Biological Applications of Nanoparticles [1st ed. 2023] 9819936284, 9789819936281

Table of contents :
Preface
Role of Nanotechnology in Healthcare Industries
Role of Nanotechnology in Agriculture
Role of Nano-Agrochemicals
Nanofertilizers
Nanopesticides
Nanobiosensor
Role of Nanotechnology in Food Sectors
Role of Nanotechnology in the Environment
Role of Nanotechnology in Aquaculture
Role of Nanotechnology in Economic Growth
Acknowledgements
About the Book
Contents
Editors and Contributors
Abbreviations
1: Fundamentals and Analytical Techniques for Biological Applications of Nanomaterials
1.1 Introduction
1.2 Types of Materials Used for Biological Applications
1.3 Synthesis Routes of Nanoparticles
1.4 Chemical Approach
1.4.1 Chemical Reduction
1.4.2 Sol-Gel Process
1.4.3 Chemical Vapor Deposition (CVD)
1.4.4 Electrochemical Process
1.5 Biological Synthesis of Nanoparticles
1.5.1 Fungi-Mediated Nanoparticle Synthesis
1.6 Characterization of Nanoparticles
1.7 Characterization Techniques
1.7.1 Scanning Electron Microscopy
1.7.2 Transmission Electron Microscopy (TEM)
1.7.3 Atomic Force Microscopy
1.7.4 High-Performance Liquid Chromatography
1.7.5 Liquid Chromatography-Mass Spectrometry
1.7.6 Matrix-Assisted Laser Desorption Ionization Time-of-Flight (MALDI-TOF) Mass Spectrometry (MS)
1.7.7 Scanning Electrochemical Microscopy (SECM)
1.7.8 Surface Enhanced Raman Scattering (SERS)
1.7.9 X-Ray Diffraction (XRD)
1.7.10 Dynamic Light Scattering (DLS)
1.7.11 X-Ray Photoelectron Spectroscopy (XPS)
1.8 Conclusion and Future Perspectives
References
2: Emerging Applications of Nanotechnology in Human Welfare with Special Reference to Biomedical Issues
2.1 Introduction
2.2 Nanotechnology in Medicine and Healthcare
2.2.1 Physicochemical Properties of Nanomaterials for Medicine
2.2.1.1 Size and Surface Area
2.2.1.2 Shape
2.2.1.3 Surface Charge
2.2.1.4 Composition and Chemistry
2.2.2 Drug Delivery
2.2.3 Therapeutics
2.2.4 Antibacterial/Antiviral Therapy
2.2.5 Tissue Regeneration
2.2.6 Diagnosis
2.3 Other Applications
2.3.1 Environment
2.3.1.1 Water Purification
2.3.1.2 Soil Remediation
2.3.2 Agriculture
2.3.3 Aquaculture and Fisheries
2.4 Challenges and Future Perspectives of Nanotechnology
2.5 Conclusion
References
3: Role of Biogenic Inorganic Nanomaterials as Drug Delivery Systems
3.1 Introduction
3.2 Complementary Characteristics of Inorganic NPs as Effective Drug Delivery Vehicles
3.3 Mechanism of ROS Production by NPs and NPs-Mediated Toxicity
3.4 Biogenic Gold NPs (AuNPs)
3.4.1 Characteristics
3.4.2 Potential Role of AuNPs in Enhanced Drug Delivery Vehicles
3.5 Biogenic Silver NPs (AgNPs)
3.5.1 Characteristics
3.5.2 Anticancer and Theranostic Application of Biogenic AgNPs
3.5.3 Antimicrobial and Antibiofilm Potential of AgNPs
3.6 Characteristics and Prospects of Nano Drug Delivery Systems
3.6.1 Surface Charge, Size and Shape of Nano Drug Delivery Systems
3.6.2 Efficient Drug Loading and Release Characteristics of Nano Drug Delivery Systems
3.6.3 Efficient Cellular Uptake and Transport of Nano Drug Delivery Systems
3.7 Competence of Biogenic Inorganic NPs in Immunomodulating Cancer Environment
3.8 Conclusion
References
4: Modeling of Nanorobots and Its Application Toward Medical Technology
4.1 Introduction
4.1.1 Targeted Drug Delivery
4.1.2 Sensing of Biological Targets and Detoxification
4.1.3 Precision Surgery
4.2 What Is Nanorobot
4.2.1 Nanosensors
4.2.2 Locomotion for Bio-Nanorobot
4.2.2.1 Modeling of Blood Flow in Arteries for Diagnostic Application of Bio-Nanorobot
4.2.2.2 Motion Control of Bio-Nanorobot for Targeted Disease Cure
4.2.3 Power Supply to Bio-Nanorobot
4.2.3.1 External Source
4.2.3.2 Internal Source
4.2.4 Communication with Nanorobot
4.3 Gaps and Future Scope of Nanorobots in Medical Field
References
5: Polymer Nanoparticles and Their Biomedical Applications
5.1 What Is Polymeric Nanoparticles?
5.2 Distinctive Features of PNPs
5.3 Preparation Technique of PNPs
5.3.1 Polymerization of Monomer
5.3.1.1 Emulsion Polymerization
5.3.1.2 Surfactant-Free Emulsion Polymerization
5.3.1.3 Mini-Emulsion Polymerization
5.3.1.4 Micro-Emulsion Polymerization
5.3.1.5 Interfacial Polymerization
5.3.1.6 Radical Polymerization
5.3.2 Dispersion Methods (Performed Polymer)
5.3.2.1 Solvent Evaporation
5.3.2.2 Emulsification-Solvent Diffusion
5.3.2.3 Salting-Out
5.3.2.4 Spray Drying
5.3.2.5 Dialysis
5.3.2.6 Nanoprecipitation
5.3.2.7 Fast Evaporation
5.3.2.8 Freeze Drying
5.3.2.9 Freeze Extraction
5.3.2.10 Spreading Evaporation
5.3.2.11 Supercritical Fluid Technology (SCF)
5.3.3 Ionic Gelation or Coacervation of Hydrophilic Polymers
5.4 Block Copolymer-Based Nanoparticles
5.4.1 Polymer Dendrimer
5.4.2 Polymer Micelles
5.4.3 Polymer Drug-Conjugates
5.4.4 Polyplexes
5.4.5 Polymerosome
5.4.6 Nanogel or Hydrogel
5.4.7 Stimuli-Responsive Nanomaterial
5.5 Polymer-Based Nanocomposites
5.6 Polymer Nanocomposites (PNCs)
5.7 Biocompatibility of PNPs
5.8 Cellular Response to PNPs
5.8.1 Phagocytosis
5.8.2 Macropinocytosis
5.8.3 Clathrin-Dependent Endocytic Pathway
5.8.4 Caveolae- (Lipid Raft) Mediated Endocytosis
5.9 PNP-Induced Immune Modulation and Vaccination Strategies
5.10 Immune Evasion
5.11 PNP-Induced Toxicity
5.12 Biomedical Applications
5.12.1 Cancer
5.12.2 Wound Healing
5.12.3 Dentistry
5.12.4 Antimicrobial Polymers
5.13 Conclusions
References
6: Nanotechnology and Plant Biotechnology: The Current State of Art and Future Prospects
6.1 Introduction
6.1.1 Nanotechnology and Its Evolution in Bioscience
6.1.2 Need of Nanotechnology in Plant Science
6.1.2.1 What Kind and Type of Nanoparticles Have Revolutionized the Biotechnology and Plant Biotechnology Sector?
6.1.2.2 What Decides the Compatibility of the NPs to the Plant World and Agriculture Applications
6.1.3 Application in Various Domain
6.1.3.1 Nanotechnology and Plant Tissue Culture
6.1.3.2 Nanotechnology and Their Role in Plant Defence Mechanisms´ Abiotic Stress Tolerance of Plants
6.1.3.3 Some Advanced Application of Nanotechnology in Plant Biotech and Agriculture
Nanoparticle as Plant Signalling Molecule Sensor and Nanosensors
Seed Nano Priming
Light Collection and Use Are Facilitated by Nanotechnology: nIR and UV Light Conversion to Visible Light and Increased Electro...
