reversible cross-linked polymeric micelles for drug delivery251

poly(propargyl glycine) middle block, and a hydrophilic glycolpolypeptide (GP) block containing galactose units to target liver cancer. The alkyne groups of the uncross-linked (UCL) micellar structures were then cross-linked by bis(azidoethy) disulfide (BADS) via click chemistry to form interface cross-linked (ICL) micelles. Cellular uptake, DOX release, and cell kill were observed in HepG2-cells.

11.2.3 pH-sensitive reversibly cross-linked polymeric nanocarriers for delivery purposes In recent years, pH-sensitive cross-linked polymeric nanoparticles have emerged as an important class of nanocarriers for drug delivery based on the subtle pH changes in the human body. The pH in the stomach is pH 1–2 compared with that in the i­ntestine (pH 5–8). The pH of the extracellular tumor microenvironment at the tumor site is slightly acidic (pH 6.5–7.2), while the pH value in blood and normal tissue is about 7.4. The endosome has a pH ranging from 5.0 to 6.5, and the pH in lysosome is even lower, varying between 4.5 and 5.0. The pH-sensitive cross-linked polymeric nanoparticles can target tumor sites or the organelles inside the tumor cells, followed by release of therapeutic payload, according to the physiological pH at these sites within the body [36–38]. For example, Liu et al. developed a well-defined poly[(ethylene oxide)-block-2-(dimethylamino)ethyl methacrylate-block-2-(diethylamino) methacrylate] (PEO-DMA-DEA) triblock copolymer, which was found to dissolve molecularly in aqueous solution at low pH, but at pH 7.1, it formed three-layer “onion-like” micelles composed of DEA cores, DMA inner shells, and PEO coronas [39]. Cross-linking of the inner shell by 1,2-bis(­2iodoethoxy)ethane (BIEE) resulted in an increase in hydrophilicity and colloid stability of the nanocarrier. At low pH the DEA cores became protonated and therefore more hydrophilic. Chan et al. reported another type of acid-sensitive core cross-linked micelle for pH-triggered drug release. It was prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization of poly(hydroxyethyl acrylate)-block-poly(n-­butyl acrylate) (PHEA-b-PBA) and an acid-labile cross-linker [14]. The cross-linked core of the micelles could be triggered to disintegrate at acidic pH. Due to the π-π interactions between DOX and the cross-linker’s phenyl ring, this nanoplatform was found to display high drug loading capacity (up to 60 wt% of the copolymer weight). Drug release rate at acidic pH was found to be significantly higher than that at neutral pH. Du et al. reported a type of polymeric vesicle with pH-tunable membrane permeability. The 210–360-nm vesicles were formed by self-assembly of a pH-responsive self-cross-linkable copolymer poly(ethylene oxide)-block-poly[2-(diethylamino) ethyl methacrylate-stat-3-(trimethoxylsilyl) propyl methacrylate] (PEG-b-P(DEAs-TMSPMA)) [40]. The walls of the vesicles swelled along with the protonation of the DEA residues under pH 7, promoting drug release. Zhao et al. developed a type of 3-carboxy-5-nitrophenylboronic acid (CNPBA) shell cross-linked micelles based on the amphiphilic dextran-block-polylactide (Dex-b-PLA) for efficient intracellular drug deliveries [41]. Due to the reversible pH-dependent ester bonds between diols and boronic acid, CNPBA-modified Dex-b-PLA showed excellent pH sensitivity. Under neutral aqueous conditions, CNPBA-Dex-b-PLA formed shell crosslinked m ­ icelles to enable DOX loading. Under acidic condition the boronate ester

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c­ ross-links hydrolyzed to release loaded DOX. In vitro release studies indicated that the release of the DOX cargo was low under physiological conditions but with a burst of drug release in response to acidic pHs. In vitro cellular toxicity of CNPBA-Dexb-PLA was low.

11.2.4 Multiresponsive reversibly cross-linked polymeric nanocarriers for delivery purposes Considering the complexity of the in vivo microenvironment, novel reversibly crosslinked polymeric nanocarriers with multiresponsiveness properties have been designed for precise drug delivery. These cross-linked polymeric nanocarriers respond to multiple stimuli, for example, pH/sugar (cis-diol), pH/reductive, pH/temperature, and temperature/reductive, will be discussed in the following sections.

11.2.4.1 pH and sugar dual-responsive reversibly cross-linked polymeric nanocarriers A few years ago, we first introduced a novel class of pH and diol dual-responsive cross-linked micelles using a facile cross-linking strategy based on boronic acid-­ catechol interactions [17]. The stability of the telodendrimer micelles was improved by cross-linking with boronate esters at the core-shell interface. The cross-linking reactants (i.e., boronic acid and catechol) were each introduced to separate amphiphilic telodendrimers through stepwise peptide chemistry (Fig.  11.10). Reaction between boronic acid and catechol of distinct telodendrimers in aqueous conditions took place concomitantly to the self-assembly of the telodendrimers into micelles, resulting in boronate ester cross-linked micelles. This novel nanocarrier shows great promise for drug delivery with minimal premature drug release at physiological glucose level (2–10 mM) and physiological pH 7.4 during blood circulation but can be activated to release drug on demand at the acidic tumor microenvironment or in the acidic intracellular compartments upon uptake in target tumor cells and/or by intravenous administration of mannitol, an FDA-approved drug, as an on-demand triggering agent. Ren et al. also introduced boronate ester cross-linking bonds into the core of micelles [42]. They developed a series of biocompatible pH-/sugar-sensitive core crosslinked polyion complex micelles based on phenylboronic acid-catechol interaction for intracellular delivery of protein. This nanoplatform composed of two polymers, poly(ethylene glycol)-b-poly(glutamic acid-co-glutamicamidophenylboronic acid) (PEG-b-P(Glu-co-GluPBA)) and poly(ethylene glycol)-b-poly(l-lysine-co-ε-3,­4dihydroxyphenylcarboxyl-l-lysine) (PEG-b-P(Lys-co-LysCA)) copolymers, which under aqueous condition could self-assemble into uniform micelles with PEG outer shell and the PGlu/PLys polyion complex core bearing boronate ester cross-linking bonds (Fig. 11.11). The cross-linked micelles were found to be stable under physiological condition but swell and disassemble in the presence of excess fructose or at endosomal pH. Either negatively or positively charged proteins could be nanoencapsulated ­efficiently under mild conditions. Burst ­release of protein occurred in response to

B

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4-Carboxyphenylboronic acid

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Fig. 11.10  Schematic representation of the telodendrimer pair (PEG5k-[boronic acid or catechol]4-CA8) and the resulting boronate cross-linked micelles in response to mannitol and/ or acidic pH values.

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Nanoengineered Biomaterials for Advanced Drug Delivery

Fig. 11.11  Illustration of protein-loaded core cross-linked PIC micelle formation and intracellular protein delivery triggered by endosomal pH.

e­ xcess fructose or endosomal pH. Cytochrome c encapsulated with this nanoplatform was able to enter HepG2 cells to induce apoptosis.

11.2.4.2 pH and reductive dual-responsive reversibly cross-linked polymeric nanocarriers Chen et al. developed a novel class of responsive cross-linked polymeric micelles that are responsive to acidic and reductive stimuli (Fig. 11.12) [43]. The 60–100-nm micelles were self-assembled from reducible poly(β-amino ester)-poly(ethylene glycol) copolymers, composed of PEG, 2,2′-dithio-diethanol diacrylate, and 4,4′-trimethylenedipiperidine. Codisplaying disulfide bonds and tertiary amines on the backbone of poly(β-amino ester) resulted in the formation of pH and reduction dual-sensitivity micelles. Encapsulated DOX could be released by lowering pH to 6.5 or addition of 2.5–5-mM dithiothreitol. Combination of dithiothreitol and lowering of pH could further enhance drug release. The tertiary amines in the core prevented the loaded DOX from diffusing out of the micelles at physiological pH by maintaining the coreshell structure. Shuai et al. created a highly packed interlayer cross-linked micelle (HP-ICM) with pH and reduction dual sensitivity based on a triblock copolymer of monomethoxy polyethylene glycol (mPEG), 2-mercaptoethylamine (MEA)-grafted poly(l-­aspartic

Reversible cross-linked polymeric micelles for drug delivery255

Reducible poly(βaminoester)s backbone (RPAE) Ionized reducible poly(β-aminoester)s backbone

pH < 6.5

Self-assembly in aqueous solution (pH > 7) High level DTT concentration

High level DTT concentration and pH < 6.5 Poly(ethylene glycol) chain (PEG)

Doxorubicin (DOX)

Fig. 11.12  Schematic illustration of DOX-loaded RPAE-PEG copolymeric micelle dissociation and release of DOX upon changes of pH value, reducing agent concentration or dual factors.

acid) (PAsp(MEA)), and 2-(diisopropylamino)ethylamine (DIP)-grafted poly(l-­ aspartic acid) (PAsp(DIP)) [36]. Poly(BLA) aminolysis with MEA and DIP was utilized to introduce cross-linkable thiol and pH-sensitive tertiary amino groups into the middle and end blocks of the copolymer, respectively. The resulting HP-ICM was highly stable, and drug release rate was extremely low at pH 7.4. However, in the presence of reducing agent and an acidic pH (~ 5), HP-ICM dissociated, resulting in drug release. Using similar strategy, Shuai et al. prepared mPEG-PAsp(MEA)-PEI for nanoencapsulation and delivery of siRNA [44]. Such pH-responsive nanoplatform is negatively charged at neutral pH of bloodstream and positively charged at acidic pH of tumor tissue (~ 6.8). Interlayer cross-linking with disulfide bonds stabilizes the nanocarrier during blood circulation but allows quick intracellular siRNA release after endocytosis. Wu et al. reported a series of galactose-based ­glycopolymer-DOX conjugates (GPDs) capable of self-assembly and disulfide cross-linking at the core to form micellar nanoparticles. DOX was covalently linked to the polymer at the core via disulfide and boronic ester bonds. The free galactose-containing units gathered on the surface of GPD NPs targeted the asialoglycoprotein receptor overexpressed on the surface of hepatocellular carcinoma. The resulting nanoparticles and encapsulated DOX were found to be stable under physiological environment but could rapidly release the drug inside endosomes of hepatocarcinoma cells, which are reductive and acidic [45].

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11.2.4.3 pH and temperature dual-responsive reversibly crosslinked polymeric nanocarriers Xu et  al. reported a pH and temperature dual-responsive polymeric nanocarrier, composed of triblock copolymer, α-methoxypoly(ethyleneoxide)-b-poly(N-(3-aminopropyl)methacrylamide)-b-poly(N-isopropyl-acrylamide) ­(mPEO-PAPMA-PNIPAM) [26]. The polymer was hydrophilic in aqueous solution at room temperature. However, when the solution temperature was increased to above the lower critical solution temperature (LCST) of the PNIPAM block, the copolymers could self-assemble into micelles with PNIPAM cores, PAPMA shells, and mPEO coronas. To generate shell cross-linked micelles with cleavable imine linkages, the PAPMA shell was cross-linked with terephthaldicarboxaldehyde (TDA) at pH 9.0. The model hydrophobic drug prednisolone 21-acetate (PA) was found to release from the swollen micelles at pH  310 nm. The styrene and dimethylaminoethyl methacrylate (DMAEMA) were grafted to the surface of the nanoparticles via atom transfer radical polymerization (ATRP). The resulting nanoparticles were sensitive to the changes in pH and temperature as well as UV irradiation. Zhang et al. reported the synthesis of dual pH- and t­emperature-sensitive cross-linked p­ olymeric ­nanocarriers based

H

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Triblock unimers and drug(PA)

PA-loaded micelles

PA-loaded SCL micelles

Dissociated SCL micelles and released PA

Fig. 11.13  Cross-linking, cleavage, and recross-linking of mPEO113-PAPMA12-PNIPAM136 triblock copolymer micelles in aqueous solution triggered by changing the solution pH.

Reversible cross-linked polymeric micelles for drug delivery257

on the self-assembly of thermoresponsive block copolymer (PAGA180-b-PNIPAAM350) [47]. 3,9-Divinyl-2,4,8,10-tetraoxaspiro[5.5]-undecane was used as an acid-labile crosslinker to generate the dual-sensitive cross-linked nanoparticles. The resulting micelles were very stable at pH ranging from 6 to 8.2 but could be degraded at acidic conditions. Jiang et al. developed a triblock copolymer, poly(2-(diethylamino)ethyl methacrylate)-b-poly(2-(dimethylamino)ethyl methacrylate)-b-poly(N-isopropylacrylamide) (PDEA-b-PDMA-b-PNIPAM), containing the well-known pH-responsive PDEA block and thermoresponsive PNIPAM block [48]. The obtained triblock ­copolymer self-­assembled into three-layer “onion-like” PNIPAM-core micelles at acidic pHs and elevated temperatures and PDEA-core micelles with “inverted” structures at alkaline pHs and room temperature. Cross-linking the PDMA inner shells of these micelles with 1,2-bis(2-iodoethoxy)ethane yielded a novel nanocarrier with pH-responsive PDEA cores and thermoresponsive PNIPAM coronas. Drug release could be dually controlled by both solution pH and temperature (Fig. 11.14).

11.2.4.4 Temperature and reductive dual-responsive reversibly cross-linked polymeric nanocarriers A core cross-linked micelle system possessing sensitivity to temperature and reduction was reported by Jiang et  al. These micelles were synthesized in a one-pot manner via RAFT copolymerization of N-isopropylacrylamide (NIPAM) and bis(2-­ methacryloyloxyethyl) disulfide (DSDMA) difunctional monomers using PAEMA as the macromolecular RAFT agent [49]. The amino groups of the outer coronas of the micelles were decorated with carbohydrate and biotin for targeting. The temperature and reduction sensitivity of the micelles were demonstrated via the rupture of disulfide bonds in the presence of dithiothreitol and the shrinking of micelle cores when heating above the phase transition temperature of PNIPAM.

PNIPAM-core micelles at 40°C, pH 5

PDEA-b-PDMA-b-PNIPAM unimers at 25°C, pH 5

PDEA-core micelles at 25°C, pH 9

Shell cross-linking BIEE, 25°C, 3 d

SCL miscelles with collapsed PNIPAM coronas at 40°C, pH 9

SCL micelles with PDEA cores at 25°C, pH 9

SCL micelles with swollen PDEA cores at 25°C, pH 5

Fig. 11.14  Schizophrenic micellization behavior of the PDEA-b-PDMA-b-PNIPAM triblock copolymer in aqueous solution.

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11.3 Summary Many reversibly cross-linked polymeric nanocarriers have been developed by taking advantages of the unique endogenous and exogenous stimuli that can be applied in clinical settings for precise regulation of drug release at the disease sites. Different cross-linking strategies are actively investigated to develop patient-friendly, biocompatible, highly-efficient, well-defined, reversibly cross-linked nanocarriers to improve the efficacy of chemotherapy in cancer treatment. Although promising, addition of stimulus-responsive cross-linkers to the nanocarrier will add complexity and cost to their preparation. Therefore robust processes that can facilitate the scale-up synthesis and manufacturing of these cross-linked polymeric nanocarriers will undoubtedly be needed for their translation into the clinics.

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Polymeric micelles as delivery systems

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Shuang Bai, Xiaoqian Ma, Tian Zhang, Yong-E Gao, Yajun Wang, Yuan Gao, Zhigang Xu School of Materials and Energy, Southwest University, Chongqing, People’s Republic of China

12.1 Introduction Organism delivery systems have been intensively investigated since it is an intelligent technical system controlling the in vivo distribution of molecules in space, time, and dose. More specifically, it is designed for delivering the functional molecules to the designated sites at appropriate time, thus maximizing the utilization efficiency, improving the curative effects, lowering the cost, and minimizing the side effects [1–3]. In the past few decades, several well-designed drug delivery systems have attracted increasing attentions from researchers in many fields, such as medical science, engineering technology, and materials science [4]. Among a large number of candidate materials for delivery purposes, the polymeric micelles (PM) have afforded promising opportunities in the development of novel delivery systems due to the tailorability endowed by polymer synthesis, functional mode, micelle formation mode, property, and composition. At present, PM have been widely applied as controlled delivery systems in medicine, bioimaging, and biomimicry. There is extensive theoretical and experimental research. In particular the PM-based delivery systems have been considered as the mainstay of in vivo diagnosis and treatment of many diseases, achieving some successful clinical applications. Stimuli-responsive polymeric prodrug introduces special design strategy. Intelligent and precise drug release can be realized responding to stimulus factors, such as external stimulus (e.g., temperature, light, ultrasound, and electric and magnetic fields) [5, 6] and tumor microenvironment (TME) stimulus (e.g., pH, glutathione, GSH, reactive oxygen species, ROS, unique enzymes, hypoxia, and adenosine triphosphate, ATP) [7–10]. Furthermore, there are many additional advantages in the polymers, such as small particle size, adjustable hydrophilicity and lipophilicity, prolonged blood circulation, reduced immunogenicity, enhanced security, increased delivery efficacy, and improved pharmacokinetic (PK). In addition, PM exhibits even higher loading rate and stability compared with other delivery systems, such as liposomes, dendrimers, and hyperbranched nanoparticles [11]. In this section, we will give a detailed description of the origin, development, application, and expectation of PM. The novel PM design approaches would be introduced and explored from an innovative perspective and framework.