Nanotechnology and Gene Sequencing
Post-Harvest Loss Reduction
6.1.3.4 Application of NPs in Plant Biotechnology and Agriculture
Plant Transformation Using NPs
6.1.4 Abiotic Stresses Control Through Nanopesticides and Nanofertilizers
6.1.4.1 Biotic Stresses Control Through Nanopesticides and Nanofertilizers
6.2 Conclusion
References
7: Functionality and Applicability of Bionanotechnology in Food Preservation
7.1 Introduction
7.2 Natural and Synthetic Nanostructures in the Food Systems
7.2.1 Metallic and Polymeric Nanocomposite Used in Food Preservation
7.2.1.1 Composites with Metallic Nanoparticles
Silver
Copper
Gold
Titanium Dioxide
Zinc Oxide
7.2.1.2 Composite with Polymer Nanocomposite
Nanoclay
7.2.2 Functionality of Food Nanotechnology
7.2.2.1 Protection Against Biological Deterioration
Antimicrobials
Increasing Bioavailability
7.2.2.2 Protection Against Chemical Ingredients
Antioxidants
Flavours
7.2.2.3 Enhancement of Physical Properties
Colour Additives
Anticaking Agents
Others
7.2.3 Nanotechnology in Food Safety and Preservation
7.2.3.1 Nanoparticles for the Detection of Food Borne Pathogens
7.2.3.2 Nanoparticles for Protection from Allergens
7.2.3.3 Nanoparticles for Preventing Heavy Metal Reduction
7.2.3.4 Nanoparticles for the Inhibition of Biofilm Formation
7.3 Application of Nanostructures in Food Preservation Sector
7.4 Future Prospects
7.4.1 Are Nanotechnology and Big Data Effective Enough for Next Industrial Revolution for Securing ``Smart Food´´?
References
8: MOF: A New Age Smart Material as Nano Carriers for Fertilizers and Pesticides
8.1 Introduction
8.2 Metal Organic Framework: A Brief History
8.2.1 Synthesis of MOF
8.2.1.1 Traditional Synthesis Methods
8.2.1.2 Electrochemical Synthesis
8.2.1.3 Sonochemical Synthesis
8.2.1.4 Microwave-Assisted Synthesis
8.2.1.5 Mechanochemical Synthesis
8.2.2 Characterization of MOF
8.2.2.1 Powder X-Ray Diffraction
8.2.2.2 Gas Adsorption-Desorption Study
8.2.2.3 Scanning Electron Microscopy
8.2.2.4 Transmission Electron Microscope
8.2.2.5 Thermogravimetric Analysis
8.3 Micronutrients
8.3.1 Iron
8.3.2 Manganese
8.3.3 Zinc
8.3.4 Copper
8.3.5 Molybdenum
8.4 Fertilizers
8.4.1 Classification of Fertilizers
8.4.1.1 Nitrogenous Fertilizers
8.4.1.2 Phosphorous Fertilizers
8.4.1.3 Potassium Fertilizers
8.5 Conventional Methods of Application vs Nanocarriers
8.6 Role of Metal Organic Framework in Agrochemical Delivery
8.7 Conclusion and Future Aspect
8.7.1 Conclusion and Future Aspect
References
9: Nanotechnology: An Answer for Mitigating Future Challenges in Aquaculture
9.1 Introduction
9.2 Nanotechnology´s Application in Aquaculture´s Various Frontiers
9.2.1 Nanotechnology for Improved Culture Systems
9.2.2 Nanotechnology in Fish Nutrition
9.2.2.1 Effect on Fish Growth
9.2.2.2 Nano-Encapsulation Technology to Increase Bioavailability
9.2.3 Fish Breeding and Gonadal Development Using Nanotechnology
9.2.4 Nanobiotechnology in Aquaculture Biotechnology
9.2.5 Nanotechnology for Fish Health Management
9.2.5.1 Nanomaterials for Diagnosis of Fish Diseases
9.2.5.2 Nanomaterials as Nanomedicine
9.2.5.3 Delivery of Nano Vaccines
9.2.6 Nanotechnology for Food Safety and Quality Assurance
9.2.6.1 Sensors for Fish Freshness
9.2.6.2 Detection of Amine
9.2.7 Nanotechnology for Aquatic Ecosystem Health Management for Sustainable Aquaculture
9.2.7.1 Nanoscale Iron for the Breakdown of Pollutants
9.2.7.2 Nanocomposites for the Removal of Pollutants
9.3 Nanotoxicity-The Cause of Concern
9.4 Conclusion
References
10: Nano-Informatics: Studies on Nano Information Platforms and Their Application in Various Sectors
10.1 Introduction
10.2 Platforms of Nanoinformatics
10.2.1 Databases of Nanoinformatics
10.2.1.1 ISA-TAB Nano
10.2.1.2 NBI Knowledgebase
10.2.1.3 CaNanolab
10.2.1.4 Toxicity Database (OECD and TOXNET)
10.2.1.5 Nanomaterial Registry
10.2.1.6 Nanoparticle Information Library (NIL)
10.2.1.7 InterNano
10.2.1.8 National Toxicology Program Database
10.2.1.9 Nanotechnology Characterization Laboratory (NCL)
10.2.2 Modelling Tools
10.2.2.1 Avogadro
10.2.2.2 Visual Molecular Dynamics (VMD)
10.2.2.3 ChemSketch
10.2.3 Visualization Software
10.2.4 Molecular Docking
10.2.4.1 AutoDock
10.2.4.2 Dock
10.2.4.3 PatchDock
10.2.4.4 GOLD and FlexX
10.3 Challenges of Nanoinformatics
10.4 Application in Industrial Sectors
10.5 Future Prospective
References
11: Nanotechnology for Pesticide Sensing
11.1 Introduction
11.1.1 Need for Pesticides
11.1.2 Types of Pesticides
11.1.3 Role of Organic and Inorganic Pesticides in Agricultural Practices
11.1.4 Detrimental Effect of Pesticides
11.1.5 Persistent Pesticides
11.2 Diagnosing of Soil Health
11.2.1 Assessment of Persistent Pesticide Levels
11.2.2 Pesticide Sensor
11.2.3 Nanotechnology-Based Sensors
11.2.3.1 Enzyme Biosensors (Inhibition-Based Biosensors)
11.2.3.2 Catalytic Biosensors
11.2.3.3 Whole Cell Biosensors
11.2.3.4 Electrochemical Sensors
11.2.3.5 Optical Sensors
11.3 Nanobiosensors for Pesticide Detection
11.4 Pesticide Contamination of Ground Water and Its Diagnosis Through Nanosensors
11.4.1 Nanosensors Adopting Optical Sensing
11.4.2 Nanosensors Adopting Electrochemical Sensing
11.5 Conclusion
References
12: An Overview of the Impact of Nanotechnology on Economy and Business
12.1 Introduction
12.2 Industry-Wise Analysis
12.2.1 Agriculture and Food
12.2.2 Construction Industry
12.2.3 Electronics and Communication
12.2.4 Environment
12.3 Exploiting Nanotechnology Commercially: Applications in the Food Packaging Industry
12.4 Progress of Nanotechnology: Role of the Government
12.5 Intellectual Property and Economy
12.6 Nanotechnology: What Are the Negative Sides?
12.7 Concluding Remarks
References
13: Nanotoxicological Issues in Agriculture and Related Regulatory Framework
13.1 Introduction
13.2 Application Areas Nanotechnology in Agriculture
13.3 Categorization of Nanomaterials in Agriculture and Food Sector
13.4 Risk Assessment of Nanomaterials
13.5 Protocols for Toxicity Evaluation of Nanomaterials
13.6 Regulatory Frameworks of Nanomaterials for Agri-Food Systems
13.7 Conclusion
References
14: Intellectual Property Management in Nano-Biology Research
14.1 Introduction
References

Citation preview

Biological Applications of Nanoparticles Biplab Sarkar Avinash Sonawane Editors

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Biological Applications of Nanoparticles

Biplab Sarkar • Avinash Sonawane Editors

Biological Applications of Nanoparticles

Editors Biplab Sarkar ICAR-Indian Institute of Agricultural Biotechnology Ranchi, Jharkhand, India

Avinash Sonawane Department of Biosciences and Biomedical Engineering Indian Institute of Technology Indore Indore, Madhya Pradesh, India

ISBN 978-981-99-3628-1 ISBN 978-981-99-3629-8 https://doi.org/10.1007/978-981-99-3629-8

(eBook)

# The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

Dedicated to my respected parents

Preface

In the last few decades, the field of ‘nanotechnology’ has expanded rapidly and is synonymous with nation building. Several engineered nanomaterials have been developed by altering the atomic arrangements and chemical compositions, which has profusely contributed to the development of mankind. This book describes the holistic role of nanotechnology and nanoscience, which have made an impact in the mainstream of scientific disciplines, i.e. material science, biological science, and engineering. specially by generating commercial vibes in every echelon of modern biology. Researchers have considered nanotechnology as ‘tiny materials with huge potential’ paving ways for exciting findings and possibilities. These whole ideas and concepts were brought forward back in December 29, 1959, by physicist Richard Feynman who acknowledged the glaze of nanotechnology entitling with the phrase, ‘There’s Plenty of Room at the Bottom’. In recent years, nanotechnology has embraced itself with the strong foundation, providing best, top-notch nanomaterials with multiple applications. The term ‘nanotechnology‘ was coined by Norio Taniguchi. Its prefix ‘nano’ denotes one billionth (thus 1 nm is 1/1 billionth of metres). One can picture ten hydrogen atoms making up about one nanometre. Hence, we need instruments to visualize the nanoscale size. Higher depth of explorations was accelerated when ‘scanning tunnelling microscope’ was developed that can monitor individual atom. Further, advanced machinery/instrument has been developed to investigate the nanoforms more intricately, which would be discussed later (Fig. 1). The ‘terminology’ of nanoscience and nanotechnology is interconnected. Nanotechnology deals with the study of fundamental principles of nanostructures, and nanotechnology deciphers its innovative applications in varied fields. Nanomaterials are defined as engineered particles with a molecular size ranging between 1nm to 100 nm. It is usually classified based on their size, origin, form, shapes, and dimensions. For size-based classification, it includes any one dimensional structures which are less than 100 nm. For classifying nanostructures based on their forms and shapes, amorphous, crystalline, composite, and polymeric forms as well as diversified shapes like spheres, rods, cones, tubes, and fibres play important roles in application. On the basis of origin, it is classified into natural, incidental, and engineered. The physical properties are linked with their size as well as their chemical compositions such as non-metal, metal, metal oxides, semiconductors, etc. vii

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Fig. 1 Timeline for major discoveries of nanotechnology

Due to structural speciality and large surface-to-volume ratios, nanomaterials exhibit novel and innovative properties which comprise chemiluminescence, high photoluminescence, quantum efficiency, optical stability, biocompatibility, cellular permeability, etc. These inherent phenomena offer physical, optical, magnetic, and chemical differences than other bulk materials and trigger great flexibility to incorporate in biomedical and other applications including nanomedicine, bioelectronics, biosensors and biochip, DNA and protein biology, constructing delivery models, etc. Detailed discussions would be followed in upcoming chapters. Several synthesis methods have been developed to synthesize nanomaterials via physical, chemical, biological, or green methods. To characterize the size and stability of nanomaterials, various high-throughput instrumentation is used including SEM, TEM, FESEM, DLS, UV-VIS spectrophotometer, AFM, XRD, and FTIR. All discussions on the related topics will be elaborated in later chapters. The highlighted applications of nanotechnology in various fields are listed below (Fig. 2).

Role of Nanotechnology in Healthcare Industries Nanomedicine is an emerging interdisciplinary field of healthcare portraying an interplay between nanotechnology and medicine. This developing field targets different physiological processes at the nanoscale level employing nanotechnology-based treatments, devices, and instruments. Nano-

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Fig. 2 Application of nanotechnology at different frontiers of biological science

therapeutics has surpassed the conventional medicines by imparting better dose response, lower toxicity, increased solubility, and enhanced bioavailability. These exceptional attributes pave the way for various biomedical applications of nanomaterials. In 2020, as per data mentioned by National Science Foundation (NSF), majority of start-up companies in the nanotechnology sector focuses on biomedical applications due to its exceptional and unique properties which significantly impact the interaction between cells and biomolecules. For instance, carbon nanotubes have been employed to transport biomolecules precisely into cells with high efficiency. Similarly, nanoparticles are applied to generate remarkable images of the tumour region. More biomedical applications use biosensor as a diagnostic tool for the purpose of gene and drug delivery. The current scenario of health issues is posing a threat to mankind worldwide. There are increased cases of various complex diseases such as Alzheimer’s, Parkinson’s, and cardiovascular diseases. Most prevalent cases of diabetes and cancer have raised global concern. Nanotechnology shows promises to deal with such critical problems by incorporating it with other innovative hybrid technologies. Another exhilarating discovery of nanotechnology introduced the development of efficient carriers to deliver drugs. For this purpose, nanomedicine is employed using nano-sized particles/carriers for enhancing the bioavailability of the drug. To maximize the bioavailability of drugs with slow release and specific molecular target, nano-robots are used. Other nano-engineered devices are introduced for the effective treatment of complex diseases such as cancer. It has been reported that biocompatible nanotools are able to locate the cancerous cells and have the ability to self-evaluate the disease, which also help in the treatment of the disease. Currently, for in vivo imaging, nanotools are equipped to process images used in MRI and ultrasound. Nano-sponges are used for drug delivery, in which drugs interact weakly within the nano-size matrix and enhance the bioavailability of drugs. It can be used to deliver drugs

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specifically at the sites in a controlled manner and cause hindrance in drug and protein degradation. As nanotechnology is expanding, its contribution to health and medicine is escalating; there are several applications other than nanomedicine, which is benefitting mankind. Studies have shown certain nanoparticles are employed as a label or tags, which has improved the sensitivity of disease testing. The incorporation of nanotools in gene sequencing has facilitated its process; mostly gold nanoparticles are used which tag itself with shorter segments (aptamer) of DNA for efficient detection of DNA sequences. Some reports have also concluded that nanotechnology can be used in tissue engineering, for repair of damaged tissues, artificial implants, and transplantation of organs.

Role of Nanotechnology in Agriculture Agriculture is a significant and stable sector responsible for economic growth of the country as it provides staple food and raw materials for various industries. The Agri-sector deals with a wide range of challenges such as climate change, reduced crop yield, deprivation of soil nutrients, decline in soil fertility, degradation of biotic elements in the soil, pathogenic infections in the crops, water drought, devoid of awareness about genetically modified organisms, and less workforce. The potential benefits of nanotechnology and nanoscience have significantly improved agricultural inputs and can provide solutions to attain sustainable development of the agricultural sector. Nanotechnology has the potential to alter the scenario of the agriculture system by improving crop yield and simultaneously conserving the ecological balance, sustainable development of the environment, and economic stability.

Role of Nano-Agrochemicals The nano-inputs used in agriculture, namely nanopesticides, nanosensors, nanofertilizers, and nano-improved products, have been employed in agricultural industries along with their objective to promote higher efficiency with environmental sustainability.

Nanofertilizers Conventional fertilizers are less effective and 8-90% is lost via volatilization and leaching. Nanofertilizers have several benefits when compared with conventional fertilizers, as their quantity is significantly decreased by slow release of the product. Nanofertilizers comprise various nanoparticles such as iron, zinc, silica, titanium oxide, etc. They help in the controlled release of the nano-elements and enhance yield productivity of the crop. Other various modified nanostructure elements have been incorporated in fertilizers to

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enhance its functionality, such as P/ZnS core shell quantum dots and gold nanorods. It has been reported that in alkaline soils deficiency, zinc is very familiar which limits agricultural productivity and can be compensated by Zinc-based nanofertilizers. It can provide plants its nutrients when required. Reports have shown that the intelligent ability of fertilizers in nanoscale form modifies the signal transmission of internal root systems. With all information, it is imperative to mention that nanofertilizers have high efficiency, reduced amount of dosage, and decline in nutrient losses in the surrounding, and help to attain sustainable agriculture.

Nanopesticides The applications of nanomaterials in plant protection against its pathogens are underexplored. It is eminent that pests are prevalent in agricultural fields affecting crops; thus nanopesticides play a significant role in the control of pests and pathogens. The modern development of nanopesticide formulation has controlled release properties with other beneficial attributes such as stable, precise, soluble, and permeable. The properties are significantly achieved by assuring the active ingredients from early degradation or enhance their efficiency of pest control for a long term. The formulation of nanopesticides leads to a decrease in the imparting dose of pesticides which is eco-friendly for humans and crop protection. Reports have shown that different formulations of nanopesticides have been introduced such as polymeric nanoparticles, inorganic nanoparticles (copper, silver, titanium dioxide), carbon nanoparticles (graphene), and nano-emulsions having cidal properties against bacteria, fungi, and pests. Recently potential nanocarriers for precise pesticide delivery have gained popularity which comprise nano-emulsions (include an oil phase, water, and surfactant) and have unique properties such as optically and kinetically stable size ranging from 20 to 200 nm. Other than nanopesticides, nano-herbicides and nano-weedicide have also been developed to tackle unwanted weeds growing and scavenging nutrients from the crops.

Nanobiosensor Biosensors are a hybrid system of transducer and receptor anticipating physical and chemical properties of the medium. Nanobiosensors are a more innovative and modified prototype of biosensors. It is connected with susceptible elements to observe the specific fragment with the help of physiochemical transducer. These sensors favour early detection, and thus quick decisions were implemented to boost the crop yield. Some unique characteristics of nanobiosensors include high sensitivity, long-term stability, large surface-volume ratio, and quick electron transfer kinetics. The applications of biosensor have been actively explored, by the use of nanoparticles including gold, cobalt, silver, and quantum dots. It has been reported that nanobiosensors are efficient to detect the analytes available in the

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soil and water bodies. More promising innovation has been conducted, to develop portable nanobiosensors by using paper chip technique incorporated with the nanosystem.