Nanoengineered Biomaterials for Advanced Drug Delivery. https://doi.org/10.1016/B978-0-08-102985-5.00012-7 © 2020 Elsevier Ltd. All rights reserved.

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12.2 Polymeric micelles 12.2.1 Classification of polymer micelles According to the principles of self-assembly, PM involved in the drug carriers can be divided into block polymer micelles, graft copolymer micelles, polyelectrolyte copolymer micelles, and noncovalently connected micelles. These PM systems would be introduced in detail as follows.

12.2.1.1 Block polymer micelles For block polymer micelles, copolymers with both hydrophilic and hydrophobic chains can be self-assembled into polymer micelles in aqueous solutions. These micelles show a unique core-shell structure, with hydrophobic core and surrounding hydrophilic shells in aqueous solutions. The most commonly applied hydrophilic chains are polyethylene glycol (PEG), polyoxyethylene (PEO), and polyvinylpyrrolidone (PVP). Hydrophobic segments are generally hydrophobic drugs (such as camptothecin and paclitaxel), near-infrared dyes, and targeted agents.

12.2.1.2 Graft copolymer micelles Due to the applications of different monomers as main and branch chains, graft copolymers can provide two or more opposite properties, such as oil/water affinity, acidity/ alkalinity, and plasticity/elasticity. Meanwhile the graft copolymer can also form a stable core-shell structure in water. For example, we have reported on a graft polymer based on cyclodextrin polyrotaxanes (CD-PRs) backbone chain, which realized the delivery of the anticancer drug doxorubicin (DOX) [12].

12.2.1.3 Polyelectrolyte copolymer micelles Some water-soluble block copolymers can be aggregated to form micelles in aqueous solution by electrostatic interaction, hydrogen bonding, or metal coordination. A flexible hydrophilic polymer block (usually PEG) forms a tethered chain assembly of dense bars, wrapped in the kernel, maintaining the space stability of the micelles. The core is formed by the aggregation of some blocks of the copolymer, and the nucleation process is the result of the intermolecular interactions (including hydrophobic action, electrostatic action, metal complexation, and interblock copolymer hydrogen bonding) [13]. For example, in 1999, Albert S and partners systematically characterized the structure of pH-dependent polyelectrolyte block copolymer micelles with fluorescence spectroscopy, dynamic light scattering, and small-angle neutron scattering, providing detailed and unique opinions into the structures of polyelectrolyte copolymer micelles [14].

12.2.1.4 Noncovalently connected micelles In the noncovalently connected micelles, the main force for connecting the core and shell is the hydrogen bond force. This approach can be directly applied for molecule assembly of random copolymers or modified polymers without the need to prepare

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block copolymers or graft copolymers. It can be applied to a variety of polymer systems in organic solvents or aqueous media [15]. For instance Orfanou and coworkers investigated the noncovalent-bonded polymeric micelles characteristics by a combination of static and dynamic laser light scattering [16].

12.2.2 The preparation method of PM The preparation of PM depends on the water solubility of polymers, while the formation of micelles would also be affected by the preparation strategy. Thus an appropriate method should be selected according to the properties of polymers. In recent years the development of nanomicelles is growing maturity, and there are several applicable methods for preparing micelles. Generally, direct dissolution method and dialysis method have been the two most common approaches [17].

12.2.2.1 Direct dissolution method In the direct dissolution method, polymers with good water solubility form micelles by dissolution, which is also the simplest way. Specifically the copolymer is dissolved in water or PBS directly by heating, mixing, or ultrasonic. For example, Wu et  al. reported large anisotropic micelles that were prepared by direct dissolution method, water-­soluble polymers dissolved in aqueous solution without heating or any other auxiliary organic solvent [18]. They interpreted the formation process of anisotropic micelles in aqueous solution. Similarly, Zepon et al. studied the self-assembly of polymers in solution state. They fully investigated the morphologies, size, and properties by dynamic light scattering, transmission electron microscopy, atomic force microscopy, and nanoparticle tracking analysis [19]. Furthermore, for single amphiphilic macromolecule, the unimolecular micelles can be obtained in organic solvent (e.g., N,N-dimethylformamide, DMF) or in water solution. The unique hydrophobic core could be served as a warehouse for controlling the drug load and release behaviors [20].

12.2.2.2 Dialysis method Selb and Gallot firstly performed a comprehensive and detailed analysis on micelles in aqueous solutions. They founded that the hydrophilicity of most block polymers was limited when being dissolved in water directly [21]. Since then, dialysis method started to be widely applied. Its detailed steps are as follows: dissolving polymers in organic solvents (e.g., dimethyl sulfoxide, acetone, and tetrahydrofuran) and then removing organic solvents by dialysis to obtain stable micelles. For example, Xu et  al. prepared various types of monomolecular micelles by dialysis method [22]. Furthermore, Jun and coworkers discussed the effects of the preparation methods on PM formation [23]. Investigators compared and discussed the dialysis method and direct dissolution method in preparing amphiphilic micelles.

12.2.3 Characteristics and advantages of PM system In recent years, nanoscale drug delivery systems based on different strategies have become the research hot spot for tumor treatment. For most nanodrug delivery

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s­ ystems, antitumor drugs are physically embedded or adsorbed and naturally released. Obviously, such a delivery system can be accompanied with nonselective drug leakage during blood circulation, leading to the toxic and side effects on normal tissues. PM system shows outstanding performances for this issue. The function of the polymers can be modified by chemical bond, thus realizing the multifunction, intelligence, safety, and high efficiency in the prodrug. In addition, the prodrug can be synthesized into delivery systems responsive to pH, GSH, ROS, enzyme, or multiple factors. Further, polymers can carry not only drugs for treatment but also near-infrared dyes for medical integration, DNA for gene therapy, and so on. In terms of performance the polymers exhibit multiple advantages, such as adjustable hydrophilicity and lipophilicity, prolonged blood circulation period, reduced immunogenicity, enhanced security, increased delivery efficacy, and improved pharmacokinetic (PK). From aforementioned results the nanomaterial-based PM can provide broad prospects for advanced therapeutics.

12.3 PM for drug and gene delivery 12.3.1 pH-responsive PM delivery systems During the past few decades, stimuli-responsive PM have been gained increasing attentions. As we know, the pH of most tumors is 6.5, which is lower than the pH of 7.4 in normal tissues. In addition, the pH of the introns and lysosomes in the tumor cells was even as low as 5.0–5.5 [24]. Hence, pH-responsive delivery systems have become a promising research hot spot. Generally, pH-responsive drug delivery systems realized the load and delivery of hydrophobic anticancer drugs mainly via hydrazone bond [25], coordination bond [26], ester bond [27], acetal bond [28], acid alterable monomer or functional group [29], electrostatic action [30], and covalent bond connection or physical adsorption. The pH sensitivity can be achieved by either the protonation of ionizable groups or the degradation of acid-cleavable bonds. Dai's group reported a dual pH-responsive drug delivery system, which synthesized from the self-assembly of a block copolymer (PDPA-b-P(FPMA-co-OEGMA)) (Fig. 12.1) [31]. The amino group of DOX reacted with aldehyde group of the polymer to form the imine bond. Owing to the protonation of the tertiary amine at pH 6.5, the DOX-loading micelles exhibited significant charge conversion ability, namely, negative charge switched to positive charge in weak acidic condition, which enhanced cellular uptake. Moreover the imine bond was cleaved at pH of lower than 5.5, thus achieving controllable release of DOX. Therefore the targeted delivery of anticancer drugs can be achieved in above pH-responsive delivery systems. In addition, the biocompatibility was superior for improving the efficiency of chemotherapy drugs and minimizing the toxicity. Messersmith’s group embedded the anticancer drug of bortezomib (BTZ) into 1,2-benzenediol (catechol) moiety through dynamic covalent chemistry. A membrane impermeable catechol presenting polymers can be formed to reduce cytotoxicity from nonselective cellular uptake of the drug, which was reversible in a pH-sensitive

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Fig. 12.1  Structure of BCP-DOX and the pH-targeted charge-conversion process. Reproduced from J. Mao, Y. Li, T. Wu, C. Yuan, B. Zeng, Y. Xu, et al., A simple dual-pH responsive prodrug-based polymeric micelles for drug delivery, ACS Appl. Mater. Interfaces 8 (2016) 17109–17117. Copyright 2016 American Chemical Society.

manner [32]. Specifically, at neutral or alkaline pH, BTZ and catechol form a stable boronate ester, which deactivated the cytotoxicity of BTZ. However, the BTZ catechol ester conjugate readily dissociated to release free BTZ and catechol groups in a low-pH condition, which realized localized drug release in the mild acidic tumor environment. By involving biotin to target cancer cells, the proteasome inhibitor BTZ can be precisely delivered to tumor cells by such polymeric carriers, thereby potentially promoting the efficacy and lowering the toxicity of BTZ. Besides, Qu’s group introduced controlled polymerization to prepare a kind of hydrophilic stimuli-responsive triblock copolymer [poly (PEGMEMA)-b-PDMAEMAb-PtBMA] with high doxorubicin (DOX)-loading efficiency of up to 50 wt% [33]. Anticancer drug of DOX was passively wrapped in the nanoparticles by electrostatic interaction. The micelles showed good stability at physiological pH and could rapidly release drug at intracellular pH. At pH 7.0 the DMAEMA as “gating” shell ensured low drug leakage, while below pH 6.0, the MAA core allowed rapid drug release due to physical shrinkage.

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In conclusion, pH-responsive polymeric drug delivery system can effectively realize the controlled release of drug and avoid unexpected drug leakage in blood circulation and normal tissues. It aimed to achieve high therapeutic effects and minimize toxicity.

12.3.2 Reduction-responsive PM delivery systems Compared with healthy tissues the tumor microenvironment was remarkably abnormal [34]. It has been reported that the level of GSH in tumor cells was 100-fold higher than that of corresponding normal tissues [35]. Taking advantage of this physiological difference, scientists have explored numerous redox-responsive nanocarriers, including micelles, liposomes, proteins, and inorganic nanomaterials [36]. Of these nanocarriers, PM attracted special attentions. In general, there are three routes to construct polymer-based reduction-sensitive drug carriers: (1) self-assembly of drug molecules with block copolymers containing reduction-responsive chemical bond, (2) physical encapsulation of reduction-responsive small molecule drugs with polymers, and (3) conjugation of drug molecules with polymer by reduction-responsive chemical bonds. Some of these nanomaterials have been approved by the Food and Drug Administration (FDA) and applied in the clinic. Disulfide bonds [37, 38], diselenium bonds [39], and succinimide-thioether bonds were frequently used inducements for reduction-responsive delivery systems [40]. Among them, disulfide bonds are susceptible to reductive agent such as GSH, cysteine, and ferrous ion, which are abundantly present in tumor microenvironment. Xu and colleagues constructed a redox-sensitive starburst polyprodrug (CCP)-based unimolecular micelles, providing high drug loading capacity and excellent stability for enhancing effects of chemotherapy. The camptothecin (CPT) grafted in polyprodrug CCP could be released under reductive tumor microenvironment (Fig.  12.2) [37]. The in vitro and in vivo results indicated that the polyprodrug CCP exhibited increased tumor accumulation, inhibitory tumor growth, and enhanced in  vivo biosafety. Additionally, Zhang et al. developed a redox-sensitive delivery system based on hyaluronic acid-deoxycholic acid (HA-ss-DOCA) conjugates for targeted intracellular delivery of paclitaxel [41]. Many cross-linkers containing disulfide bonds can be applied to cross-link polymer micelles, thus improving the stability of polymer micelles. These nanoparticles can be decross-linked in reductive environment to promote the release of drugs from the gel matrix. Lee et  al. prepared cross-linked polymer micelles (SCMs) with GSH-responsive shell by cross-linking PEG-b-PLys-b-PPha with 3,3′-dithiobis (sulfosuccinimidylpropionate) (DTSSP), which facilitated the release of entrapped anticancer drugs under intracellular glutathione level [42]. Further investigation verified the enhanced therapeutic efficiency of SCMs in this study compared with the conventional ones.

12.3.3 ROS-responsive PM delivery systems ROS, a series of reactive ions and free radicals such as singlet oxygen (1O2), hydroxyl radical (OH), hydrogen peroxide (H2O2), superoxide (O2 −), and hypochlorite ion (OCl−), play important roles in regulating cell signaling pathway and promoting cell

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Fig. 12.2  (A) Illustration of the synthesis and formation process of GSH-responsive starburst polyprodrug (CCP) and (B) the enhanced permeability and retention effect (EPR)-mediated cell uptake and tumor enrichment for enhancing the efficacy of chemotherapy. Reproduced from X. Shi, M. Hou, X. Ma, S. Bai, T. Zhang, P. Xue, et al., Starburst diblock polyprodrugs: reduction-responsive unimolecular micelles with high drug loading and robust micellar stability for programmed delivery of anticancer drugs, Biomacromolecules 20 (2019) 1190–1202. Copyright 2019 American Chemical Society.

proliferation [43]. In general, ROS can be generated from both endogenous and exogenous sources. Mitochondria, endoplasmic reticulum, and NADPH oxidase are the three major intracellular sites that produce ROS. However, excessive ROS can lead to nonspecific impairment of proteins and DNA, thus inducing several diseases [44]. The intracellular ROS levels would be higher in tumor microenvironment compared with that of healthy tissue. Making full use of the unique property, a variety of drug delivery systems sensitive to ROS have been exploited and investigated for the biomedical applications, including, but not limited to, inorganic nanoparticle-based systems, liposomes, hydrogels, vesicles, and polymer-based nanocarriers. Recently, sulfur-containing linkers such as thioether, thioketal, and vinyl dithioether have been utilized to develop ROS-sensitive delivery system that delivered chemotherapeutic drugs or photosensitizer to cancer cells. The sulfur-containing linkers

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can be rapidly cleaved by ROS oxidants [45]. Owing to the higher ROS levels inside tumor cells, copolymers undergo hydrophobic-hydrophilic transition, thus inducing specific endosome escape in cancer cells. The ROS-responsive micelles not only preserved the bioactivity of the payload but also exhibited selective cytotoxicity in cancer cells over normal cells. By incorporating ROS-responsive linkers, such as boronic ester, selenium/tellurium, polyproline, thioether, and thioketal, a wide range of polymeric nanoplatform has been designed for realizing tunable drug release. For example, Hu and colleagues reported the ROS-responsive polyprodrug nanoreactors with cleavable thioketal functional moiety (Fig. 12.3), which could realize mitochondrion-specific drug release and mitochondrial ROS upregulation, resulted in an enhanced efficacy of chemotherapy [44]. Besides cancer treatment, this design strategy is also promising in the treatment of other ROS-related diseases. The polyprodrug nanoreactors provided endogenously

Fig. 12.3  The mitochondrion-specific and dual-targeting polyprodrug for self-circulated drug release with ROS burst. Reproduced from W. Zhang, X. Hu, Q. Shen, D. Xing, Mitochondria-specific drug release and reactive oxygen species burst induced by polyprodrug nanoreactors can enhance chemotherapy, Nat. Commun. 10 (2019) 1704. Copyright 2019 American Chemical Society.

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activated therapeutic amplification, and we anticipated that it would contribute to the development of theranostics with superior performance. In addition, several ROS-responsive drug delivery systems have been developed based on monoselenide, since the hydrophobic monoselenide can be transformed to hydrophilic selenone or selenoxide under oxidative conditions. Yan and colleagues constructed a selenium-containing (HBPSe) nanocarrier for achieving hydrogen peroxide-triggered DOX release (Fig. 12.4) [46]. The nanocarrier was composed of hydrophobic selenide groups and hydrophilic phosphate segments in the dendritic backbone. The ROS levels would be elevated in cancer cells, leading to phase transition of selenide groups from hydrophobic to hydrophilic, thus realizing fast and selective intracellular drug release. Like organoselenium compounds, organotellurium compounds have been described as promising agents for tuning the ROS levels, since they could be oxidized from the divalent to the tetravalent state. Xu and coworkers reported a tellurium-containing polymer micelle system, which was self-assembled into core-shell micelles in aqueous solution [47]. After treating with ultra-low concentration of H2O2 (100 μM) or clinically relevant dose of γ-ray radiation (2 Gy), these tellurium-containing polymeric micelles were rapidly swelled, and the particle size was instantly increased. The marked ROS responsivity of tellurium-containing micelles under the aforementioned two conditions indicated that it might be a promising nanoplatform integrated both chemo- and radiotherapies. Many other types of ROS-responsive drug delivery system were also applied in drug delivery, such as aminoacrylate, peroxalate ester, and polyproline [48, 49].

Fig. 12.4  Synthetic routes of multicore/shell micelle for H2O2-triggered drug release and cancer therapy. Reproduced from J. Liu, Y. Pang, Z. Zhu, D. Wang, C. Li, W. Huang, X. Zhu, D. Yan, Therapeutic nanocarriers with hydrogen peroxide-triggered drug release for cancer treatment, Biomacromolecules 14 (2013) 1627–1636. Copyright 2013 American Chemical Society.

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12.3.4 Dual-responsive PM delivery systems Although stimuli-responsive PM-based nanomedicines show promising application prospects, most of them have been limited by the targeting effects. Multiple ­stimuli-responsive structure would be modified on the surface of nanomedicines to enhance the targeting ability. For instance Wang’s group developed a tumor ­acidity-sensitive clustered polymeric drug delivery system [50]. Under acidic microenvironment the PEG surface could be escaped, and PAMAM-Pt micelles with positive charge would be released, which could promote the cellular uptake. After entering cells the grafting Pt drug could be further escaped from PAMAM-Pt micelles under reductive environment. It was interesting that the designed cluster/Pt micelles showed an improved tumor penetration ability, prolonged blood circulation period, and enhanced chemotherapy efficacy. Furthermore, Chen and coworkers reported a hierarchical tumor microenvironment-responsive nanomedicine (HRNM) for programmed drug delivery [51]. Firstly, authors designed one polyprodrug of poly(2-(­hexamethyleneimino)-ethyl methacrylate)-poly(oligo(ethylene glycol) monomethyl ether methacrylate)-poly (reduction-responsive camptothecin) (PC7A-POEG-PssCPT), which could be self-­ assembled into water-soluble micelles. Further the targeting moiety of RGD endowed HRNMs with prolonged blood circulation. Under acidic tumor tissue the hydrophobic PC7A could be protonated and converted into hydrophilic block with positive charge, which further improved the uptake efficiency. Finally, for the dual-responsive PM delivery system, the grafted drug of CPT could be released from HRNMs under a GSHtriggered model, reaching an enhanced chemotherapy efficacy. Furthermore, Shen and coworkers reported a γ-glutamyl transpeptidase (GGT)-responsive and glutathione (GSH)-responsive polymer-camptothecin (CPT) conjugate with a long blood circulation for augmenting the tumor penetration and enhanced chemotherapy (Fig. 12.5) [52]. When the obtained CPT nanomedicine was contacted the tumor cells, the feature of GGT-mediated cationization will lead to a rapid caveola-mediated endocytosis effect (Fig. 12.5A), which could effectively release most of drugs and improve the drug distribution in tumor cells. Additionally, part of CPT release is subjected to a GSHtriggered model (Fig. 12.5B) and the conjugate showed a GGT-catalyzed hydrolysis process (Fig. 12.5C). This tumor m ­ icroenvironment-responsive nanomedicine might provide a novel strategy for the development of therapeutic polymers based on physiological signals.

12.4 PM for fluorescent dye delivery Besides therapeutic agents the delivery of fluorescent dye is also an important technique for visualizing or monitoring the internal structure and dynamic processes of living bodies, which could be further utilized for early diagnosis of tumors [53]. Several technologies with own characteristics have been developed to meet the clinical needs [54]. Traditional bioimaging techniques such as magnetic resonance imaging (MRI), positron emission tomography (PET), X-ray computed tomography (CT), photoacoustic imaging, ultrasound imaging, single-photon emission computed

Fig. 12.5  Scheme and characterization of γ-glutamyl transpeptidase (GGT)-responsive and glutathione (GSH)-responsive nanomedicine for enhanced chemotherapy efficacy. Reproduced from Q. Zhou, S. Shao, J. Wang, C. Xu, J. Xiang, Y. Piao, et al., Enzyme-activatable polymer–drug conjugate augments tumour penetration and treatment efficacy, Nat. Nanotechnol. 14 (2019) 799–809. Copyright 2019 Springer Nature.

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1.2 pHe/pHi

“OFF” state

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Polymers: O O

R=

O

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R PEG114-b-(PR-r-NIR)

NIR

8.5

8.0

7.5

7.0

6.5

6.0

5.5

5.0

pH

Fig. 12.6  Synthesis and characterization of pH-responsive nanoprobes. Reproduced from Y. Wang, K. Zhou, G. Huang, C. Hensley, X. Huang X. Ma, et al., A nanoparticle-based strategy for the imaging of a broad range of tumours by nonlinear amplification of microenvironment signals, Nat. Mater. 13 (2014) 204–212. Copyright 2013 Springer Nature.

t­omography (SPECT), polymeric fluorescent probes show their own merits, such as low cost, prominent sensitivity, wide applicability, favorable biocompatibility, multichannel detection ability, excellent cell and tumor penetrability, and noninvasiveness [55]. Therefore, as a diversified and effective imaging method, fluorescent probes exhibit great application prospects in clinical practices. For example, Wang and coworkers established the pH-responsive and nontoxic fluorescence nanoreporters, with which the signals in tumor microenvironment could be nonlinearly amplified (Fig. 12.6) [56]. Nanotechnology has dramatically promoted the development of fluorescent probes [57]. Many fluorescent probes have been synthesized and applied for bioimaging, including organic dyes [58], fluorescent proteins [59], metal complexes [60], semiconductor nanoparticles [61], and other nanoparticles [62]. Among them, organic dyes are most widely applied as prominent scaffold of fluorescent probes. The commonly used organic dyes with high quantum yields included rhodamines, phthalocyanines, and fluorescein. However, the water solubility of organic dyes was generally poor, thus seriously affecting their dispersibility in water. However, the weak lightfastness of organic fluorescent dyes and the nonnegligible side effects limit their applications in biomedical imaging. Currently the polymeric fluorescent probe has been prepared by introducing the small fluorescent molecule into the side chain and the chain end of the polymer or by the polymerization of a fluorescent functional monomer [63]. The fluorescent polymer could overcome the limitations of small fluorescent molecules; in addition, there are many other advantages: (1) good stability and the chromophore that is chemically bonded to the macromolecular polymer, which would be more stable; (2) uniform distribution of chromophores, good luminescence, and photoconductivity; (3) good film

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formation; (4) membrane detection that can be repeated for many times, with facile operability and high processing efficiency. Nanoparticles obtained from amphiphilic fluorescent polymers represent a novel fluorescent nanomaterial, which are effective tools to improve the photostability and biocompatibility of dyes. Owing to the facile modification and functionalization of polymers, some functional bonds or molecules (such as target molecule embracing nucleic acids, proteins, and sugars) could be introduced to the polymeric fluorescent probe. It can improve the sensing performance and bioimaging efficiency of fluorescent probe in complex physiological environment [64, 65]. For instance, Pu’s group reported the design of semiconducting polymer nanoparticles as biodegradable afterglow luminescence probes for molecular imaging in living mice (Fig. 12.7) [66]. Furthermore, Wang and coworkers reported a polymeric fluorescent probe Nano-Cz, which were produced from the amphiphilic polymer DSPE-mPEG2000 and carbazole-based SO2 molecule probe. The resulted PM was mitochondrion targeted, which could be stable in 100% water solution. The relevant experimental results further indicated that PM could efficiently lower the redundant interactions between biomacromolecules and dyes [67].

12.5 Conclusion Nanotechnology-based drug delivery systems show unique advantages over traditional medicine during the treatment of cancer. Advances in polymer-related nanoscience and nanotechnology have introduced a revolutionary change to produce new biomaterials with tailored properties and functionalities for targeted biomedical applications. Polymer-based controllable drug release systems exhibit several advantages, including adjustable chemical structure, various functions, high drug loading capacity, and good biocompatibility. Therefore these systems can effectively solve the problems such as poor water solubility, low bioavailability, uncontrollable release of drug molecules, and low therapeutic efficiency. The aforementioned unique advantages support the applications of PM in nanomedicine-based tumor therapy. Both the inherent and modifiable properties of PM make it perfectly suitable for drug delivery purposes. Meanwhile, with the rapid development in medicine, molecular biology, bioimaging, biomimicry, and oncology, we believe that PM system will play more important roles in drug delivery and will open new doors in the oncotherapy.

Acknowledgments This study was supported by the National Natural Science Foundation of China (No. 51703187, 31671037), Fundamental Research Funds for Central Universities from Southwest University (No. XDJK2019B005), and the Basic and Frontier Research Project of Chongqing (cstc2018jcyjAX0104).

Fig. 12.7  Synthesis of semiconducting polymer nanoparticles (SPNs). Reproduced from Q. Miao, C. Xie, X. Zhen, Y. Lyu, H. Duan, X. Liu, et al., Molecular afterglow imaging with bright, biodegradable polymer nanoparticles, Nat. Biotechnol. 35 (2017) 1102. Copyright 2019 Springer Nature.

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Mohammad Zaki Ahmada, Javed Ahmada, Musarrat Husain Warsib, Basel A. Abdel-Wahabc,d, Sohail Akhter e,f,g a Department of Pharmaceutics, College of Pharmacy, Najran University, Najran, Kingdom of Saudi Arabia, bDepartment of Pharmaceutics, College of Pharmacy, Taif University, Taif, Kingdom of Saudi Arabia, cDepartment of Pharmacology, College of Medicine, Assiut University, Assiut, Egypt, dDepartment of Pharmacology, College of Pharmacy, Najran University, Najran, Kingdom of Saudi Arabia, eCenter for Molecular Biophysics (CBM), CNRS UPR4301, Orleans, France, fLE STUDIUM Loire Valley Institute for Advanced Studies, Orleans, France, gNanomedicine Research Lab, Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, New Delhi, India

Abbreviations DDS drug delivery system LSPR localized surface plasmon resonance MDR multi drug resistance ME microemulsion MNPs metallic nanoparticulates MNS magnetic nanoparticles MWR microwave radiation NDDS novel drug delivery system NIR near infrared NPs nanoparticles NSM nanostructured material SPIONs superparamagnetic iron (Fe) oxide nanoparticles SPR surface plasmon resonance

13.1 Introduction 13.1.1 Nanotechnology Drug delivery systems (DDS) are one of the greatest promising applications of human health care and represent an eternally progressing field for medical sciences [1]. In spite of vast development in the field of DDS, still, it is a crucial challenge for formulation scientist to develop an appropriate carrier that is efficient for drug delivery to the body with maximum benefit to risk ratio. Recent development in materials science has initially empowered the advancement of DDS. From last few decades the emergence of nanomedicine in the field of nanotechnology has generated great interest among Nanoengineered Biomaterials for Advanced Drug Delivery. https://doi.org/10.1016/B978-0-08-102985-5.00013-9 © 2020 Elsevier Ltd. All rights reserved.

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formulation scientist in developing novel drug delivery system (NDDS) [2–10]. The aim of nanomedicine is to maximize the therapeutic activity and to minimize the adverse effect of drugs [11]. It is the implementation of nanotechnology in the field of medicine. Nanotechnology is the science of engineering and mechanization at the nanoscale. It deals with particle size range of about 1–100 nm [12]. Therefore nanomedicine is the interdisciplinary research involving physics, chemistry, biology, pharmaceutical engineering, and drugs aiming to attain advances in biomedical application to diagnose and treat the disease [6–10]. Unusual structural disorder, miniaturize size, high surface area-to-volume ratio, increased quantum effect, and high reactivity of nanostructured materials (NSMs) make them unique from their bulk counterpart [13–16]. Efficacy of the drug from most of the DDSs is directly related to particle characteristics, that is, particle size distribution, surface area, volume, and shape [17]. Owing to their small size and large surface area, NSM shows enhanced drug solubility and dissolution [17–19]. NSM has received more attention because they can be tailored for targeted delivery and controlled release of drugs [17–19]. These salient features of NSM can be used to conquer the impediment in the conventional dosage form. The use of NSM provides incomparable liberty to customize the intrinsic properties of the drug in DDS such as drug release characteristics, dissolution, solubility, bioavailability, t1/2, and immunogenicity [13]. Another important feature of NSM is its comparable size of the cell organelles in the human cell [20], and this property makes them a potential candidate for DDS, as the variety of physiological processes take place at nanoscales [21]. For treating the disease conjoint with nature, it is important to use the same scale; therefore NSMs are of great interest in DDS [20]. There has been a revolutionary intensification in the availability of commercially available NSM-based therapeutic products [13]. A worldwide perlustration of pharma industry pursuing NDDS indicates that nanomedicine is taking root in the industry [22]. Recent development in the area of nanomedicine has made exceptional progress toward bioavailability enhancement of low bioavailable drugs [8]. These NDDS has achieved significant recognition in the last two decades because of their potential to enhance the therapeutic index of drugs [8, 23–25]. Nowadays, NSMs are widely used with many commercially available preparations. For example, Feridex superparamagnetic iron (Fe) oxide nanoparticles (SPIONs) as a contrast agent in the liver had gained FDA approval in 1996 [26]. Similarly, Feraheme (ferumoxytol), INFed, Ferrlecit, and Venofer have been approved by FDA as an injection for treatment of iron-deficiency anemia in chronic kidney disease [27–29]. Following IV injection, these iron oxide nanoparticles (NPs) coated with hydrophilic polymer allows gradually slow dissolution of iron (Fe) [29]. This allows rapid IV administration of high dose without free Fe in the systemic circulation and thus prevents toxicity [29–31]. The most widely used NSM are classified as metallic nanoparticulates (MNPs), carbon-based NPs, semiconductor NPs, and polymer-based NPs and nanocomposites. Among all the previously listed NSM, MNPs have demonstrated prominent therapeutic application. This chapter is aimed at detailed description of the synthesis and biomedical application of MNPs in drug delivery. Also, toxicity concern associated with the use of MNPs is discussed.

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13.2 Metallic nanoparticlates MNPs and their fabrication are a progressive area attracting scientific research in the field of nanobiotechnology [6, 32] and remain to be a proliferating research field with substantial prominence on imaging and drug delivery [33–35]. These versatile classes of MNPs such as iron oxide NPs, magnetic NPs, gold NPs (AuNPs,) silver NPs (AgNPs), nanoshells, nanocages, and quantum dots have become the center of attraction for therapeutic and diagnostic potential [36], biosensors [37], and detection of antigens [38] due to their exceptional intrinsic properties, and it has figured out several new pathways in nanotechnology [4–10, 14, 32]. The optical properties such as surface plasmon resonance (SPR) MNPs are of great interest because of their ability to control optical field [39, 40]; that is, they can be tuned from visible (500 nm) to near infrared (NIR) (1300 nm), which make them exceptional contenders for biomedical application [40]. Their small size and large surface area are equipped with more point of contact when the high level of binding are required [41]. Furthermore, the high surface area to volume ratio of MNPs lets them easily interact with other particles, increased the diffusion rate, and is feasible at the lower temperature [14]. Availability of large surface area and ease of surface modification [42, 43] allow them to conjugate with ligands, antibodies, and various drugs of interest [6, 10, 21] (Fig. 13.1A). For example, Mukherjee et al. reported the gold nanocomposite system functionalized with nanocore having an antiangiogenic molecule and VEGF antibody-2C3 (AbVF), along with anticancer agent gemcitabine [44]. AuNPs functionalized with anticancer drug and antiangiogenic agent can destroy the cancer cell, and the same time, it will prevent the survival of other tumor cells [44, 45]. Atypical surface modifications improve the cellular uptake of MNPs and can be headed toward the target site. Furthermore, MNPs have been suggested as nontoxic for drug delivery and gene delivery applications [46–48]. Moreover, these MNPs can provide precise and personalized therapies for various disease and combine concurrently diagnostic and therapeutic potential into a single carrier, that is theranostic agent [48, 49] (Fig. 13.1B).

Fig. 13.1  (A) Multifunctional MNP-based delivery systems targeting, delivery, and imaging. (B) Combination of nanotechnology, therapeutics, and imaging (~ Theranostic).