Role of Nanotechnology in Food Sectors Nanotechnology has remodelled the conventional method for food sectors. Its application has extended to varied fields of food science including food microbiology, processing and packaging, safety, and preservation. General classification has been done to summarize the applications of nanotechnology in food industries, nano-oriented food ingredients employed as food additives, smart nutrient delivery, nano-fillers for enhancing the durability of the material used in packaging termed as ‘smart packaging’, nano-detection of food such as gases, chemicals, and food pathogens and also helps to add nutritive value to the food increasing its quality. Food industries are adopting the smart packaging system, because it has several benefits other than increasing the shelf lives of the food. Furthermore, nano-coating on the food surface acts as a barrier, even it has antimicrobial properties extending the shelf life of the food product. It has been reported that silver NPs have been used in plastic food bins serving as disinfectant for controlling the growth of pathogenic microbes. More innovative approaches in nanotechnology have been introduced such as food labelling including nano-based inks smartly recognized by nanosensors.

Role of Nanotechnology in the Environment Nanotechnology has brought a revolutionary approach for counteracting challenges such as pollution hindering the natural functioning of the ecosystem. Usually, soil and groundwater are contaminated by toxic pollutants including organic and inorganic toxicants. To tackle these challenges, nanotechnology has provided a cost-efficient way to eliminate heavy metals, volatile organic compounds (VOCs), dyes, and other contaminants from the water sources. It has been reported that several nano-compounds such as bio-nanocomposites and super-adsorbent hydrogels are efficient to treat wastewater. Studies have shown that soil remediation is carried out by metal oxide nanoparticles and carbon nanotubes having propensity to absorb toxic contaminants from the soil. Other than the remediation process, nanotechnology also directly influences soil productivity; for instance, nano-zeolites and nanoclays increase the water holding ability of soils facilitating slow water release during hydric scarcity. This system can be used for both reforestation and agriculture. Nano-purification systems are being designed to purify water, since more than 60% demand of water is going to be increased by 2030. The purification system is based on improvement in analysis monitoring, disinfection, desalination, water conservation, recycling and sewage treatments with improvement in lifestyle.

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Role of Nanotechnology in Aquaculture Aquaculture has significantly contributed to food security in recent decades by meeting the enormous need for simple, digestible, animal protein. However, environmental deterioration and the prevalence of diseases are seen as the industry’s major impediments. Nanotechnology can offer innovative approaches for administering medications and introducing vaccinations, which has the potential of ensuring the pathogen-free, cultured protection of farmed fish. Other uses in the marine and aquaculture industries include water purification, fish pond sterilization, fish nutrition with nanofeed, and the control of aquatic diseases. Nanotechnology has frequently been utilized to clean water and produce fish. The use of nanotechnologies in seawater shrimp farming exhibits that the nanosystem was able to enhance water quality, reduce water exchange rates, and increase shrimp survival and productivity. Also, the fishing and aquaculture industries may set an example by integrating nanotechnology with cutting-edge innovations including rapid disease diagnosis and enhanced fish absorption of hormones, medications, and nutrients.

Role of Nanotechnology in Economic Growth The demand of nano-based goods is globally increasing. It is a basic necessity of comprehending the potential benefits on environment, human beings, and overall ecosystem. In international market, nano-based products were evaluated to be 8.5 billion US dollars in 2019. A prediction has been made that the growth would be at 13.1% annual rate between the year 2020 and 2027 (NEW YORK, Oct. 5, 2016 /PRNewswire/--). The rapid share of nanotechnology associated with its versatile application of nanostructures used in the medical and health sector, cosmetics, aeronautics, food sectors, agriculture, environmental remediation, automobiles, paints and coating, etc. is increasing leaps and bounds. The commercial growth of nanotechnology is due to its unique nanomaterial attributes, and usually metal nanoparticles such as graphene, silver, zinc, tellurium, gold, and copper are widely used in several consumer products. Current book entitled Biological Applications of Nanoparticles is a holistic illustration of modern biological utilities of nanoparticles encompassing the fields like medicine, agriculture, fishery, environment, bioinformatics, food technology, and sensors which will work as substantial foundation of knowledge for students and budding researchers to launch carrier in this interdisciplinary subject. Moreover, some new and innovative chapters like nanotechnology in the interphase of patent laws and IPR, business, regulatory issues and policy, etc. are also incorporated to make students aware of societal and commercial aspects of this new technology. Hence, our attempts of editing this book will be proved successful when it will help to ignite and

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trigger young minds to think, accept, and initiate future research using nanotechnological tools for biological innovations. Ranchi, Jharkhand, India Indore, Madhya Pradesh, India

Biplab Sarkar Avinash Sonawane

Acknowledgements

The current book Biological Applications of Nanoparticles is a product of teamwork by learned authors and peer editorial team. Hence, I would like to extend gratitude to all contributors for sharing chapters on important topics related to nanotechnology and biology interactions. It gives me immense pleasure to express my gratefulness to Dr. Arunava Pattanayak, Director, ICAR-IIAB, Ranchi, Jharkhand, and Dr. T.R. Sharma, Joint Director (Research), ICAR-IIAB, Ranchi, Jharkhand, for their support and inspiration for developing a student friendly book on biological applications of nanotechnology. Furthermore, I would like to extend my obligation and appreciation to Mr. Rishav and Miss Rima for their valuable contributions and hard work during the editing of the book. Moreover, I would like to express my gratitude towards Dr. Bhavik Sawhney, Senior Editor, Springer Nature (Biomedicine) for his help and guidance during the journey of editing this important book.

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About the Book

In recent years, nanotechnology has emerged as a multi-disciplinary subject at the interphase of engineering, material, physical, chemical, and life sciences. Due to its engineering origin, nanotechnology tools showed a delayed entry into biological research and development, and primarily as a xenobiotic candidate. At the first phase of nano-bio intervention, it somehow focused towards biomedical field introducing novel drug delivery systems, nanomedicines, nano-diagnostic, nano-machines, etc. However, second and third generation nanomaterials have recently been introduced illustrating 3D-based nanocomposites, nano-inspired gene editing, nano-microfluidicbased diagnostics, nanosensors, and nanochips, and these innovations are demanding discussion. But other important sectors specially related to agrarian economy like agriculture, food science, bio-energy, environment along with social implications of these technology also require attention. There are wide differences in the mode of applications when shifting of nanotechnology practices is undergoing from lab to land, minute to major, transportable quantities. In this regard, nanoscale delivery of agricultural input like fertilizer, pesticide, feed, and medicine is revolutionizing the innovations as well as nano-business arena. Field applications of nanotechnology tools require cautions towards the occupational health around peripheral ecosystem. Hence, awareness of environmental safety and policy is the need of the hour to begin any endeavour and venture in this regard. On the other side, bio-nanotechnology, DNA and protein nanotechnology, and nano-bioinformatics are developing as a finest tool at the outcome of extensive research conglomerating nanotechnology and biotechnology. The proposed applications of DNA and protein nanotechnology are wide-ranging pervading medical technologies like targeted drug delivery to nanolithography, constructing molecular imprinting for enzymes, polymers, antibodies, and designing AI-based memory in nano-electronics. Nano-biobusiness is innovation-driven commerce, which is a projected 125 billion US Dollar market by 2024 and nanoparticles like graphene oxide, carbon nanodots, and mesoporous silica are performing meticulously and future nano-technocrats should be aware of these pecuniary matters. Intellectual property regimes in nanobiology are advancing at a rapid pace with the highest rate of patent filing. As nanotechnology is a science of converting

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conventional materials into nanoscale, proper knowledge and modalities of IPR are required to venture into nano-innovation. In this scenario, a textbook is highly needed to showcase the recent trends and advances in the subject and to highlight the gaps which are dominantly prevalent. This breach is functioning as a barrier to free exchange of knowledge, ideas, intellectual property as well as business acumen across the disciplines and sectors. To this end, our effort to present a compiled textbook entitled Biological Applications of Nanoparticles is a cordial endeavour. This textbook written by experienced and erudite domain experts contains a plethora of knowledge illustrating recent progress in applied aspects of nanotechnology and nanobiotechnology encompassing medicine, agriculture, fishery, environment, etc. Moreover, it focuses on nanotechnology research and its versatile biological applications to make the student ready for any future footstep.