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13.3 Fabrication of metallic nanoparticulates The fabrication of MNPs usually considers two different common methods named as dispersion method or top-down process and condensation method or bottom-up process [14, 32, 50, 51]. In top-down process, coarse particles are reduced in size to generate MNPs. This can be achieved by the application of high-intensity ultrasonic generators operating at frequencies of 1,200,000 rpm [32, 50]. Another dispersion method involves the production of an electric arc within the liquid [50]. Because of the intense heat, metal is dispersed as vapor from the electrode, which further condensed to form the MNPs [32, 50, 51], whereas in bottom-up approach, materials of subnanostructure dimensions are caused to assemble to build up nanostructure [14, 32, 50–53]. This can be achieved by a high degree of supersaturation followed by growth of nuclei [50]. Based on these two approaches, different groups have reported a variety of physical and chemical method for production of MNPs, for example, thermal decomposition [54–57], sonochemical [58–60], microemulsion (ME) [61, 62], chemical reduction [53, 63–66], polyol method [32, 67–69], microwave-assisted method [32, 70–72], and biological or green synthesis [32, 43, 73–77] of MNPs.

13.3.1 Thermal decomposition Thermal decomposition is a contemporary, easiest, and most convenient method for fabrication of highly stable monodispersed MNPs [78, 79]. This method required high temperature in the range of 400–525 K, long reaction time, catalyst, and inert atmosphere [32, 80–82]. By this method, monodisperse MNPs with controlled size can be essentially fabricated from an organometallic compound such as metal cupferronates [Mx Cupx] (M = metal ion; Cup = N-nitrosophenylhydroxylamine, C6H5N(NO) O-) [82, 83] or carbonyls [82, 84] [M(acac)n], (M = Fe, Mn, Co, Ni, Cr; n = 2 or 3, acac = acetylacetonate) [83], in high-boiling organic solvent with stabilizing surfactant [82, 85, 86] such as oleic acid [87], hexadecylamine [88], and fatty acid [89]. However, this method produces organic soluble MNPs and results in the limited application in the field of nanomedicine [78, 81]. Another disadvantage associated with this method includes the protracted purification process before the biomedical application [81, 90], and surface treatment is essential after fabrication of MNPs [91].

13.3.2 Sonochemical synthesis This is an eco-friendly approach without high temperatures, high pressures, or prolonged reaction times [92, 93], which combines sonochemistry, electrochemistry [92], and interaction between matter and energy [94]. In this method, ultrasound waves are applied to the electrochemistry processes [95, 96], where the metal salt solution is subjected to reduction in the aqueous phase [32]. The interaction between ultrasonic energy and matter leads to consequences of acoustic cavitation, that is, the formation, growth, and implosive collapse of bubbles in liquid [32, 93, 94]. Throughout the process, high temperatures, pressures, and cooling rates can be attained during the collapse of the bubble; these result in an extensive range of chemical reaction that is

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usually not accessible under normal circumstances; these allow the synthesis of an immense variety of astonishing MNPs (Fig. 13.2) [92, 93]. This technique uses the titanium horn as an ultrasound probe for acoustic irradiation [93, 97]. The sonochemical method has been successfully used for fabrication of plentiful nanocomposites, and its utility has been successfully confirmed in the production of iron oxide NPs [81, 97–100]. This method is useful for the synthesis of controlled particle size and morphology of MNPs within narrow size distribution [32, 101].

13.3.3 Microemulsion Microemulsion (ME) is transparent and thermodynamically stable, colloidal DDS [102, 103]. It is a spontaneous isotropic liquid mixture of polar phase and nonpolar phase stabilized by suitable surfactant usually in combination with a cosurfactant (Smix) [32, 102–104]. Like emulsion, ME have two types: (a) oil in water (O/W) in which oil droplets are dispersed in a continuous phase of water and (b) water in oil (W/O) that consist of water droplets as a dispersed phase in the continuous phase of oil [105].

Fig. 13.2  Sonochemical reaction method for the production of MNPs. From H. Xu, B.W. Zeiger, K.S. Suslick, Sonochemical synthesis of nanomaterials. Chem. Soc. Rev. 42(7) (2013) 2555–2567,with permission.

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It is a well-known fact that lipophilic surfactant produces W/O ME [106, 107]. Here, in W/O ME, polar parts of the surfactant molecules are directed inside toward aqueous phase, while nonpolar parts are attracted outside by oil phase [81, 105, 106]. This type of arrangement is called reverse micelle [81, 105, 106] as shown in Fig. 13.3A. The transformation of metallic salt in reverse micelle has received considerable attention for the synthesis of MNPs [105, 108, 109]. For the production of MNPs, nanodroplets of water formed from W/O ME are used as a nanoreactor to control the growth of particles [105, 110, 111]. This nanoreactor containing reagent allows rapid coalescence, mixing, aggregation, and precipitation for fabrication of MNPs [81]. By mixing two identical W/O ME consisting the reactant of interest, the nanodroplets continuously collide, coalesce, further break, and conclusively precipitate in the reverse micelles [78, 81, 109] (Fig 13.3B). Since reactions take place inside the nanodroplets, that finally control the size of MNPs [81, 105], the size of water droplets in W/O can be adjusted in the range of 5–50 nm by tuning the component of ME [81, 105].

13.3.4 Chemical reduction Chemical reduction for fabrication of MNPs has been greatly employed. This is a relatively simple and easy method for the synthesis of stable MNPs in solution. The major advantages associated with this process are ease of fabrication, controlled size distribution, and thermally stable and monodisperse MNPs [18, 52, 112]. Metal precursor; reducing agent [63, 64, 113, 114] such as NaBH4 [115], ethylene glycol [116], glucose [113, 116], citrate [53, 113, 116, 117], ascorbate and elemental hydrogen [113, 116]; and stabilizing agent such as polyvinyl alcohol (PVA) [113], polyvinylpyridine [32, 118],

Fig. 13.3  (A) A schematic representation of the W/O microemulsion droplet. (B) Strategy of preparing highly monodispersed MNs inside the w/o microemulsion droplets.

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bovine serum albumin (BSA) [113], citrate [53, 113], and cellulose [113] are the three basic components needed for chemical reduction method for the production of MNPs [32, 113] (Fig. 13.4A). Shape, size, and size distribution of MNPs can be easily manipulated by governing the various process parameters such as the use of strong or weak reducing agent [32, 119] by regulating the molar ratio of metal precursor to the molar ratio of reducing agent used, or controlling the molar ratio of metal precursor to the molar ratio of capping agent used [32, 120]. Other factors such as reaction temperature, time duration, and pH condition play a crucial role in determining the physicochemical properties of MNPs [32, 113, 121].

13.3.5 Laser ablation Basically, it’s a physical method for the synthesis of MNPs and is characterized by the absence of any contamination such as counterion and surface active molecules [122]. In other words, ultrapure NPs can be generated by this method without contamination from the reactor [123, 124], because this method does not include any chemical reagents or does not require several reaction steps [32]. Ablation means removal of surface atoms along with breaking of the chemical bond and thermal evaporation (multiphoton excitation) [123]. In this method the solid surface is ablated by the beam of the laser as a source of energy in a gas or liquid medium [32, 123–125]. The photon

Fig. 13.4  (A) Schematic representation of synthesis of MNPs by chemical reduction method. (B) Laser ablation synthesis of MNPs.

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from laser irradiation on solid target results in heating and photoionization of irradiated area [125, 126]. Afterward, some materials are removed from the solid target as a vapor or liquid drops or solid fragments or as expanding plasma [125, 126]. Ablation is followed by seeding, nucleation, the growth of nucleation and coalescence, and finally the formation of MNPs [127, 128] (Fig.  13.4B). By monitoring the certain parameters such as time, laser power, or duration of photolysis, the size of MNPs can be manipulated [113, 129]. For instance, short irradiation and low laser power result in AgNPs with a size range of 20 nm, whereas 5 nm AgNPs were generated with longer irradiation and high laser power [130].

13.3.6 Polyol method This is the versatile fabrication method for the production of high-quality MNPs by reducing dissolved metallic salt (halides, sulfate, and nitrates) or direct precipitation of metals in high-boiling, multivalent alcohol (polyols) [32, 81, 131–133]. Polyol or polyalcohol such as polyethylene glycol (PEG) that is used in this process takes advantage of water equivalent but high-boiling liquid [133]. Hence, polyol acts like water in terms of solubility of metal salt precursor due to their high dielectric constant [32, 81, 133, 134]. Also, these polyalcohol acts as a reducing agent for instantaneous synthesis of MNPs and colloidal stabilization of MNPs [32, 81, 133, 134]. Furthermore the high boiling temperature of polyols (298–593 K) bypasses the requisite of high pressure or necessity of autoclave [133]. In short, polyol synthesis can be deliberately considered as one step reaction pot combining multifarious features at the same time. In this method, metallic salt or oxides (precursor compounds) are dissolved or suspended in multivalent alcohol. The reaction mixture is heated to high temperature (453–472 K). During the reaction process the precursor compounds are solubilized in polyol and form intermediates followed by seeding of metallic nuclei, which form MNPs [67, 68, 81]. This method is widely used for the production of specific shapes and biocompatible MNPs. Furthermore, high biocompatibility allows optimal cellular uptake of functionalized MNPs [132, 133, 135].

13.3.7 Microwave-assisted method Microwave radiations (MWRs) are electromagnetic waves with the wavelength ranging from 1 mm to 1 m and with frequencies between 300 MHz and 300 GHz [136]. Microwave-assisted synthesis of MNPs has been progressively applied in fields of materials science including nanomedicine [137–144]. Microwave-assisted synthesis of MNPs is considered as a promising alternative with environmental benefits [145]. This is a significantly effective technology for fabrication of MNPs due to its simple homogeneous and consequently dramatic increase in the reaction rate compared with conventional heating [136, 139, 146]. Furthermore, controlled microwave-assisted heating process results in decreased reaction time, increased production yields, and dramatic reduction of overall production cost, and more important is the production of ultra-pure NPs with decreased environmental pollution [140, 141].

Metallic nanoparticulate delivery systems287

13.3.8 Green synthesis The advancement in the biological process or green technology for the fabrication of MNPs has been emerging as a substantial branch of nanobiotechnology. This technology does not include any harmful chemical and delivers effective products in an eco-friendly manner [147–150]. Therefore green synthesis of MNPs has the advantages of nontoxicity, economical, reproducibility in production, easy scaling-up, and well-defined morphology, and more important is the enhanced biological compatibility of NSM that makes green synthesis attractive [75, 145, 150]. Noble MNPs such as platinum, gold, or silver are manufactured by green technology that are widely applied in the field of nanomedicine [149, 151, 152]. Plant-mediated synthesis of MNPs is the most adopted method since it is ecofriendly and is a source of varieties of metabolites [150, 153, 154]. Plant extract such as enzymes, protein, amino acids, vitamins, or any other biomolecules may act both as reducing and capping agent during biosynthesis of MNPs [154, 155]. An outline for biosynthesis of MNPs using plant extract is presented in Fig. 13.5. The use of microorganism for green synthesis of MNPs has also materialized as an alternative approach as compared with the conventional chemical or physical method. Microbial systems involving bacteria, fungi, actinomycetes, and yeasts have been widely used for the production of varieties of MNPs [32, 81, 145]. Unique antimicrobial activity of silver against infectious microorganism offers promising utilizations of AgNPs in nanomedicine. Moreover, green synthesis of AgNPs using microbes has gained momentum due to its simplicity and potential to fabricate the NPs of different but controlled size, shapes, and morphology [149, 151]. Commonly used bacteria for the biosynthesis of AgNPs includes Bacillus subtilis, Lactobacillus acidophilus, Enterobacter cloacae, Staphylococcus aureus, and Pseudomonas stutzeri [32, 81, 145, 149, 151]. Similarly, AuNPs have also been synthesized by the green process in the presence of Shewanella algae [156] and Rhodopseudomonas capsulata [157]. However, bacteria or fungi take comparatively longer incubation time in growth media to reduce the metal salt; on

Fig. 13.5  Green synthesis of MNPs using plant extract.

288

Nanoengineered Biomaterials for Advanced Drug Delivery

the other hand a water-soluble phytochemical from plant extract performs the same in a moment [152, 158]. Therefore in plant mediated green synthesis, MNPs are most appropriate contenders compared with microbes [152].

13.4 Application of metallic nanoparticulates in drug delivery and theranostics As discussed earlier, the most fascinating properties of MNPs are their size, very similar to cell organelles. Their unique physical dimensions facilitate them to infiltrate through the physiological or biological membrane that is usually impermeable for macromolecules. In the field of DDS, MNPs have been used for more than three decades [6–10]. The most of the currently used API is poorly water soluble [159] and results in poor bioavailability. The bioavailability of poorly bioavailable drugs is known to make strides by converting the drug in nanometric size to enhance the drug dissolution [160]. This, in turn, results in a high concentration gradient for better absorption, leading to better bioavailability [161, 162]. Additionally, MNP surfaces can be easily tuned to alter the pharmacokinetics and or pharmacokinetic properties [38, 163]. For instance, polyethylene glycol (PEG) coating over MNP surface efficaciously intensifies the circulation time within the body, accordingly reducing nonspecific uptake by mononuclear phagocyte system [4–7, 38, 164]. Moreover, surface chemistry of MNPs also allows the conjugation of targeting ligands such as peptides, antibodies, or nucleic acid sequence to target specific diseased organ or tissue (Fig.  13.1A) [4, 6, 7, 38]. After the administration of functionalized MNPs into the human body, it increases the drug payload at target site while substantially minimizing the risk of adverse effects; by these means, therapeutic agents are delivered at target site into specific cell; therefore diagnosis and treatment occurs at the cellular level [165, 166] and results in better therapeutic efficacy and enhanced patient compliances [167, 168]. Due to aforesaid prominent features, MNPs have proven to be the most versatile and extensively used vectors in nanomedicine (Table 13.1).

13.4.1 Gold nanoparticles Gold (Au) and Au-incorporated amalgamate have the long history of being used in the different system of indigenous medicine [3]. AuNPs have enticed considerable attention of formulation scientist due to their exceptional properties such as catalysis activity, biocompatibility, and exquisite optical and electrical features [242]. Furthermore, high surface-to-volume ratio of AuNPs enables them to increase the light absorption and scattering efficiency by four to five times as compared with their bulk part [10]. These characteristic features make them captivating tools for diagnosis and disease therapy particularly for cancer [10]. Precisely synthesized, these AuNPs with different morphologies and surface chemistry can be tuned to suit a variety of application in nanomedicine. Furthermore, AuNPs in specific shapes such as nanostars, nanorods, nanoshells, or nanocages exhibit unique SPR that strongly favor their applicability

Table 13.1  Examples of metallic nanoparticle system used in targeted drug delivery and theranostic. MNPs

Target

Model used

Major outcome

References

AuNPs conjugated with antibiotic

In vitro antibacterial activities

Vancomycin-resistant enterococci (VRE)

[169]

AuNPs conjugated antibiotic

In vitro antibacterial activities

Enhanced activities against VRE strains and gram-negative bacteria Enhanced antibacterial activity

AuNPs@LL37/pDNAs complexes

Diabetic wound healing

Accelerated wound healing Faster reepithelization Improved granulation tissue formation High VEGF expression Enhanced antibacterial activity compared with pure LvN alone Significantly enhanced antibacterial activity Synergistic effects on the potency of pefloxacin against Escherichia coli Enhanced oral bioavailability of antibiotic in controlled manner Excellent bactericidal activity Reduced MIC and MBC against MDR gram-positive and gram-negative bacteria compared with free drugs

[171]

Gold nanoparticles (AuNPs)

●

●

●

●

●

Escherichia coli DH5a Micrococcus luteus Staphylococcus aureus strain Human keratinocyte Diabetic mice

●

[170]

●

●

●

Au-BRN-LvN-NPs AuNPs conjugated with antibiotic AuNPs conjugated with antibiotic

In vitro antibacterial activities In vitro antibacterial activities In vitro antibacterial activities

AuNPs conjugated with antibiotic AuNPs conjugated with antibiotic

In vivo antibacterial activities In vitro antibacterial activities

Staphylococcus aureus Escherichia coli Acinetobacter baumannii ●

●

Fecal strain of Escherichia coli

Rabbit Multidrug resistant (MDR) bacterial infections

●

[172] [173] [174]

[175] [176]

●

Continued

Tumor

AuNPs conjugated with monoclonal anti-HER-2 IgG2a antibodies

Lung tumor

Tumor

MTX-AuNP

PTX-AuNPs

●

Tumor Epidermal growth factor receptor (EGFR) (anti-EGFR D-11)

Tumor

Antibody drug conjugated AuNPs

●

–

AuNPs grafted Hydrogel conjugated with antibiotic

Functionalized AuNPs

Target

MNPs

Table 13.1  Continued

HT-29 human colon adenocarcinoma cells SK-BR-3 human breast adenocarcinoma cells A549 tumor cell lines HCT116 tumor cell lines In  vivo mice bearing xenograft tumors

HT-adenocarcinoma cells In  vivo mice bearing xenograft tumors

–

Mouse ascites model of Lewis lung carcinoma (LL2)

●

●

●

●

●

●

●

–

Model used

●

●

●

●

●

●

●

●

●

●

●

Switchable on/off release properties Suitable candidate as a carrying vehicle for controlled drug release Nontoxic nanotheranostic Enhanced anticancer activity Extensive tumor growth inhibition in mice Improved cellular internalization Enhanced anticancer activity Drastically reducedHT-29 colon cancer cell viability Optimized controlled Enhanced cellular uptake Selective tumor cytoxicity Equivalent cell death to tumor cells with less than half the time of exposure as compared with free compound Several times higher cytotoxic effects compared with an equal dose of free MTX Enhanced drug loading ●

Major outcome

[182]

[181]

[180]

[179]

[178]

[177]

References

Dox-AuNPs

MDR cancer cell

●

●

Human lung adenocarcinoma cell line Sprague-Dawley rats

●

●

●

●

●

DOX-Hyd-AuNPs

MDR cancer cell

MCF-7/ADR cancer cells

●

●

●

5-FU-AuNPs

Skin cancer

A431 tumor-bearing mice

●

●

LIN-AuNPs-CALNN

Tumor cell

●

●

MCF-7 Balb/c mice

●

●

●

Immunostimulatory TLR7AuNPs

Tumor cell

Dox-AuNPs

Cancer cell

Balb/c

●

●

●

FA receptor-overexpressing cancer cells

●

●

●

Enhanced cellular uptake Avoid P-gp efflux in cancer cells Prolonged circulation of Dox Reduced drug clearance (CL) and improved half-life (t1/2) Enhanced antiproliferation effect Improved cellular internalization Significantly enhanced cytotoxicity Induced elevated apoptosis Enhanced drug permeability Improved anticancer activity Enhanced cellular uptake Exert enhanced cell growth arrest against MCF-7 Nontoxic to normal cell Induce local immune activation Enhanced antitumor activity Prolonged survival of animal Enhanced cellular internalization PH-responsive release Enhanced CT imaging

[183]

[184]

[185] [186]

[187]

[188]

Continued

Table 13.1  Continued MNPs

Target

Model used

Dtxl-AuNPs

Liver cancer

●

●

HepG2 cancer cell line ICR mice

Major outcome ●

●

●

●

Dox-PEC-AuNPs

Dox-AuNPs

Cancer cell cells overexpressing asialoglycoprotein receptor Breast tumor

HepG2 cancer cell line

●

●

●

●

●

●

The human fibroblast cell line MCF-7 cells Nude mice

●

●

●

Phloridzin and phloretin conjugated AuNPs (PhlAuNP and Pht-AuNP)

Cancer cell

HeLa

●

●

Higher cytotoxicity against human liver cancer cells Nontoxic to normal cell Enhanced anticancer activity in animal model Prolonged survival of animal Increased cellular uptake Excellent stability under varying pH Increased anticancer activity Synergistic (chemotherapy and photothermal therapy) cytotoxicity response Sensitization of cancer cells to payloads Improved therapeutic efficacy and decreased systemic toxicity of the MNPs Synergistic effect between the AuNP and each of the respective drugs Significant multifold increases in the antineoplastic activity of both phloretin and phloridzin

References [189]

[190]

[191]

[192]

Bleomycin and Dox conjugated AuNPs

Tumor cell line

HeLa cells

Improved cellular uptake via active targeting Strongly enhanced anticancer activity Improved transgene expression Enhanced cellular uptake Enhanced cellular uptake Accumulate at the specific tumor site Enhanced antitumor activity Enhanced in vivo gene delivery Nontoxic to normal cell Enhanced antitumor activity Suppressed the proliferation of CD44(+) GC cells Enhanced cellular internalization capability Improved anticancer activity Enhanced targeted delivery Controlled miRNA release remotely with an NIR laser Enhanced brain specific delivery

●

[193]

●

Dendrimer modified  FA-AuNPs FA functionalized AuNPs

Gene

Mammalian cancer cell line

●

[194]

●

Gene

●

●

MCF-7 Mice

●

[195]

●

●

●

●

Dendrimer G5entrapped AuNPs

Gastric cancer (GC)

Peptide-Conjugated AuNP-HDM2

Wild-type p53 protein on cancer cell Cancer cell

miRNA-AuNPs

Gold nanorod-DARPP-32 siRNA complexes siRNA-AuNPs siRNA-AuNRs

CD44 + gastric cancer cells

●

[196]

●

DARPP-32, ERK, and PP-1 Green fluorescent protein (GFP) Cancer cell

RB cells

●

[197]

●

Human embryonic kidney cells (HEK293T) Dopaminergic neuronal (DAN) cells HEK

●

●

●

HepG2 cells

[198]

●

●

●

Enhanced cell transfection Reduced GFP fluorescence Improved siRNA transfection efficiency Enhanced anticancer effect

[199] [200] [201]

Continued

Table 13.1  Continued MNPs

Target

Model used

Major outcome

siRNA-AuNPs

Bcl-2 and VEGF protein

Glioblastoma cells

●

siRNA-AuNRs

Cancer cell

●

●

●

●

AuNC-siRNA

Pancreatic cancer

●

●

143B cancer cells 143B-fluc cells PC-3 tumor-bearing mice Panc-1 cells Balb/c nude mice

●

●

●

●

●

●

●

Enhanced cytocompatibility Enhanced  gene silencing to inhibit the expression of Bcl-2 and VEGF proteins Effective photothermal therapy and photoacoustic imaging Significantly enhanced synergistic antitumor activity Downregulation of NGF expression Inhibition of tumor progression Inhibit pancreatic cancer via NGF knockdown Increased stability of siRNA and prolonged the circulation lifetime High safety and low toxicity in  vivo compared with free siRNA

References [202]

[203]

[204]

Silver nanoparticles (AgNPs) AgNPs AgNPs

In vitro antibacterial activities In vitro antibacterial activities

●

●

●

●

Bacillus subtilis Escherichia coli Pseudomonas aeruginosa Staphylococcus epidermidis

Enhanced antibacterial activity

[205]

Enhanced antibiofilm activity

[206]

AgNPs

In vitro antibacterial activities

●

●

Escherichia coli Staphylococcus aureus

Enhanced durable antibacterial activity Nontoxic to eukaryotic cells Enhanced antibacterial activity

●

[207]

●

AgNPs

In vitro antibacterial activities

Pseudomonas aeruginosa Staphylococcus aureus Staphylococcus epidermidis Human dermal fibroblasts (HDFs) Staphylococcus aureus Streptococcus pyogenes Pseudomonas aeruginosa Escherichia coli Staphylococcus aureus Streptococcus pyogenes Pseudomonas aeruginosa Escherichia coli Staphylococcus aureus Escherichia coli Staphylococcus aureus Bacillus sp. Escherichia coli Klebsiella pneumoniae Human cervical cancer cell line (HeLa) Escherichia coli ●

[208]

●

●

AgNPs Res-AgNPs

Cancer cell In vitro antibacterial activities

●

●

Enhanced antitumor activity Improved the antibacterial activity of resveratrol

[208] [209]

Improved the antibacterial activity of resveratrol

[209]

Enhanced antibacterial activity

[210]

Enhanced broad-spectrum antimicrobial activities

[211]

Dose-dependent anticancer activity Improved photostability of CUR Enhanced antibacterial activity

[211]

●

●

Res-AuNPs

In vitro antibacterial activities

●

●

●

●

AgMSNPs-Ofloxacin Pentagonal AgNPs

In vitro antibacterial activities In vitro antibacterial activities

●

●

●

●

●

●

Pentagonal AgNPs

Cancer cell

Ag-CUR-NCs

In vitro antibacterial activities

●

[212]

●

Continued

Table 13.1  Continued MNPs

Target

Model used

Major outcome

References

Ag-CUR-NCs

Skin cancer

Skin cell lines

●

Improved photostability of CUR Increased anticancer activity Minimal toxicity to skin cells Improved anticancer activity Biocompatible NPs Hemolytic activity less than free MTX Concentration-dependent cytotoxicity Induction of apoptosis and necrosis cell death of HeLA cells Enhanced cytotoxic activity

[212]

●

●

MTX-AgNPs

Tumor

●

●

AgNPs

Cervical cancer

MCF-7 Human Corneal Epithelial Cell (HCEC) line

HeLA

●

[213]

●

●

●

[214]

●

AgNPs

Tumor

●

●

●

AgNPs

Lung cancer

●

●

HT-29 MCF-7 MOLT-4 A549 MRC-5

●

●

●

AgNPs/Ag-Cl-NPs

Brain tumors

GBM02 glioblastoma cells

●

●

Magnetic/Ag theranostic nanocomposite

Nasopharyngeal carcinoma

CNE cells

●

●

Enhanced cellular uptake Improved anticancer activity Nontoxic to normal cell More effective anticancer activity Considerably lower antiproliferative effect toward healthy human astrocytes Enhanced antiproliferative activity against CNE cells Inhibit the expression of EGFR

[215]

[216]

[217]

(229

Dox-loaded Ag@SiO(2)@ mTiO(2) NPs

Breast cancer

MCF-7

Enhanced drug loading Greater therapeutic effect compared with the free drug Simultaneous bimodal imaging and drug delivery for cancer therapy Enhanced targeted drug delivery Improved anticancer activity Important step toward application of nanomedicine Destruction of cell wall Inhibition of bacterial propagation

●

[218]

●

●

Dox-FA-AgNPs

Folate-receptor expressing cancer cells

Cancer cell line

Antibacterial activity

[219]

●

AgNPs-oligonucleotide Qe-AgNPs/siRNA

●

●

●

MDR bacteria SKH1 female nude mice

●

[220] [221]

●

Magnetic nanoparticles (MNS) Ferrofluids SPIO-Dox

Squamous cell carcinoma Tumor MRImonitoring chemotherapy

Rabbit

●

●

●

●

HT-29 cancer cells Male Sprague Dawley rats

●

●

●

●

FA conjugated MNS-Dox

Cancer

KB cell line

●

●

●

●

No systemic toxicity Enhanced antitumor activity High drug loading Reduced drug toxicity on normal cells Better signal contrast enhancement Significantly reduced tumor size High loading drug efficiency Enhanced site-specific drug delivery pH-dependent release and substantial cellular internalization Enhanced anticancer activity

[222, 223] [224]

[225]

Continued

Table 13.1  Continued MNPs

Target

Model used

SPIO/Dox-NPs

Cancer

●

●

Murine C26 colon carcinoma cells Mice

Major outcome ●

●

●

●

MNS-Dox-Mel

Tumor

MCF-7

SPIO-MagnetoliposomesDox

Cancer

Rat C6 glioma

●

●

●

●

●

●

PTX-CUR MNS

Brain tumor

Mice bearing orthotopic glioma

●

●

●

●

PTX-MNS

Tumor

●

●

●

●

HepG2 HEK293 BALB/c mice New Zealand rabbit

●

●

●

Enhanced cellular uptake Enhanced the cytotoxicity effect Significantly higher tumor inhibition Prolonged animal survival Enhanced synergistic effect of drugs Greater antitumor efficacy Controlled release of drugs Decreased cell viability Enhanced antiglioma effect Noticeably decreased in tumor volume Enhanced cellular uptake and brain delivery Enhanced apoptosis induction Synergistic effects on anticancer activity Enhanced survival rate of animal Enhanced biocompatibility Low toxicity to normal cell and highly toxic on tumor Effective tumor-specific cell targeting

References [226]

[227]

[228]

[229]

[230]

CAP-PTX-MNS

Lung cancer

A549 cells

●

●

PTX-MNS

Brain tumor

Human brain glioblastoma U251 cells

●

●

Magnetoliposomes-PTXSPIO

Tumor

●

●

MDA-MB-231 cell line Female BALB/c nude mice

●

●

●

PTX-SPIO-NPs

Breast cancer

MDR MCF-7 cells

PTX-SPIO-NPs

Glioblastoma

●

●

●

●

U87MG cells Orthotopic U87MG tumor model mice

●

●

●

MTX-MNS

Tumor

MCF-7

●

●

Enhanced effective drug concentration Synergistic effect on growth inhibition of cells Enhanced cellular internalization Improved programmed cell death via apoptosis and generation of ROS Enhanced targeted drug delivery Minimized cytotoxicity to normal cell Improved anticancer effect Significantly reduced cell survival Improved therapeutic efficacy Concentration dependent cellular uptake Enhanced accumulation of NPs at target site Improved anticancer efficacy with prolonged survival of animal Improved cellular uptake Enhanced anticancer activity

[231]

[232]

[233]

[234]

[235]

[236] Continued

Target

Tumor

Cancer

Cancer

Breast cancer

MNPs

MTX-MNS

Magnetic nanocomposites MTX

Dox-MPDA@HA-MTX

MTX-MNS

Table 13.1  Continued

A human bladder cancer cell line (T24) BALB/c

●

●

●

MCF-7 HFF-2 and HEK-293 cell lines

MCF-7 HepG2 HUVEC Cancer cell line

●

●

●

●

Model used

References

●

●

●

●

●

●

●

●

●

●

●

Preferential tumor accumulation Enhanced tumor activity Prolonged survival of animal Enhanced biocompatibility to normal cell Improved cellular internalization to tumor cell Enhanced anticancer activity

[240, 241]

[239]

Enhanced nanochemother- [237] mia  for a localized and  relapse-free destruction Fostered reduction of tumor volume Impaired induction of angiogenic signaling Enhanced biocompatibility Increased uptake of MNPs into tumor cells and an impairment of proapoptotic signaling High anticancer activity while [238] low toxicity to normal cells

Major outcome

Metallic nanoparticulate delivery systems301

in oncology [243, 244]. Because of the presence of negative charge on AuNPs, it can be readily functionalized with different kinds of biomolecules such as genes, protein, antibody, drugs, and or targeting ligand [166, 245, 246]. For example, thiol (-SH) groups interact with Au nanomaterials, which in turn easily linked with biomolecules and provide selective nuclear targeting [166].