About the Book

Contents

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Fundamentals and Analytical Techniques for Biological Applications of Nanomaterials . . . . . . . . . . . . . . . . . . . . . . . . Jasmine Swain, Niharika Das, Jatin K. Sinha, Rojalin Sahu, and Soumya R. Mohapatra Emerging Applications of Nanotechnology in Human Welfare with Special Reference to Biomedical Issues . . . . . . . . . . . . . . Tanishq Meena, Yogesh Singh, V. S. Sharan Rathnam, Tanmay Vyas, Abhijeet Joshi, and Avinash Sonawane

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Role of Biogenic Inorganic Nanomaterials as Drug Delivery Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hira Ateeq, Afaf Zia, Qayyum Husain, and Mohd Sajid Khan

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Modeling of Nanorobots and Its Application Toward Medical Technology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Koena Mukherjee and Anup Kumar Sharma

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Polymer Nanoparticles and Their Biomedical Applications . . Monika Singh and Pradip Paik

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Nanotechnology and Plant Biotechnology: The Current State of Art and Future Prospects . . . . . . . . . . . . . . . . . . . . . 101 Sourav Das, Saikat Ghosh, Abishek Bakshi, Shweta Khanna, Birendra Kumar Bindhani, Pankaj Kumar Parhi, and Rahul Kumar

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Functionality and Applicability of Bionanotechnology in Food Preservation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 Rachna Yadav, Shweena Krishnani, Niharika Rishi, Ragini Singh, and Rajni Singh

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MOF: A New Age Smart Material as Nano Carriers for Fertilizers and Pesticides . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 Sanchari Basak, Puja Bhattacharyya, Prasad Eknath Lokhande, and Sandip Chakrabarti

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Contents

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Nanotechnology: An Answer for Mitigating Future Challenges in Aquaculture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 Arabinda Mahanty, Tandrima Mitra, Ipsita Mohanty, Lopamudra Behera, Siddhartha Pati, Rishav Sheel, Rima Kumari, Sanjay Kr Gupta, and Biplab Sarkar

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Nano-Informatics: Studies on Nano Information Platforms and Their Application in Various Sectors . . . . . . . . . . . . . . . . 163 Koel Mukherjee, Hrithik Bhadaria, Santhosh Pillai, Madhubala Kumari, and Biplab Sarkar

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Nanotechnology for Pesticide Sensing . . . . . . . . . . . . . . . . . . . 177 Arnab Kumar Sarkar, Dipjyoti Kalita, Trishna Moni Das, Devabrata Sarmah, Klaus Leifer, and Sunandan Baruah

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An Overview of the Impact of Nanotechnology on Economy and Business . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201 Sutirtha Bandyopadhyay, Hari Charan Dorbala, and Sudipta Mandal

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Nanotoxicological Issues in Agriculture and Related Regulatory Framework . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217 Arnab Roy Chowdhury, Dhruba Jyoti Sarkar, Binay K. Singh, and Biplab Sarkar

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Intellectual Property Management in Nano-Biology Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 Anjan Sen

Editors and Contributors

About the Editors Biplab Sarkar is currently working as Principal Scientist (Nanobiotechnology) at ICAR-Indian Institute of Agricultural Biotechnology, Ranchi, Jharkhand. His group is focusing on nanotechnology-driven research for agricultural benefits. He published more than forty-five international papers and worked at ‘Centre of excellence’ (COE), Nanotech., AIT, Thailand, on nanoparticle synthesis and characterization. He executed two DST and four ICAR institute funded projects on nano-formulations and nanoencapsulation for agricultural use. His group developed novel methods of formulating anti-bacterial nanosilver from rohu waste tissues (Patent a.-3255/ Mum/2012) and nanocomposite hydrogel for wound healing (Patent a.-9172/ 2019-KOL). For the first time, he reported the growth-promoting role of nanosilver, unleashed the dose-dependent molecular activity of magnesium and iron nanoparticles in zebra fish, and framed the futuristic application of nanoscale selenium and zinc. He also worked on nano-zeolite, nano-hydrogel, and nanoliposomes for use in the farming sector. He already published two books as editor and twenty book chapters. He used to deliver lectures on nanotechnology applications at national and international forums. Avinash Sonawane is working as professor at IIT-Indore. He is an elected fellow of Royal Society of Biology (FRSB), UK; Humboldt Fellow, Germany; Swiss National Science Fellow, Switzerland; EMBO Fellow, Germany; and JSPS Fellow, Japan. He has more than fifty international publications and four patents. Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) infection in animals, presents diverse outcomes in different host cells. His group has identified several novel Mtb virulence and antigenic determinants that subvert host innate immune responses such as autophagy, oxidative stress, peroxisome biosynthesis, host antimicrobial peptide synthesis, genomic stability, and T cell activation using mice and zebrafish infection models. They demonstrated that nanoparticle encapsulated anti-TB drug delivery through polymer, chitosan, etc. admixed with metal and

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metal oxide nanoparticles can exhibit targeted delivery and higher efficacy in animal models.

Contributors Hira Ateeq Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, India Abishek Bakshi Kusuma School of Biological Sciences, Indian Institute of Technology, New Delhi, India Sutirtha Bandyopadhyay Indian Institute of Management, Indore, Madhya Pradesh, India Sunandan Baruah Department of Botany, Gauhati University, Guwahati, India Sanchari Basak Amity Institute of Nanotechnology, Amity University Uttar Pradesh, Noida, India Lopamudra Behera Crop Protection Division, Nano-biopolymer Laboratory, ICAR-National Rice Research Institute, Cuttack, India Hrithik Bhadaria Department of Biotechnology, Indian Institute of Technology, Chennai, India Puja Bhattacharyya Amity Institute of Nanotechnology, Amity University Uttar Pradesh, Noida, India Birendra Kumar Bindhani School of Biotechnology, KIIT Deemed to be University, Bhubaneswar, Odisha, India Sandip Chakrabarti Amity Institute of Nanotechnology, Amity University Uttar Pradesh, Noida, India Arnab Roy Chowdhury ICAR-National Institute of Secondary Agriculture, Namkum, Ranchi, Jharkhand, India Sourav Das Indian Institute of Technology, Kanpur, Uttar Pradesh, India Trishna Moni Das Department of Applied Sciences, Gauhati University, Guwahati, India Hari Charan Dorbala Indian Institute of Management, Indore, Madhya Pradesh, India Saikat Ghosh School of Biotechnology, KIIT Deemed to be University, Bhubaneswar, Odisha, India Sanjay Kr Gupta ICAR-Indian Institute of Agricultural Biotechnology, Ranchi, Jharkhand, India

Editors and Contributors

Editors and Contributors

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Qayyum Husain Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, India Abhijeet Joshi Department of Biosciences and Biomedical Engineering, Indian Institute of Technology (IIT), Indore, Madhya Pradesh, India Dipjyoti Kalita Department of Botany, Gauhati University, Guwahati, India Mohd Sajid Khan Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, India Shweta Khanna Indian Institute of Technology, Kanpur, Uttar Pradesh, India Shweena Krishnani Amity Institute of Microbial Technology, Amity University Uttar Pradesh, Noida, Uttar Pradesh, India Rahul Kumar Amity Institute of Biotechnology, Amity University Jharkhand, Ranchi, Jharkhand, India Madhubala Kumari Department of Bioengineering and Biotechnology, Birla Institute of Technology Mesra, Ranchi, Jharkhand, India Rima Kumari ICAR-Indian Institute of Agricultural Biotechnology, Ranchi, Jharkhand, India Klaus Leifer Angstrom Laboratoriet, Uppsala University, Uppsala, Sweden Prasad Eknath Lokhande Department of Mechanical, Manufacturing and Biomedical Engineering, Trinity College Dublin, The University of Dublin, Dublin, Ireland Arabinda Mahanty Crop Protection Division, Nano-biopolymer Laboratory, ICAR-National Rice Research Institute, Cuttack, India Sudipta Mandal Indian Institute of Management, Indore, Madhya Pradesh, India Tanishq Meena Department of Biosciences and Biomedical Engineering, Indian Institute of Technology (IIT), Indore, Madhya Pradesh, India Tandrima Mitra School of Biotechnology, KIIT University, Bhubaneswar, India Ipsita Mohanty Leonard and Madlyn Abramson Pediatric Research Center, Children Hospital of Philadelphia Research Institute, Philadelphia, PA, USA Soumya R. Mohapatra School of Biotechnology, KIIT University, Bhubaneswar, Odisha, India Koel Mukherjee Department of Bioengineering and Biotechnology, Birla Institute of Technology Mesra, Ranchi, Jharkhand, India Koena Mukherjee EIE Department, NIT Silchar, Silchar, Assam, India Niharika Das School of Applied Sciences, KIIT University, Bhubaneswar, Odisha, India

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Pankaj Kumar Parhi Department of Chemistry, Fakir Mohan University, Balasore, Odisha, India Pradip Paik School of Biomedical Engineering, Indian Institute of Technology-(BHU), Varanasi, Uttar Pradesh, India Siddhartha Pati NatNoV Bioscience, Balasore, Odisha, India Santhosh Pillai Department of Biotechnology and Food Technology, Durban University of Technology, Durban, South Africa Niharika Rishi Amity Institute of Microbial Technology, Amity University Uttar Pradesh, Noida, Uttar Pradesh, India Rojalin Sahu School of Applied Sciences, KIIT University, Bhubaneswar, Odisha, India Arnab Kumar Sarkar Centre of Excellence in Nanotechnology, Assam down town University, Guwahati, India Biplab Sarkar ICAR-Indian Institute of Agricultural Biotechnology, Ranchi, Jharkhand, India Dhruba Jyoti Sarkar ICAR-Central Inland Fisheries Research Institute, Barrackpore, West Bengal, India Devabrata Sarmah Department of Botany, Gauhati University, Guwahati, India Anjan Sen Anjan Sen and Associates, Kolkata, India V. S. Sharan Rathnam Department of Biosciences and Biomedical Engineering, Indian Institute of Technology (IIT), Indore, Madhya Pradesh, India Anup Kumar Sharma EIE Department, NIT Silchar, Silchar, Assam, India Rishav Sheel ICAR-Indian Institute of Agricultural Biotechnology, Ranchi, Jharkhand, India Binay K. Singh ICAR-Indian Institute of Agricultural Biotechnology, Ranchi, Jharkhand, India Monika Singh School of Biomedical Engineering, Indian Institute of Technology-(BHU), Varanasi, Uttar Pradesh, India Ragini Singh College of Agronomy, Liaocheng University, Shandong, China Rajni Singh Amity Institute of Microbial Technology, Amity University Uttar Pradesh, Noida, Uttar Pradesh, India Yogesh Singh Department of Biosciences and Biomedical Engineering, Indian Institute of Technology (IIT), Indore, Madhya Pradesh, India Jatin K. Sinha School of Applied Sciences, KIIT University, Bhubaneswar, Odisha, India

Editors and Contributors

Editors and Contributors

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Avinash Sonawane Department of Biosciences and Biomedical Engineering, Indian Institute of Technology (IIT), Indore, Madhya Pradesh, India Jasmine Swain School of Biotechnology, KIIT University, Bhubaneswar, Odisha, India School of Applied Sciences, KIIT University, Bhubaneswar, Odisha, India Tanmay Vyas Department of Biosciences and Biomedical Engineering, Indian Institute of Technology (IIT), Indore, Madhya Pradesh, India Rachna Yadav Amity Institute of Microbial Technology, Amity University Uttar Pradesh, Noida, Uttar Pradesh, India Afaf Zia Dr. Ziauddin Ahmad Dental College, Aligarh Muslim University, Aligarh, India

Abbreviations

AA AC AgNPs AI AIBN AOPs APS APX ATRP AuNPs BIS CFIA CIBRC CLRP CNT CNTs CS/TPP DBMS DCL DCNP DDL DML DQL dsDNA EC ECHA EP EPA EPR EU EUS FAO FCO FFDCA FIFRA FSSAI

Ascorbic acid Activated carbon Silver nanoparticles Artificial intelligence 2,2-azobisisobutyronitrile Adverse outcome pathways Ammonium persulfate Ascorbate peroxidases Atom transfer radical polymerization Gold nanoparticles Bureau of Indian Standards Canadian Food Inspection Agency Central Insecticides Board and Registration Committee Controlled and living radical polymerization Carbon nanotube Carbon nanotubes Chitosan tripolyphosphate Database management system Data control language Down conversion nanoparticles Data definition language Data manipulation language Data query language Double stranded deoxyribonucleic acid European Commission European Chemicals Agency Electroporated Environmental Protection Agency Enhanced permeability and retention European Union Epizootic ulcerative syndrome Food and Agricultural Organization Fertilizers Control Order Federal Food, Drug and Cosmetic Act Federal Insecticides, Fungicides and Rodenticides Act Food Safety and Standards Authority of India xxvii

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GF GFP GM GO GPX GR GRAS GSI HPMA IATA ISO KPS LDH LDH LHRH MEMS MONPS MS media NaSS NCLNFT NIL NIOSH NMP NMs NPs OECD PAR Pc PCL PCL PDADMAC PDS PDT PEG PHAC PHPMA Pig A PLGA PMA PNCs PNPs POD POSS PS I and II PS/GONG PTC

Abbreviations

Graphene Green fluorescence protein Genetic modified Graphene oxide Glutathione peroxidation Ascorbate reductases Generally recognized as safe Gonadosomatic index N-(2-hydroxypropyl)methacrylamide Integrated approaches for testing and assessment International Organization for Standardization Potassium persulfate Lactate dehydrogenase Layered double hydroxide Luteinizing hormone releasing hormone Microelectron mechanical system Metal oxide nanoparticles Murashige and Skoog media Sodium-4-styrenesulfonate Nanotechnology Characterization Laboratory Nanofiltration technology Nanoparticle Information Library National Institute for Occupational Safety and Health Nitroxide-mediated polymerization Nanomaterials Nanoparticles Organization for Economic Co-operation and Development Photosynthetically active radiation Critical pressure Poly (ε-caprolactone) Polycaprolactone Poly(diallyldimethylammonium chloride) Phytoene desaturase Photothermal (PTT) and photodynamic Polyethylene glycol Public Health Agency of Canada Poly(hydroxypropyl methacrylamide) Phosphatidylinositol glycan, class A Poly(D,L-lactic-co-glycolic acid) Silver/poly(methacrylic acid) Polymer nanocomposites Polymer nanoparticles Peroxidases Polyhedral oligomeric silsesquioxanes Photosystem I and II Polystyrene graphene oxide nanocomposite Plant tissue culture

Abbreviations

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PVDF/GF PVP QD RAFT rGO ROs SCENIHR SCF SiRNA SNP SOD ssDNA SWCNTs Tc TEMED TPC UCNP VMD WPMN WSSV WST XST

Poly(vinylidene fluoride)/graphene Polyvinylpyrrolidone Quantum dots Reversible addition-fragmentation transfer chain Condensed graphene oxide Reactive oxygen species Scientific Committee on Emerging and Newly Identified Health Risks Supercritical fluid technology Small interfering ribonucleic acid Single nucleotide polymorphism Superoxide dismutase Single stranded deoxyribonucleic acid Single-walled carbon nanotubes Temperature N,N,N,N-tetramethylethylenediamine Total phenolic compounds UP conversion nanoparticles Visual molecular dynamics Working Party on Manufactured Nanomaterials White spot syndrome viral infection Water-soluble tetrazolium salt Xueshuantong Injection

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Fundamentals and Analytical Techniques for Biological Applications of Nanomaterials Jasmine Swain, Niharika Das, Jatin K. Sinha, Rojalin Sahu, and Soumya R. Mohapatra

Abstract

Nanotechnology encompasses systems from engineering, physics, chemistry, and biology. Rapid breakthroughs in science and technology have created new prospects in healthcare, electronics, food and ecology. Nanoparticles, nanowires, nanofibers, and nanotubes are used in biosensing, biological separation, bio-imaging, and anticancer treatment because of their unique features and functionalities. Their high volume/surface ratio, solubility, and multi-functionality open new doors. There are several key applications for nanoparticles and derived formulations that are pertinent to our daily lives. Because of their plethora of different uses, it is critical that these nanoparticles be well characterized in terms of their physical, chemical, and Jasmine Swain, Niharika Das, Rojalin Sahu and Soumya R. Mohapatra contributed equally with all other contributors. J. Swain School of Biotechnology, KIIT University, Bhubaneswar, Odisha, India School of Applied Sciences, KIIT University, Bhubaneswar, Odisha, India N. Das · J. K. Sinha · R. Sahu School of Applied Sciences, KIIT University, Bhubaneswar, Odisha, India S. R. Mohapatra (✉) School of Biotechnology, KIIT University, Bhubaneswar, Odisha, India e-mail: [email protected]

biological features. This book chapter aims to outline the fundamentals of, and various analytical methodologies for, biological applications based on nanotechnology. Further, it gives a general idea about the types of materials used for biological application, their synthesis route, characterization, and the basic techniques involved in characterization. Keywords

Nanomaterials · Nanoparticle characterization · Spectroscopy · Biosynthesis · Analytical techniques Highlights • Nanotechnology has the potential to significantly alter our lives. Over the next 20 years, advances in nanotechnology are expected to bring several breakthroughs and new opportunities to the global economy. Various synthetic techniques can be used to create nanoparticles, which can then be used in a variety of nanomedical and biological applications; however, some require methodical and rigorous characterization of generated nano-materials before ascertaining authorization for biological use. As a result, this chapter focuses on explaining the fundamentals of nanotechnology as well as the analytical procedures involved in nanotechnology and its characterization in relation to its use in biological contexts.