13.4.1.1 AuNPs in drug delivery AuNPs also known as colloidal gold are a nanometric suspension of gold [10]. AuNPs have exceptional optical properties with high absorption efficiency without the effect of photobleaching [246, 247]. It is well-known fact that targeted drug delivery is far better than conventional drug delivery. AuNPs conjugated with drug molecules play a decisive role in targeted endocellular disease therapy [169, 170, 246]. Antibiotic or other chemotherapeutic moieties can be easily conjugated with AuNPs. For example, antibiotic (ampicillin, streptomycin, and kanamycin) has been conjugated with AuNPs [170]. Furthermore, AuNPs have been explored as a useful model system to explore the multivalent interaction of ligand-receptor pairs, where vancomycin-capped AuNPs ostensibly act as a rigid polyvalent inhibitor of vancomycin-resistant enterococci [169]. Similarly, antimicrobial peptide (LL37) grafted ultrasmall gold nanoparticles (AuNPs@LL37, ∼ 7 nm) for the topical treatment of diabetic wounds was developed by Wang et al. [171]. This combined system promoted the angiogenesis and inhibited bacterial infection in diabetic wounds, resulting in accelerated wound closure rates, faster reepithelization, improved granulation tissue formation, and high VEGF expression [171]. Furthermore, Bagga et al. [172] developed a bromelain-capped AuNPs as the NDDS to exaggerate the efficacy of the levofloxacin (LvN). The Au-BRN-LvNNPs confirmed improved antibacterial activity compared with pure LvN alone [172]. Likewise the antibacterial activity of nanoconjugate gentamicin and amikacin with AuNPs against clinical isolates of Acinetobacter baumannii was reported by Rad et al. [173]. Amikacin bound to AuNPs showed excellent antibacterial activity (94.5%); also, gentamicin bound to AuNPs have a good antimicrobial effect (50%) contrast to gentamicin alone [173]. Along with drug delivery application, also, AuNPs are useful candidate for bioavailability enhancement of conjugated drugs. For example, Anwar et al. [174] evaluated the antimicrobial efficacy of AuNPs conjugated with a newly fabricated cationic ligand; 4-dimethyl aminopyridinium propylthioacetate (DMAPPTA) in comparison with pure compound and antibiotic pefloxacin against the fecal strain of Escherichia coli. The minimum inhibitory concentration (MIC) of pefloxacin + DMAP-PTA-AuNPs mixture was found to be decreased by 50% in concentration as compared with drug alone, which clearly indicates that functionalized AuNPs amplified the potency of antibiotic [174]. Similarly, Jabri et al. reported that lecithin-gum tragacanth mucoadhesive hybrid gold nanocarrier shows enhanced bioavailability of Amphotericin B in the animal model [175]. Furthermore, functionalized AuNPs against MDR bacterial infections were reported by Pradeepa et al. [176]. These NPs showed excellent bactericidal activity and reduced MIC and minimum bactericidal concentration (MBC) against MDR gram-positive and gram-negative bacteria in comparison with free drugs [176]. An interesting switchable on/off drug release from

302

Nanoengineered Biomaterials for Advanced Drug Delivery

AuNP-grafted dual light- and temperature-responsive hydrogel for controlled drug delivery of ofloxacin was developed by Amoli-Diva et al. [177]. AuNPs have been established as one of the bewildering nanovectors for cancer therapy due to their size, shape, and size dependents localized surface plasmon resonant (LSPR) properties. AuNPs conjugated with exclusive antibodies for a receptor present on cancer cell have been used for targeted delivery to the cancerous cell [178–180]. In addition to the conjugation of AuNPs with targeting ligand, surface or core of AuNPs can be functionalized with PEG or surface charge and decorated with anticancer drugs [3]. For example, the functionalized surface of AuNPs combined with methotrexate (MTX) results in improved cellular internalization and greater cytotoxic effects on various tumor cell lines compared with an equal dose of the free drug [181]. In another study, AuNPs (~ 2 nm) were covalently functionalized with paclitaxel (PTX). TGA analysis of this hybrid AuNPs reveals the loading of ~ 70 molecules of PTX per AuNP [182]. PEG-decorated doxorubicin (Dox)-AuNPs have been reported to overcome multidrug resistance (MDR) in Caco-2 cell monolayers [183]. Furthermore, Dox-AuNPs-PEG exhibited sustained and pH-dependent drug release profiles and exhibited antiproliferation effects against the A549 cells [183]. Similarly, Wang et al. have developed Dox-tethered responsive AuNPs to facilitate the cellular internalization of the drug and to overcome the MDR in cancer cells [184]. DoxAuNPs achieved greater cellular uptake and retention of drug in MDR MCF-7/ADR cancer cells as compared with free Dox. Thus Dox-AuNPs significantly improve the cytotoxicity of Dox and encourage elevated apoptosis of MCF-7/ADR tumor cells [184]. Similarly, enhanced efficacy of 5-fluorouracil (5-FU) against skin cancer and its reduced systemic side effect were observed when it was loaded with AuNPs [185]. Linalool (LIN)-loaded AuNPs conjugated with CALNN peptide for improved drug uptake and induction of cell death on cancer cell line was developed by Jabir et al. [186]. LIN-AuNPs-CALNN was found to exert cell growth arrest against MCF-7 cell line [186]. Efficacy of AuNPs (~ 5 nm) coated with a mixture of 1-octanethiol and 11-mercaptoundecanesulfonic acid for the delivery of an immunostimulatory TLR7 ligand to tumor-draining lymph nodes was first time reported by Mottas et al. [187]. Upon subcutaneous injection of functionalized NPs into tumor-bearing mice, the particles were rapidly conveyed to the tumor-draining lymph nodes. There, they foster the activation of the tumor-specific cytotoxic T-cell and induce a local immune activation [187]. Similarly, Zhu et  al. presented the fabrication of multifunctional ­dendrimer-based theranostic Dox-conjugated AuNPs for anticancer activity and computed tomography (CT) imaging with targeting specificity [188]. Moreover, Wan et al. [189] reported the productivity of docetaxel (Dtxl)-decorated AuNPs. In vitro anticancer activity demonstrated that Dtxl-AuNPs had a great potential of cytotoxicity against HepG2 cancer cell line [189]. Pectin (PEC)-capped AuNPs conjugated with Dox for hepatocarcinoma was developed by Borker et  al. [190]. The in  vitro anticancer activity of the DOX-PECAuNPs in human Caucasian hepatocyte cells shows greater potential in killing these cells as compared with free Dox [190]. Similarly, codelivery of AuNPs and hollow AuNPs with Dox-loaded thermosensitive liposomes results in synergistic cytotoxicity response [191]. Payne et al. [192] developed dihydrochalcone-functionalized AuNPs

Metallic nanoparticulate delivery systems303

for antineoplastic activity. Evaluation of cytotoxic potency of the functionalized AuNPs against HeLa cells results in significant toxicities against cancerous cell [192]. Bleomycin and Dox-conjugated AuNPs for cancer treatment have been reported. Therapeutic potential of the Au nanohybrid drugs was robustly improved by the active targeting of AuNPs to HeLa cells with a momentous reduction of the half-maximal effective drug concentration, through blockage of HeLa cancer cell cycle [193].

13.4.1.2 AuNPs in gene delivery Advances in the understanding of molecular biology of human diseases and gene therapy have opened the new strategy for the treatment of the genetic disorder and acquired disease [194, 248]. Recent advancement in gene therapy has demonstrated that they are competent enough to deliver all kinds of decoy oligonucleotides, such as ­single-stranded RNA (ssRNA) and double-stranded or single-stranded DNA (dsDNA or ssDNA) [246]. AuNPs provide an attractive platform for successful delivery of DNA and RNA. Additionally, heavy metal AuNPs protect these nucleic acids from nuclease. Recently, dendritic stabilized AuNPs have shown great potential for efficient delivery of plasmid DNA [194]. This finding has a vital role for the application dendrimer modified Au nanocomplexes as a scaffold for folic acid (FA) targeted plasmid DNA delivery [194]. Similarly, lipid-coated AuNPs functionalized with FA as gene vectors for targeted gene delivery was found to be gathering at the specific tumor site and demonstrated improved in vivo gene delivery capability. Additionally, no significant damage was observed in the animal after treatment [195]. Hyaluronic acid-modified polyamidoamine dendrimer G5-entrapped AuNP conjugated with METase gene significantly impedes the gastric tumor by targeted destruction of the mitochondrial function of CD44 (+) gastric cancer stem cell [196]. Restraint of the interaction between p53 and HDM2 is a persuasive therapeutic approach in cancers that harbor a wild-type p53 protein such as retinoblastoma (RB). Taking this into consideration, Kalmodia et al. utilize the biocompatible of AuNPs to deliver anti-HDM2 peptide to RB cells [197]. Furthermore, it was suggested that upregulation of p53 might presumptively mediate apoptosis through the induction of p53-inducible (micro-RNA oligonucleotides) miRNAs [197]. Because of the size-dependent SPR effect, AuNPs have confirmed the successful delivery of small interfering RNA (siRNA) to the target site [198]. Florentsen et  al. have recently quantified the loading of specifically attached miRNA AuNPs. Furthermore, they also demonstrated that it can be released from the AuNP by the thermoplasmonic mechanism inside living cells [198]. Similarly, Bonoiu et al. utilized the siRNA complexed Au nanorods (AuNRs) conjugated with DARPP-32 to target dopaminergic neurons [199]. Furthermore, these nanoplexes were demonstrated to emigrate through an in vitro model of the blood-brain barrier (BBB) [199]. siRNA vector based on noncovalently conjugate of siRNA-AuNP core enveloped into a lipid layer provides proficient cellular internalization of siRNA followed by precise gene silencing [200]. Recently, AuNRs loaded with hTERT siRNA assembled on the surface of nanofibers for mild photothermal effect with improved cellular internalization of AuNRs-siRNA and the succeeding release of siRNA in the cytoplasm was reported by

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Qin et al. [201]. Both phenomena intensify the gene-silencing effect and accordingly offer the possibility of greater therapeutic outcome [201]. Qiu et al. demonstrated the utilization of 5-poly-(amidoamine) dendrimers partly grafted with β-CD as a nanoreactor to entrap AuNPs for improved cellular internalization of siRNA to glioblastoma (GBM) cells [202]. AuNP DENPs-β-CD carrier facilitates the efficient delivery of siRNA to glioma cells, additionally, it shows acceptable biocompatibility once conjugated with the siRNA, and permits enhanced gene silencing and block the expression of Bcl-2 and VEGF proteins [202]. Min et al. prepared a theranostic AuNRs that grant the photoacoustic imaging along with combined gene and photothermal therapy [203]. This combined therapy using siRNA/Zn(II)DPA-AuNRs demonstrated the extensive antitumor activity in a PC-3 tumor mouse model [203]. The annihilation of gene expression of nerve growth factor (NGF) may have a great perspective in pancreatic cancer treatment [204]. Au nanocluster-aided siRNA (AuNC-siRNA) delivery allows efficient NGF gene silencing and improved pancreatic cancer treatment. The AuNC-siRNA complex results in improved stability, prolonged systemic circulation time of siRNA, enhanced cellular uptake, and tumor accumulation of siRNA [204]. Furthermore the AuNC-siRNA composite effectively downregulates the NGF expression in Panc-1 cells and in pancreatic tumors and potently inhibits the tumor progression in pancreatic tumor models [204].

13.4.2 Silver nanoparticles The therapeutic uses of Ag have been documented in the traditional system of medicine since 1000 BC. Ag has a long history of being used as a health additive in traditional Indian and Chinese medicine. AgNPs generally represent the particles of Ag with the size range of 1–100 nm in size [21]. AgNPs have impressively attracted the attention of the scientific community because of their versatile range of accepted biomedical application especially their potency against microbes, antiinflammatory effects, and wound healing properties [249, 250] including drug delivery, diagnosis, and coating for medical devices [250]. Functionalized AgNPs have gained momentous interest as DDS, and promising substrates controlled the release of therapeutic agents at targeted in vivo. Furthermore, AgNP biocompatibility via enhanced surface modification along with noteworthy optical properties [251] have also improved the appropriateness of AgNP state-of-the-art DDS.

13.4.2.1 AgNPs in drug delivery Ag is an oligodynamic antimicrobial agent, that is, exposure to relatively low concentrations of the metal can result in considerable reduction of viable microbes. Clinical significance of AgNPs as the effective antimicrobial agent in wound care has fortified nanomedicine research with AgNPs. Furthered antimicrobial activity of AgNPs may be due to improved permeability of Ag+ in microbial cells enabling the destruction of the cell [205]. Furthermore, AgNPs have a great perspective to unravel the complications of MDR bacteria [252]. Additionally, AgNPs disrupt the formation of biofilm with solid surface and thus prevent MDR [206].

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Salvioni L et al. developed the AgNPs with potent antimicrobial activity with low toxicity, suitable for pharmaceutical preparations administrable to humans and/or animals as needed [207]. Similarly, Chowdhury et al. [208] reported the green synthesis of AgNPs with potent antimicrobial activity against clinically relevant pathogens such as E. coli, P. aeruginosa, S. aureus, and S. epidermidis. Notably, these green AgNPs were nontoxic to human dermal fibroblasts (HDFs) [208]. Park et al. suggested the green synthesis of resveratrol (Res)-loaded Ag nanocarrier for antibacterial activity [209]. Furthermore, Res-AgNPs revealed the greater antibacterial activity against gram-positive and gram-negative bacteria compared with that of Res alone [209]. Similarly, silver core@silica mesoporous (AgMSNPs) and dye-doped silica NPs functionalized with ofloxacin show excellent antibacterial activity against S. aureus and E. coli [210]. Another green approach for the fabrication of AgNPs for broad-spectrum antimicrobial potency against an array of bacterial pathogens with remarkable MIC was reported by Khan et al. [211]. Abdellah et al. studied the biological activity of Agcurcumin (CUR) nanoconjugates (NCs) [212]. Further, they reported that conjugation of CUR with Ag in the nanometric systems results in improved photostability of CUR. Moreover the enhanced antibacterial activity of the Ag-CUR-NCs) with minimal toxicity to skin cells was also observed [212]. It is a great achievement to develop a novel nanometric system for the labeling, targeting, and therapy for cancer. The attainment of any therapeutic agents for tumor stance by its potential to reduce/eliminate a tumor without any inconvenience to neighbor healthy tissues. As discussed earlier, NPs conjugated with therapeutic and or targeting moieties offer great developments in therapeutics through target/site specificity. For example, Muhammad et al. used MTX-conjugated and PEG-capped AgNPs for anticancer activity. The conjugated AgNPs show excellent anticancer activity against MCF-7 cell line [213]. Furthermore the hemolytic activity of these conjugated NPs was considerably less than MTX alone [213]. Al-Sheddi et al. [214]developed the green-synthesized AgNPs for Human cervical cancer cells (HeLa). The cell cycle analysis and apoptosis/necrosis assay data exhibited AgNP-induced SubG1 arrest and apoptotic/necrotic cell death [214]. Yadav et al. [215] investigated the antiproliferative activity of Camellia sinensis-mediated AgNPs on MCF-7 human breast cancer cell line, MOLT-4 human leukemia cancer cell line, and HT-29 human colon cancer cell line. The synthesized AgNPs exhibited superior activity against these three different human cancer cell lines [215]. Similarly, Fard et al. reported that green-synthesized AgNPs show significant cellular toxicity against A549 cell line [216]. Eugenio et al. [217] investigated the antiproliferation activity of temozolomide (TMZ) conjugated Ag/AgCl-NPs against GBM02 cells (and of human astrocytes). The combined treatment (Ag/AgCl-NPs + TMZ) inhibited the proliferation of GBM02 by more than 50% [217]. Zhao et  al. developed a multifunctional magnetic/Ag theranostic nanocomposite conjugated to an epidermal growth factor receptor cetuximab (C225) against nasopharyngeal carcinoma cell (NCEs) [253]. Furthermore, MTT analysis revealed that magnetic/Ag/C225 theranostic nanocomposite could constrain the proliferation of CNEs in a dose- and time-dependent manner [253]. Biocompatible triplex Ag/SiO(2)/ mTiO(2) core-shell NPs for bimodal imaging and Dox delivery was developed by Wang et al. [218]. Furthermore, they demonstrated that drug-loaded core-shell NPs

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perform superior therapeutic activity compared with the free drug, due to the improved cellular internalization [218]. Dox-conjugated AgNPs coated with folic acid (Dox-AgNPs-FA) to target the folate receptor on tumor cell was developed by Wang et  al. [219]. Dox-AgNPs-FA shows exceptional receptor-mediated cellular uptake. Furthermore, Dox was slowly released from Dox-AgNPs-FA into the cytoplasm, and apoptosis was induced [219].

13.4.2.2 AuNPs in gene delivery AgNPs can be functionalized to incorporate nucleic acid that makes them ideal for gene therapy. For example, Lee et al. [220] developed AgNP oligonucleotide conjugates based on DNA. This technique was an important step toward the multipurpose application of nanomedicine including molecular diagnostic labels [220]. Quercetin (Qe) combined with AgNP-conjugated siRNA (Qe-AgNPs/siRNA) was developed by Sun et al. [221]. Qe-AgNPs/siRNA demonstrated the enhanced effect on many kinds of bacteria, including the most prominent MDR species. The in vitro study suggested that Qe-AgNPs/siRNA could demolish the cell wall and prevent further bacterial propagation [221]. Following intravenous tail injection of Qe-AgNPs/siRNA in the bacteremia mice model, systemic infection of bacteria and the inflamed cells in the tissues gradually decrease [221].

13.4.3 Magnetic nanoparticles The drug delivery application of magnetic nanoparticulate system (MNS) has evolved since late1970s [254–256]. MNS consists of core-shell structure, where the core is an iron oxide, that is, magnetite (Fe3O4) or maghemite (γFe2O3) and is usually polymer such as dextran, PVA or silica, or other heavy metal such as Au [257–259]. Furthermore a number of different groups have reported the fabrication of magnetoliposomes [260– 264]. These MNSs have typical iron oxide core surrounded by the liposome. MNS offers some extraordinary possibilities in nanomedicine. Their controlled particle size distribution places them at dimensions that are comparable with virus, protein, or gene [258, 259]. This makes them enable to get close to a biological entity of interest [258, 259]. Furthermore, they follow the Coulomb’s law and can be manipulated to respond time-varying magnetic field [257, 258, 265].

13.4.3.1 MNS in drug delivery In magnetically targeted delivery, therapeutic moieties are conjugated with biocompatible MNS and administrated into the patients via parenteral routes. After the administration of MNS into systemic circulation, external, high-magnitude magnetic fields are applied manually to direct the conjugates toward target inside the body (Fig. 13.6) [258, 259, 264]. Once the drug/MNS conjugate congregated at a specific site, the drugs are released by either change in physiological condition such as pH, temperature, or via enzymatic activity [222, 223]. For example, targeted delivery of MNS in the form of ferrofluids (FFs) bound to anticancer agent mitoxantrone (MXT) to treat the squamous cell carcinoma in rabbits was developed by Alexiou et al. [222].

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Fig. 13.6  Schematic representation of a MNS delivery system: high magnitude magnetic fields are applied manually to direct toward target.

Following IV administration, application of external magnetic field results in thorough and enduring absolution of squamous cell carcinoma with no sign of toxicity [222]. Furthermore the concentration of the FFs-MXT in the tumor region, which was under the influence of an external magnetic field, was found to be much higher than in the absence of one [223]. Recently, several anticancer drugs including Dox, MTX, and PTX have been conjugated with MNS for cancer-targeted drug delivery. Liang et al. [224] developed the functionalized superparamagnetic iron oxide (SPIO) NPs conjugated with doxorubicin (Dox) (SPIO-Dox) for a tumor magnetic resonance imaging (MRI) enhancement and chemotherapy. The in vitro study suggested that DNA cross-link was more serious and results in lower DNA expression and more cell apoptosis for HT-29 cancer cells [224]. Furthermore the in  vivo study demonstrated the better accumulation of SPIO-Dox at the tumor site and significantly smaller tumor size with minimal cardiotoxicity and hepatotoxicity [224]. Similarly, FA-conjugated bifunctional MNS for targeted delivery of Dox was reported by Rana et al. [225]. Furthermore, enhanced cellular internalization of the functionalized MNS in cancer cells overexpressing folate receptors was confirmed by fluorescence microscopy and flow cytometry studies [225]. Mosafer et al. investigated the SPIONs-Dox coloaded theranostic NPs against murine C26 colon carcinoma cell. Greater cellular uptake of SPIONs-Dox followed by a considerably enhanced antitumor activity and prolonged survival of mice bearing

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C26 colon carcinoma xenografts was observed [226]. Furthermore, they found that these conjugated MNS enhance the contrast of MRI at the target site [226]. Citric acid-biocompatibilized MNS for codelivery of Dox and melittin (MEL) was demonstrated by Hematyar et  al. [227]. The in  vitro anticancer activity on MCF-7 breast cancer cell line demonstrated a synergistic effect between DOX and MEL, which led to significantly potent antitumor efficacy [227]. Recent studies have demonstrated the use of thermosensitive magnetoliposomes conjugated with Dox for in vitro and in vivo cytotoxicity in rat glioma C6 [228]. The in vitro results suggested that cell viability decreased to 79.2% after heat treatment alone and to 47.4% for Dox-loaded magnetoliposomes without application of alternating magnetic field [228]. The in vitro experiments showed that the cell viability decreased to 79.2% after heat treatment alone [228]. Also, in vivo results demonstrated that magnetic drug targeting has a strong antiglioma effect with a tumor volume growth inhibition and complete regression [228]. Dual-targeting strategy for codelivery of PTX- and CUR-loaded magnetic PLGA NPs was developed by a combination of magnetic guidance and transferrin ­receptor-binding peptide T7-mediated active targeting moiety [229]. The combined drugs yielded synergistic effects with more than 10 times upsurge in cellular uptake and inhibition of tumor growth. Additionally, the antiglioma treatment efficacy of the delivery system revealed greater treatment effectiveness and reduced adverse effects [229]. Similarly, effective tumor-specific targeting in the presence of external magnetic field was observed with novel PTX-loaded biocompatible MNS [230]. A dual cancer treatment approach by integrating cold atmospheric plasma (CAP) with PTXloaded MNS for targeting A549 cells was demonstrated by Yu et al. [231]. An in vitro study displayed the synergistic effect of CAP and PTX on growth inhibition of A549 cells [231]. Furthermore, it was also observed that CAP induces the accumulation of PTX-loaded MNS inside the tumor cells and increases the minimum effective drug concentration to a level that might be favorable to reduced drug resistance [231]. Wang et al. evaluated the PTX-loaded MNS for antitumor effects in the human brain (GBM) U251 cells [232]. PTX-MNS was proficiently internalized by the U251 cells. Moreover, inhibition of the targeted cell proliferation, migration, and programmed cell death was also observed [232]. Similarly, Zheng et al. explored the theranostic efficacy of tumor-specific, pH-responsive, peptide-modified, magnetoliposomes-PTX [233]. Furthermore, in vivo antitumor activity confirmed the theranostic effectiveness of magnetoliposomes-PTX in MDA-MB-231 tumor-bearing model [233]. RiveraRodriguez et  al. reported that MNS hyperthermia potentiates the PTX efficacy in sensitive and resistant breast cancer cells [234]. Recent investigation has suggested the enhanced potency and concentration-dependent cellular internalization of PTXloaded SPIO-PEGylated NPs against GBM [235]. Furthermore, enriched accumulation of NPs in the brain of GBM-bearing mice with magnetic targeting was confirmed by the ex vivo biodistribution study [235]. Also, in vivo safety evaluation proved that it does not induce any systemic toxicity compared with Taxol [235]. Farjadian et al. [236] demonstrated that hydroxyl-modified MNS is a powerful carrier for MTX to be applied as an anticancer agent. They investigated the anticancer behavior of MTX conjugated MNS on MCF-7 cell line, which showed enhanced cellular toxicity [236]. Tumor-destructive importance of MTX-coupled MNS (MTX-MNS)

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along with magnetic heating (Nanochemothermia) was investigated by Stapf et  al. [237]. Nanochemothermia remarkably reduced the tumor volume in the murine bladder xenograft model. Moreover, nanochemothermia also impair the induction of angiogenic signaling by diminishing the levels of VEGF-R1 and MMP9 [237]. Similar, Wu et  al. investigated the magnetic nanocomposite MTX delivery system against cancer MCF-7 and HepG2 cancer cell line [238]. Furthermore the in  vitro study confirmed the potency of nanocomposites against cancer while low toxic to normal cells [238]. Li et al. developed a MTX-loaded theranostic NPs for chemophotothermal treatment (PTT) [239]. Furthermore, preferential enhanced targeting and accumulation to tumor cells, pH/laser-responsive release, and high tumor cell-killing efficiency was observed with prepared theranostic NPs [239]. Nosrati et al. studied the in vitro cytotoxicity study of MTX conjugated MNS against MCF-7 breast cancer cell line [240, 241]. The prepared MTX-MNS showed a considerable anticancer activity against MCF-7 cell line [240, 241]. Furthermore, hemolysis assay and cytotoxicity study that results on HFF-2 and HEK-293 cell lines show that as-prepared MNPs were biocompatible [241].

13.5 Metallic nanotoxicity Nanoparticulate systems are benefitting humankind from past several years among these MNPs that have strong potential for use in biomedical applications such as drug design and delivery systems. However, in  vivo fate and toxicity are critical aspects when applying MNPs for therapeutic and diagnostic purposes, which is prerequisite for evaluation. Different engineered MNPs have been developed for biomedical applications, and the effect of these NPs is established by several factors. Among these factors, particle size and shape and aptitude to intermingle with the neighboring tissue significantly impact the toxicity of MNPs. These particulate systems cause overload to the phagocytic cells, reducing defensive mechanism and further reduced the immunity strength of body. Due to the nonbiodegradable nature or slow degradation rate, these NPs may accumulate in the different organs and exposed to the organism, because of their high surface area. Due to this interaction, NPs can affect the proteins and enzymes and thus disturb the various biological processes within the body. Globally, various researches have been carried out by the scientists on the toxicity issues of NPs. Boyes et al. stated that the NPs could be situated in three locations that is (1). in the luminal wall of brain microvascular endothelial cells, (2) in the astrocyte foot processes, or (3) maintained by the basement membrane [266]. Hirst et al. stated that CeO2 NP biodistribution and its potential applications are related to their hazard taxation. It was observed that after subcutaneous injection of silver NPs in rats, it is transferred to the blood and distributed throughout the brain. After analysis, swollen astrocytes, BBB destruction, and neuronal degeneration were observed in the rat model [267]. Ma et al. found that after administering high dose of nanoparticulate anatase TiO2, it may lead to brain injury and also alter some glial into filamentous shapes

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and some into inflammatory cells [268]. Wang et  al. injected TiO2 nanosuspension via the gastrointestinal tract and observed the fatty degeneration of the hippocampus and brain lesions in ICR mice [269]. In another study, TiO2 NPs was administered subcutaneously to pregnant mice. It was translocated to the offspring and found that it affects the daily sperm production by reducing the total count and ultimately affects the genital system of the male offspring. It was also observed that the cranial nervous system was also altered, and an elevated number of apoptosis cells was found in the olfactory bulb of the brain [270]. Gold nanoparticles have been shown great potential in the arena of biomedical applications, but the facts about their toxicity issues in animals are still very limited. The different findings have been reported related to the fate and toxicity of AuNPs in different animal models such as mice, rats, rabbits, and swine. Many researchers have been reported that the biodistribution of AuNPs was depended on the size of NPs. Sonavane et al. investigated the biodistribution of different size of citrate-coated AuNPs (15, 50, 100, and 200 nm) after IV administration in mice. In biodistribution study, it was found that all sizes of AuNPs were presented in different organs like the liver, lungs, and spleen, but the highest amount of AuNPs were accumulated in all the tissues including the blood, liver, kidneys, lung, spleen, stomach, heart, and brain that were found for 15-nm AuNPs. Remarkably, it was observed that 15- and 50-nm AuNPs were able to cross the BBB, while 200-nm AuNPs show very small presence in different organs such as the blood, stomach, and brain [271]. Cho et al. found that single intravenous administration of 13-nm PEG-coated AuNPs in mice could induce acute inflammation and apoptosis in the liver. They also observed that these NPs were accumulated up to 7 days in the liver and spleen and also had a long systemic circulation. Further, it was stated that PEG-coated AuNPs were also found in different cytoplasmic vesicles, spleen macrophages, and lysosomes of liver Kupffer cells [272]. From the different biodistribution studies, we can find that irrespective of the animal models, size and dosage, and coating of the AuNPs, after AuNPs administration, the main targeted tissues are mainly the liver and spleen. Both of these are the part of the immune system and engaged in the uptake and metabolism of exogenous bodies. The deposition of AuNPs in the lungs was observed due to the protein recognition by collectins, which help to form a group of surfactant proteins responsible for innate immunity in the lungs [273]. Additionally, AuNPs were also investigated that it crosses the BBB and accumulate in the brain, [271] which may cause an adverse effect to the neural systems. Iron oxide NPs also have shown great interest in terms of its clinical applications for diagnostic and therapeutic uses due to their promising biocompatibility and biodegradability behavior. Several studies found the accumulation of iron in different tissues via administering iron oxide NPs by different routes. Kim et al. [274] observed that after IP administration of silica-/RITC-coated magnetic nanoparticles [MNPs@ SiO2(RITC)], NPs was quantified in different organs such as the lungs, liver, kidneys, spleen, brain, heart, testes, and uterus. Here, RITC reflects Rhodamine B isothiocyanate. Maximum concentrations of iron were estimated in the liver and spleen. Additionally, MNPs@SiO2(RITC) were also found to cross the BBB. In general, iron oxide NPs were found physiologically well tolerated as per toxicity issues [275].

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However, Zhou et al. observed that the γ-Fe2O3 after inhalation led to oxidative stress, which was allied with a proinflammatory response in the lungs, in a dose-dependent manner [276]. Zhu et al. reported that Fe2O3 NPs exposure (i.t. installation using twosized Fe2O3 particles (22 and 280 nm)) to the lungs could persuade oxidative stress [277]. Wang et  al. reported the adverse impact on the central nervous system after inhalation of Fe2O3 NPs due to the occurring of neuron fatty degeneration in the CA3 area of the hippocampus [278]. Wang et al. performed a neurotoxicity study in mice by repeated low-dose intranasal administration of nano- and submicron-sized iron oxide particles. A greater alteration and a more significant response were observed in the case of nanosized Fe2O3 than the submicron-sized particles. After the treatment with Fe2O3 NPs, ultrastructural modifications in nerve cells of the olfactory bulb and slight dilation in the rough endoplasmic reticulum were observed in TEM images. An increased number of lysosome in the hippocampus was also found [279]. These findings showed that intranasal administration of nanosized Fe2O3 NPs could induce more severe oxidative stress and damages to nerve cell in the brain as compared with larger particles. A prolong retention of dextran-coated iron oxide NPs were observed in the liver and spleen of mice. After analyzing NPs deposited in these organs, no morphological changes or any damaged cells were observed [280]. Silver nanoparticles (AgNPs) are being used commercially for the wide range of the products [281]. Different studies have been done related to the distribution and deposition of AgNPs. After administering AgNPs in rats either by subcutaneous injection or inhalation, particles have been quantified in various organs such as the lungs, liver, spleen, kidney, and brain [282]. Moreover, in contrast to others NPs, AgNPs have shown more toxicity related to cell viability, lactate dehydrogenase leakage, and generation of reactive oxygen species [283]. Differently coated AgNps showed different grades of cytotoxicity. Foldbjerg et al. have stated dose-dependent cytotoxicity and cellular DNA adduct formation after administering polyvinyl-/pyrrolidone-coated AgNP nm to human lung cancer cell line in the size range of 6–20 [284]. One more study also showed that peptide-coated AgNPs were more cytotoxic as compared with citrate-coated silver NPs of the same size (20 nm). In this study, human leukemia cell line was used, and the cytotoxicity was determined by WST-1 assay [285]. It is required to address the toxicity-related problems of AgNPs in suitable experimental models in terms of standard protocols with respect to the liver, lungs, kidney, and central nervous system disorders and prominently subjected to endocrine functions.

13.6 Conclusion In this chapter, we described a detailed outline about the MNPs, their types, synthesis, physiochemical properties, and their potential biomedical applications. We also discussed the toxicity related studies of different MNPs. Due to their small nanosize range, MNPs possess large surface area, which makes them an appropriate candidate for different diagnostic and therapeutic applications. Different synthetic techniques can be valuable to control the size and specific morphology of MNPs. However, MNPs

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are useful for various drug delivery applications, but still, there are some health-risk alarms raised due to their accumulation in various organs of interest and passes the BBB. Various reports have been stated about toxicity issues of MNPs based on different mechanisms. Different presumed mechanisms of toxicological damage have been evaluated, that is the generation of reactive oxygen species, protein misfolding, membrane perturbation, and direct physical damage. Uncontrollable use and expulsion to the natural environment is another factor, which should also be considered to make the use of MNPs more suitable and eco-friendly. In conclusion a hands-on approach is needed, and the regulatory concerns should follow for fabrication and application of MNPs. In addition, to facilitate the safe development and execution of engineered MNPs, a fundamental understanding of metallic toxicity could also have a constructive sequel.