# The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 B. Sarkar, A. Sonawane (eds.), Biological Applications of Nanoparticles, https://doi.org/10.1007/978-981-99-3629-8_1

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• Through this comprehensive overview of NP characterization methods, we highlighted the use of each method, emphasizing its benefits and limitations, as well as demonstrating how they can be successfully coupled and complement one another. • A review of the field of nanocomposite engineering seeks to explain why different nanomaterial interfaces exhibit different bulk properties and behaviours. This review is expected to contribute in some small way to the growth of this burgeoning field and to pique the interest of new researchers.

1.1

Introduction

Nanotechnology is an exciting area of research with numerous practical applications. Manufacturing novel and promising nanoscale materials are crucial to its success (Rastogi et al. 2018). The word “nanotechnology” was proposed by Professor Norio Taniguchi at Tokyo Science University in 1974 (Bhagyaraj and Oluwafemi 2018). National Nanotechnology Initiative (NNI) of the United States defines nanotechnology as the study of creating materials at the molecular or atomic level for various purposes (Balzani 2005). The history of nanotechnology began in China and India around the fourth and fifth centuries BC, according to a study by Paul and Chugh (2011), ancient medical practitioners developed gold colloids called “Swarna Bhasma” with medicinal potential (Dykman and Khlebtsov 2011). As a fast-expanding category of materials, nanostructures have sparked immense attention in a wide range of applications in physics, biology, chemistry, engineering, and biomedical engineering (Mourdikoudis et al. 2018a). It provides scope for delivering several technical advancements in the coming years. Nanotechnology is used to synthesize, develop, and create nanomaterials (NMs) used as antioxidants, antimicrobials, anticancer agents, treatments, assays, and nanosensors (Jain 2003; Daraio and Jin 2012). There are several key applications for nanoparticles (NPs) and derived formulations that are pertinent

to our daily lives. Nanoparticles have a wide variety of uses, ranging from pharmaceuticals and medication delivery to the creation of more efficient solar cells. Nanotechnology is progressively being developed for enhanced biotechnology; therefore, it may now be termed nanobiotechnology. Last few years have seen an explosion in the study and development of synthesis of nanoparticles, as well as the creation of nanowires and nanopatterns, as well as nanoscale phenomena and features (Daraio and Jin 2012). Because of their plethora of different uses, it is critical that these nanoparticles be well characterized in terms of their physical, chemical, and biological features (Beek et al. 2004; Baxter and Aydil 2005; Law et al. 2005; Nakayama et al. 2008). There is a range of analytical methods which can be applied to assess the size and other physical properties of nanoparticles. Most physical properties may be analyzed using more than one approach. Because each methodology has benefits and drawbacks, picking the best method sometimes needs a combinatorial characterization strategy (Mourdikoudis et al. 2018a). Nanoparticles interact biologically and toxicologically both in vivo and in vitro (Maksimović et al. 2015). This necessitates methodical and rigorous characterization of generated nano-materials before ascertaining authorization for biological use (Fig. 1.1). Therefore, the major goal of this chapter is to explain the basics of nanotechnology and the analytic procedures involved in nanotechnology and its characterization in relation to use in biological contexts.

1.2

Types of Materials Used for Biological Applications

Nowadays, nanotechnology is commercially exploited to a great extent. Due to their small size (1–100 nm), nanoparticles have unique qualities including enormous surface area, outstanding electrical properties, thermal and mechanical stability, and excellent optical and magnetic properties. Modern improvements in modeling and development of biomedical tools

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Fig. 1.1 Depiction of steps involved in nanotechnology focusing on biological application

and applications resulted in the use of nanomaterials in areas such as pharmaceutical research, diagnostic kits, imaging, medication delivery, and magnetic resonance imaging (MRI) (Yaqoob et al. 2020). Nanomaterials based on pure metals are also known as metal nanoparticles, examples include gold, copper, silver, zinc, titanium, iron, platinum, alginate, and magnesium nanoparticles; these metallic nanoparticles have garnered a lot of interest for their antimicrobial properties (Yaqoob et al. 2020; Hasan 2015). For example, there has been a lot of interest in gold nanoparticles, for their low toxicity, simple manufacturing, and strong binding with biological molecules (Elahi et al. 2018). Similarly, silver nanoparticles offer remarkable antibacterial effects against deadly viruses, microbes/germs, and other nucleus-containing pathogens (Hasan 2015). Metal oxides, including TiO2, BiO3, ZnO, FeO, MnO2, CuO, Ag2O, Al2O3, and others, are used in a variety of medicinal settings because of their antibacterial qualities (Yaqoob et al. 2020). TiO2 (Yaqoob et al. 2020) and ZnO (Sirelkhatim et al. 2015) nanoparticles demonstrate antimicrobial properties, whereas Al2O3 (Swaminathan and

Sharma 2019) nanoparticles have numerous applications and demonstrated antimicrobial activity. Scientists are also interested in metal sulfide and metal-organic framework (MOF) nanoparticles because of their drug-loading capability, informal bioactivity, excellent renewability, and non-toxicity (Yaqoob et al. 2020; Hasan 2015). For instance, metal-organic frameworks (MOFs) based on zinc, copper, or manganese are routinely employed for antibacterial and drug delivery purposes in the medical sector (Yaqoob et al. 2020). Nanoparticles made of doped metals or metal oxides are more efficient and effective in biological applications. Doped nanoparticles have little self-toxicity and could be used in pharmaceuticals. Many reported nanoparticles such as ZnO nanoparticles doped with Mg or Sb may have greater antibacterial activity. Cu-doped TiO2 nanoparticles were injected in the condition of reduced graphene oxide (rGO), which acted as solid support. Several metal sulfides, notably AgS, FeS, CuS, and ZnS, are significant for biomedical applications (Yaqoob et al. 2020), were used as innovative antibacterial agents. Singlewalled carbon nanotubes (SWCNTs) have also been widely studied for their antimicrobial

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activity. Researchers have related SWCNTs’ antimicrobial activity to a number of factors, such as length (1 μm, 1–5 μm or ≥5 μm), and the longer nanotubes found to be more active at the same weight concentrations (Dong et al. 2012). Alloy nanoparticles possess properties that are different from those of bulk samples. Compared to ordinary metallic NPs, bimetallic alloy nanoparticles show more advantages than NPs made from one metal alone. Ag flakes have the greatest electrical conductivity of any metal filler, and their oxides possess considerably superior conductivity to those of many other metals. Furthermore, Fe3O4 (magnetite) and Fe2O3 (maghemite) are magnetic nanoparticles that are noted for their biocompatibility. In addition to its use in cancer therapy (magnetic hyperthermia), MRI is also being researched for its potential in guided medication delivery, gene therapy, stem cell sorting, DNA analysis, and other therapeutic diagnosis (Hasan 2015).

1.3

Synthesis Routes of Nanoparticles

Multiple synthesis approaches are being refined to improve characteristics and reduce input costs. Some approaches have been adapted to enable the generation of nanoparticles with enhanced optical, mechanical, physical, and chemical capabilities. Basically, nanoparticles are created using physical, chemical, and biological methods (Elkhateeb et al. 2022). Figure 1.2 illustrates how nanoparticles are created using physical, chemical, and biological methods. Microorganisms, enzymes, fungi, and plants or plant extracts are used in biological nanoparticle synthesis, considered to be an eco-friendly alternative compared to that of chemical and physical roots (Hasan 2015). In this chapter, we will discuss chemical and biological methods of synthesizing nanoparticles.

1.4

Chemical Approach

The chemical method is one of the most commonly used approaches for synthesizing NPs

(Swaminathan and Sharma 2019). For nanoparticle synthesis, chemical methods have proven uncomplicated and often allow for large quantities of nanoparticle synthesis to be achieved. Furthermore, it is also possible to control particle size even at the nanometer level during the chemical synthesis of nanoparticles (Mageswari et al. 2016). The following sections describe some of the techniques that are used for synthesis.