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Oluyomi Stephen Adeyemia, Chiagoziem Anariochi Otuechereb, Adewale Adewuyic, Anne Adebukola Adeyanjud, Oluwakemi Josephine Awakana, David Adeiza Otohinoyie a Medicinal Biochemistry, Nanomedicine and Toxicology Laboratory, Department of Biochemistry, Landmark University, Omu-Aran, Kwara, Nigeria, bDepartment of Biochemistry, Redeemer’s University, Ede, Osun, Nigeria, cDepartment of Chemical Sciences, Redeemer’s University, Ede, Osun, Nigeria, dDepartment of Biological Sciences, McPherson University, Seriki-Sotayo, Ogun, Nigeria, eAll Saints University, College of Medicine, Belair, Saint Vincent and the Grenadines

14.1 Introduction Nanotechnology is an emerging field that encompasses the production of materials with nanoscale dimension in the range 1–100 nm. The nanoscale size gives these materials their uniqueness and properties that distinguish them from bulk materials [1]. Among the several nanomaterials known, metal nanoparticles have been outstanding with a wide range of applications, which cuts across different fields of research. Metal nanoparticles may be synthesized with the possibility of improving on its functionality by way of modification with biocompatible chemicals, which allows them to be coupled with drugs and antibodies [2]. One of the common methods used for the synthesis of metal nanoparticle includes the use of organic solvents and toxic reducing agents [3, 4]. Unique properties exhibited by metal nanoparticles have granted them applications in different areas like materials science, physics, chemistry, and medicine [3]. These superb properties are based on their shape, size, surface morphology, and polydispersity. These properties enhance their interaction with biomolecules on cell surfaces and within cells promoting applications in drug delivery and disease treatment. However, they are expected to be biocompatible, selective toward the target site, and stable over a period. Precious metals such has gold in their nanoparticle present more excellent properties, which make them find more applications and as a result placing more demand on them. The small size of nanoparticles confers unique properties such as enhanced reactivity and increased surface area-to-volume ratio among others. Together, these properties not only do engender the exploration of nanoparticles for diverse applications in different disciplines but also do underscore the prospects of nanoparticles for use in cellular or tissue-specific targeting, tight barrier transport, codelivery of drugs for combination therapy, enhanced bioavailability of poorly water-soluble drugs, and permission of a real-time assessment of drug

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­efficacy [5–7]. For example, in the biomedical field, there is an increasing application of nanoparticles in drug delivery, antiinfective agents, diagnostics, and therapeutics [8]. Nanoparticles have been applied to improve drug half-life, drug solubility, and disease diagnosis [9]. Additionally, nanoparticles have been used to circumvent various setbacks associated with the traditional protocol in drug formulations such as poor drug efficacy and potency due to undesirable degradation, a big particle size impeding the blood barrier penetration, and side effects from certain drugs such as in the case of chemotherapy [6, 7, 9]. Current advancement in nanotechnology has been attracting attention to nanoparticle research, most especially in the field of medicine. The initiative and concept of using nanoparticle in medicine are taken as a means to find an alternative to the current treatment for multifactorial diseases such as cancer. Most currently available treatments for cancer include radiation therapy, chemotherapy, and surgery. These treatments have been used in a long time and have recorded success but with some shortcomings, thus underscoring search for better treatment options [10]. Nanotechnology offers the platform for addressing some cancer therapy shortcomings with the capacity of specifically targeting tumor cells without harming healthy tissues. Nanoparticles hold prospects for various applications in diverse disciplines due to their unique properties, for example, their distinctive sizes; they have been reported to have the ability to cross the blood-brain barrier and able to reach targets that were previously reported difficult to access [11]. Furthermore, comparative analysis showed that 100-nm nanoparticles had a higher uptake by 2.5 when compared with 1-μm particles and by 6 when compared with 10-μm particles [12]. Though particles at 200 nm and more tend to activate the lymphatic system leading to faster clearance, it has been observed that particles at 100-nm diameter tend to be ideal for drug delivery [13]. Apart from particle size the surface properties play a major role. It is usually expected that the surface of NPs used in drug delivery has the ideal targeting ligands, the stability and receptor binding of the drug, and the proper surface curvature and reactivity, thus preventing aggregation [14]. Since nanoparticles have a tendency to be hydrophobic, increasing their binding to plasma components, causing increased clearance, thus the idea of coating NPs with hydrophilic materials like polymers, surfactants or copolymers has been linked with increased bioavailability time [7]. Aside from the general properties of nanoparticles necessary for drug delivery, the ability of nanoparticles to easily and slowly off-load the drug to the targeted site is necessary [7, 14]. Although the type of nanoparticles used determines how the drug is off-loaded at target sites, it also depends on temperature, pH, drug solubility, drug diffusion rate, and NP matrix erosion for easy drug distribution [7, 14a].

14.2 Gold nanoparticles and drug delivery applications Among various nanoparticles, metallic nanoparticles have been identified to have a good drug delivery advantage [15]. For example, gold NPs (AuNPs), due to their negative charge, can be functionalized using diverse materials. AuNPs are also biocompatible and nontoxic, with macroscopic quantum tunneling effect and surface plasmon

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resonance bands, which aid their drug delivery potential [16, 17]. Gold nanoparticles are particles of gold in the nanoscale within the size range 1–100 nm. This is also referred to as colloidal gold, which when in solution can either be an intense red or a dirty yellowish color. It can exist in the oxidation states of + 1 and + 3; however, it preferably exists in the nonoxidized state. It is very stable in its nanoform and being a good electron conductor, and it has strong optical response. It also shows strong optical character extending from visible to a near-infrared range, which is referred to as a surface plasmon resonance band [18]. It has unique properties due to its small size. Depending on the manufacturing route and method, it can be produced into various shapes and sizes. The crystallinity can also be controlled; usually, anisotropic shapes are produced using stabilizing polymers to control growth, which goes a long way in achieving properties of interest. It may exist in different shapes such as nanorod, nanocluster, nanoshell, branched, nanocube, nanosphere, and nanostar as shown in Fig. 14.1 [19]. The different shapes have become useful tools in cancer diagnostics and therapeutic development due to their optical and physical properties.

14.2.1 Preparation of gold nanoparticles Several methods have been used in the past to achieve the synthesis of gold nanoparticle, but this can be grouped into two. The top-down and bottom-up methods [20]. For the latter the synthesis of gold nanoparticles stems from individual molecules due to chemical and biological reduction, which takes place in two stages (nucleation and successive growth), while for the former, bulk gold is broken to smaller forms, which later generate the nanoparticle of required specification. The steps involved depend on the specific property required. Different techniques have also been embraced in the preparation making use of metal ion precursor. Some of these include ­electrochemical,

Nanocluster Nanorod Nanoshell

Nanostar

Branched Nanosphere Nanocube

Fig. 14.1  Shapes of gold nanoparticle [19].

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solvothermal, chemical, photochemical, laser, and irradiation [21]. One of the commonly used method of producing gold nanoparticle is the Turkevich method. This method involves the use of sodium citrate that reduces AuCl 4 − in hot aqueous solution to produce gold nanoparticle of specific size. However, to produce particles of various sizes, method developed by Brust et al. [22] that makes use of NaBH4 to reduce gold salts in the presence of alkane thiols is preferable. Recently, Iqbal et al. [23] described the synthesis of gold nanoparticles by NaBH4 reduction method.

14.2.1.1 Gold nanoparticle as a tool in cancer diagnostics and treatment Currently available treatments for cancer include radiation therapy, chemotherapy, and surgery. These treatments have been used in a long time and have recorded success but with some shortcomings, thus underscoring search for better treatment options. Features, such as physical, chemical, and biological properties of nanoparticles, can be manipulated, and these have opened up various possibilities to explore them in drug delivery [24]. Gold nanoparticles have become the first choice for researchers among the various organic and inorganic nanoparticles, due to its unique optical and surface plasmon resonance (SPR) properties. Its optical properties are employed in ultrasensitive detection and imaging-based therapeutic techniques for the treatment of deadly diseases, such as cancer [25]. Cancer is a disease state caused by abnormal cell growth. Currently the treatment of cancer depends on the use of chemotherapeutic drugs, which involves chemotherapy or radiation therapy, to target and kill the cancer cells [26, 27]. However, there are limitations due to several side effects that are often associated with these treatments because of the damage caused to the surrounding healthy tissues. Now, with the utilization of a nanoparticle-based drug delivery approach for treating cancer cells, these limitations would be overcome [26, 27]. Properties such as nonimmunogenicity, size, and nontoxicity make gold nanoparticle viable for the treatment of cancer functioning mostly as tumor-targeting delivery agents. This has in recent times focused more on enabling higher dose delivery to target tissues in biological systems and as such reducing nonspecific side effects. Study involving the use of gold nanoparticle has shown effectiveness against the treatment of human breast carcinoma cells [28]. Practically, gold nanoparticle functions as an agent for treating cancerous cells by bringing clusters of the nanoparticle into the cancer cell while blasting the affected region with infrared laser pulse. This energizes the gold nanoparticles, increases its temperature, and finally destroys the cancer cells without destroying the healthy cells since the nanoparticles are not administered to the level of clustering the healthy cells. The most commonly used method of administering the gold nanoparticle is the receptor-mediated endocytosis [29] as illustrated in Fig. 14.2. The gold nanoparticles are selective toward the cancer cells easily leaving the healthy cells. This is promoted by modifying the nanoparticles with an antibody that specifically recognizes the cancer cell, clusters round it, and attaches firmly to the surfaces of the cancer cells. The antibody drives this process. This stage is followed by exposing the tissue to a laser pulse that penetrates the tissue without the gold nanoparticle absorbing the laser light but warms up the gold nanoparticles that eventually heats up the cancer cells and dries the surrounding fluid within the cells to destroy them

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Fig. 14.2  Illustration of receptor-mediated endocytosis. From O'Day D.H., Introduction to the Human Cell: The Unit of Life & Disease, 2nd ed., Emeritus Press, USA, 2012, 300pp. ISBN-13: 978-1-4566-0970-2.

[30]. A recent study by Yang et al. [31] revealed the significant role gold nanoparticle plays in reducing the side effects of currently known techniques in cancer treatment via a combined use of radiation therapy and chemotherapy. It was reported that gold nanoparticle has the capacity of enhancing a local radiation dose and controlled delivery of anticancer drugs. Previous studies also showed that gold nanoparticle could enhance radiation dose and serve as an anticancer drug carrier [31–33]. This serves as a platform for tumor-targeted drug delivery and in chemotherapy. This drug delivery ability of gold nanoparticles has numerous advantages over the direct application of drugs. These include increased bioavailability to a tumor site, flexibility of combining different treatment techniques, and enhanced specificity toward a target tumor [34, 35]. A previous study revealed PEGylated gold nanoparticles perform to expectation when applied in treating a tumor with no reoccurrence of disease [36]; other studies have also showed the conjugation of gold nanoparticle with photosensitizers to be effective in cancer treatment [37].

14.2.1.2 Theranostic application of gold nanoparticles A classical definition of theranostics as a novel multifunctional approach describing materials that optimize the dual roles of therapy and diagnostic imaging has been put forward [37a]. With respect to nanosized materials, nanotheronostics entails the coupling of treatment delivery with therapy response monitoring in real time, thereby decreasing the potential of over- or underdosing patients. Synthesis of nanoscale structures of inert metals like gold is currently generating heightened interest because gold nanoparticles possess excellent optical and physical properties, which are attractive for several biomedical applications. For more effective treatment of cancer, AuNPs are

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being deployed for diagnostic and therapeutic purposes simultaneously. Specifically the ability to passively accumulate on tumor cells provides AuNPs the opportunity to become an attractive contrast agent for X-ray-based computed tomography (CT) imaging in vivo [38]. Using photothermal therapy with AuNPs proved effective against gastrointestinal adenocarcinoma with the destruction of cancer cells and in vivo effects ranging from tumor volume regression to complete remission of the tumors [39]. The theranostic potential of gold nanoparticles has also found relevance in the treatment of prostate cancer. Currently, patients are subjected to radical prostatectomy, but this could result in incontinence and impotence, especially in patients with incomplete prostatectomy during surgery. In view of this a AuNP-based theranostic agent targeting prostate-specific membrane antigen has been developed. This nanoparticle system, loaded with a fluorescent photodynamic therapy drug, Pc4, is expected to provide surgical guidance for prostate tumor resection and therapeutic intervention when surgery is insufficient [40]. Similarly, generating current interest is the theranostic application of gold nanoparticles in virus detection. Over the years, there had been technical difficulties in establishing systems for virus detection, largely due to the simple structure and nanoscale size of viruses. However, AuNPs are presently being employed to detect various viruses (Hantaan, Rift valley fever, Ebola, Dengue, Hepatic C viruses etc.) [41]. Hopefully, this powerful technique will positively impact on the global objective of virus control and elimination.

14.2.1.3 Gold nanoparticles in cancer immunotherapy Immunotherapy is a type of cancer treatment that targets stimulation of the host immune system so that it can recognize and eliminate cancer cells that could bypass the immune recognition. Cancer cells have the potential to downregulate the expression of surface antigens and the costimulatory molecules, thereby reducing recognition by and stimulation of T cells [42]. In addition, immunosuppressive cytokines such as IL-10 and TGFβ are also secreted by tumor cells, thereby creating an environment that is not conducive to dendritic cell (DC) maturation. More so, they have ability to induce apoptosis in T cells [42]. Finally, cancerous tissue can also attract a number of immune suppressive cell types to the tumor microenvironment. Therefore the goal of cancer immunotherapy is to target these immune suppressive populations and then stimulate immune effector cells against tumors. Recently the prospects of AuNPs in immunotherapy delivery have been reported [43]. The AuNPs are inert but can be functionalized, and their sizes and/or shapes can easily be modified to serve as carriers for ligands or drugs for delivery. Furthermore, their optical properties can also be harnessed for the purpose of immune therapies [44]. Few of the likely mechanisms of action of gold nanoparticles in cancer immunotherapy are as follows.

Attenuation of TLR9/IL-1β and TGF-β1 pathways In recent times, AuNPs have been attracting attention for immunogenic effects. For example, the ability of AuNPs ( 150 degrees, the interaction of a liquid phase with a solid phase [15, 20, 21]) and externally low roll-off angle ( 150 degree), while a high degree of atomic defects showed a superhydrophilic behavior with zero-degree contact angle. The results demonstrated that the roughness was not significantly different for different specimens and by increasing of hydrophilic nature the platelet activation was promoted [27]. The interior surface of blood vessels is covered with a monolayer of ECs with glycocalyx layer, which prevents protein adsorption as initiating step of thrombus formation [28– 31]. Recently, negatively charged glycosaminoglycans were organized into a polymer brush with nanoscale domains to mimic the EC’s glycocalyx. The interaction of albumin and fibrinogen as the two important blood proteins with the prepared surface showed the irreversible adsorption of these proteins onto glycocalyx-mimicking layer. Further investigations with single-molecule microscopy showed a new mechanism that glycocalyxmimetic nanostructures prevent the formation of fibrin networks on the surface [32].

31.2.1.1 Methods for fabrication of nanostructured surfaces Nanostructured surfaces have a high surface-to-volume ratio, which makes them advantageous for biological applications [33]. The nanoscale structure can facilitate the proliferation of cells and tissue healing [33, 34]. Therefore design and fabrication of nanostructured surfaces in the field of biomaterials are attractive for scientists. This section reviews the anodization, chemical etching, and electron beam physical vapor deposition methods as the common nanosurface fabrication approaches.

Fig. 31.4  Defect-rich nanoassembly of 2-D MoS2. (A) Formation of various degrees of atomic defects in MoS2 by changing the ratio of sulfur precursors. (B) Wettability behavior of various atomic defect structures. (C) The roughness (Rq) morphology and values of samples obtained by AFM analysis for 400- and 25-μm2 imaging area. (D) SEM images of various atomic defects in MoS2 nanoassemblies with an average size of 1.5–3 μm. (E) Platelet adhesion and activation on MoS2 samples. Reproduced with permission from M.K. Jaiswal, K.A. Singh, G. Lokhande, A.K. Gaharwar, Superhydrophobic states of 2D nanomaterials controlled by atomic defects can modulate cell adhesion, Chem. Commun. (2019).

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31.2.1.2 Anodization Nanoscale surface can be produced by various approaches, and the anodization is the simplest and the most cost-effective method [35]. In 1857, for the first time, Buff reported that aluminum can form a thicker oxide layer in an aqueous solution when electrochemically oxidized, which is known as anodization phenomenon [36]. Anodization is an electrochemical approach to produce nanotubes, nanopores, and other nanostructured morphologies on metallic materials [37–41]. Ti sheet is a common substrate for anodization and production of nanotubes [42–45]. The nanotubes have been formed by using a mixture of 0.5-wt% hydrofluoric acid and acetic acid at the anodization voltage of 20 V and different concentrations [34].

31.2.1.3 Chemical etching Chemical etching is an effective approach to create nanostructured morphology on metallic and polymeric substances [37]. Wet chemical etching has been employed to produce nanoscale surface. The results demonstrate that by enhancing the etching time, the surface topography shifts from nanometer roughness (10 min of etching) to micrometer-sized roughness (90 min of etching) [46, 47].

31.2.1.4 Electron beam physical vapor deposition Micro- and nanoenvironment of the intimal layer that facilitate endothelial cell attachment and elongation were fabricated using electron beam physical vapor deposition. Primarily, electron beam physical vapor deposition method was applied to pure titanium to evaporate it into NPs, which were deposited on the template and altered the roughness. Then the poly(dimethylsiloxane) (PDMS) was casted to produce textured patterns. The results demonstrate PDMS films with periodic arrays of nanogrooves (500 nm) with spacings of 22–80 μm [48].

31.2.2 Nanoparticles Nanoparticles (NPs) have special properties and mostly used as drug delivery vehicles. They can be functionalized with drug molecules to deliver them to target sites [37, 49, 50]. It has been shown that hybrid collagen-based cardiac patches containing gold NPs are able to enhance the expression level of connexin-43 in rat cardiomyocytes under electrical stimulation and recover the cardiac function of a myocardial scar model. In addition, the results displayed an increase of vascular density and shrinkage of scar tissue [51]. Carbon nanotubes (CNTs) as conductive nanomaterials can be used to increase the viability and function of cardiomyocytes [52–55]. For example, single-walled CNTs were dispersed in gelatin hydrogel to prepare tissue-engineered cardiac tissue. The CNTs in these structures provided native microarchitecture, which leads to myocardial contractility and the expression of electrochemical associated proteins [56]. Among blood-contacting surfaces, small-diameter (