1.4.1

Chemical Reduction

The reduction of a metal occurs when electrons are transferred from the reducing agent to the oxidized metal. In order to synthesize nanoparticles, inorganic and organic reducing agents such as sodium citrate, ascorbate, sodium borohydride (NaBH4), elemental hydrogen, polyol process, Tollens reagent, and N, Ndimethylformamide (DMF), and poly (ethylene glycol)-block copolymers are commonly employed (Mageswari et al. 2016). Without changing the oxidation state of the oxidized metal species, the reducing agent can form an intermediate with it and the reduction process can be initiated. For example, by raising the temperature, it can be carried out gradually, producing conditions conducive to the formation of highly crystalline structures of regular shape. Silver particles are formed by reducing silver nitrate with glucose in a polyvinyl pyrrolidone (PVP) solution. NaOH is applied to speed up the process. There was no change in colloid stability or detection of Ag+ across a mole ratio of 1.4–1.6 of NaOH to AgNO3. Transmission electron microscope (TEM) images revealed that particle dispersion enhanced with increasing PVP concentration and that colloid-like particle dispersion emerged when the weight ratio of PVP to AgNO3 was larger than 1.5. X-ray diffraction (XRD) spectra showed silver simple compounds when the reductant was sufficient and the reactants were mixed slowly (Wang et al. 2005). Material science and technology require improved copper nanoparticle production methods. A simple approach was used to produce

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Fig. 1.2 Detailed schematic representation compiling the different techniques suitable for nanoparticle production. Recent advances indicate an inclination toward a green synthesis of nanoparticles

starch-protected Cu nanoparticles. The work showed a promising way of chemically reducing copper nanoparticles. Cubic Cu and Cu2O nanoparticles stabilized by starch were measured to be 28.73 and 25.19 nm in size using X-ray diffraction. Simple and inexpensive, this methodology is well-suited for the industrial production of Cu and Cu2O nanoparticles. Improved synthesis methods for Cu2O and Cu nanocrystals and a better understanding of their characteristics may lead to advances in catalysis and photoactivated energy conversion (Khan et al. 2016).

1.4.2

Sol-Gel Process

A wide range of materials can be used in this method to create nanoparticles in desired shapes (particles, fibers, or films). Dissolve the metal salt precursors, such as metal alkoxide, metal oxide, or hydroxide, metal-organic, or metal-inorganic salts (sol). When sol is completely dry, a polymer matrix develops, enclosing the solvent in a solid (gel). Drying the gel, then calcining and sintering generate the final ceramic product (Ranjan et al. 2016). Regulated heating in an autoclave or under vacuum converts gel into finely divided powder.

This can make homogenous blends of two or more entities since atomic mixing is easier in a liquid than in a solid (Omran 2020a). Sol-gel method can produce nickel oxide nanoparticles in agarose polysaccharides. The obtained sample has fcc-structured NiO, according to XRD. The prepared NiO is spherical and 3 nm in size, according to TEM. NiO nanoparticles are superparamagnetic at 300 K due to uncompensated moments on their surface and ferromagnetic at 4.2 K (Alagiri et al. 2012). M. Mallahi et al. synthesized bismuth oxide nanopowders by sol-gel technique. Generation of homogeneous sol-gel formation and raw powders obtained from the gel decomposition process are two basic steps involved in the sol-gel process. Single-phase is obtained at a lower temperature than standard solid-state approach (Mallahi et al. 2014).

1.4.3

Chemical Vapor Deposition (CVD)

The motion of gases inside a compartment that contains the heated items to be coated is the basis of chemical vapor deposition (CVD). As a result

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of a chemical reaction taking place close to the hot surface, thin films are formed on the surface, and by-products thrown out from the chamber together with enduring unreacted gases. CVD exists in many forms, i.e., they can be built in either hot or cold wall reactors. The use of toxicants during deposition is, on the other hand, a major downside of CVD because some precursors are exceedingly poisonous, caustic, and flammable. Consequently, photons, lasers, plasma, ions, and hot filaments have been used to improve CVD processes. Furthermore, CVD has several advantages in thin film deposition: (a) CVD films are accurate, and (b) settled down materials are highly pure and lay down swiftly (Omran 2020b). Heejin Lee et al. coated TiO2 photocatalyst onto a glass bead using a chemical vapor deposition (CVD) technique with T-junction equipment. With this easy procedure, TiO2 nanoparticles were entirely coated onto the glass bead, with a consistent shape, and the coating time was shortened. Coating time was used to control the amount of TiO2 deposited on the substrate. The considerable cost savings gained by using this simple CVD technique have been documented in this work, including a shorter coating time and the requirement for less catalyst while generating better catalytic activity. Nonetheless, more research on enhancing photocatalytic activity should be carried out (Lee et al. 2011). Atmospheric pressure CVD was used by Chan-Soo Kim et al. to produce carbon nanotubes (CNTs) at a range of reactor temperatures. During thermal CVD CNT development, a large number of charged nanoparticles arise for the first time. When these nanoparticles weren’t in the gas phase, no CNTs developed. Temperature, methane, and hydrogen flow rates affect charged nanoparticle size distributions (Kim et al. 2009).

1.4.4

Electrochemical Process

As the name implies, nanoparticles are created by transferring an electric flow between two electrodes divided by an electrolyte. This technology has advantages of cheap costs, simple

procedures, versatility, quick accessibility of equipment instruments, less pollution (pure product), and is an environmentally acceptable (eco-friendly) process, so this technology is widely used to make a wide range of nanomaterials and has received a lot of research attention to advance its fundamental knowledge and industrial applications (Gupta et al. 2013; Ma et al. 2017). A single-step electrochemical method was used to make cadmium sulfide (CdS) NPs having an average size of 5 nm. After a 2-h reaction at roughly 70 °C, stable NPs are created using cadmium nitrate (Cd(NO3)2), ethylene glycol, elemental sulfur, and KNO3 as the supporting electrolyte. Silver NPs with a size of around 20 nm have been produced in ethanol solution using both potentiostatic and galvanostatic methods (Bensebaa 2013). In order to fabricate silicon nanofilms in N,N, N-trimethyl N-hexylammonium bis (trifluoromethanesulfonyl)imide, Tsuyuki et al. used SiCl4 as a precursor and exposed the film to light. Adding AlCl3 to the system resulted in aluminum-doped silicon nanofilms. Using the template deposition technique, silicon and germanium nanowires were produced electrochemically inside the ionic liquids [BMPy][NTf2] or 1-hexyl-3-methylimidazolium bis (trifluoromethanesulfonyl) imide containing GeCl4 and SiCl4 as precursors. The triflate ionic liquid can be used in the electrochemical synthesis of nanoparticles of nickel and iron with a typical size of 3 nm (Lebedeva et al. 2021).

1.5

Biological Synthesis of Nanoparticles

Given a plethora of preparation techniques, a great majority entail intricate protocols, extreme temperatures, and hazardous substances as reducing agents, resulting in large expenses and minor particle surface contaminations (Hebbalalu et al. 2013). The biological synthesis method uses biological catalysts, resulting in an environmentally safe way to synthesize (Hebbalalu et al.

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2013; Kruis et al. 2000; Sastry et al. 2003; Ahmad et al. 2003). (a) Plant-Mediated Synthesis of Nanoparticles Plant-mediated Nanoparticles may be synthesized in a variety of ways, ranging from physical to chemical methods. It has been dubbed a “green” methodology and the most dependable ecologically friendly method for producing nanoparticles from plant species (Gowramma et al. 2015; Makarov et al. 2014). Synthesis of various nanoparticles has received less research interest than trying plants to create metallic nanoparticles (Nadagouda and Varma 2008; Elavazhagan and Arunachalam 2011). Most procedures involve active reducing agents such as amino acids, flavonoids, nicotinamide adenine dinucleotide phosphate (NADP) reductase, and secondary metabolites. In addition to each metal having a different reduction potential, this has a significant impact on how metals or metal precursors are synthesized. High reduction potential speeds up metal precursor reduction. When the decreasing rate is low, nucleation and growth phases approach equilibrium. (b) Bacteria in Synthesis of Nanoparticles Microbes can form inorganic compounds either within their cells or outside of them in the extracellular environment. Researchers have put a lot of emphasis of their attention on bacteria as a type of microorganism in order to know how metallic nanoparticles may be produced by them. Bacteria can be grown quickly and are easy nanoparticle targets. Researchers have spent years synthesizing nanomaterials. Microorganisms or bacteria-derived components can be employed to produce silver nanoparticles extracellularly and intracellularly (Singh et al. 2015). Bacteriamediated ZnO NP synthesis has been carried out using Bacillus subtilis and further used to decolorize azo dyes (i.e., Congo Red and Rubine GDB) that are commonly found in textile effluent in India (Swain et al. 2022).

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Several taxonomically diverse bacterial species produce silver nanoparticles (Sweet et al. 2012; Narayan and Sakthivel 2010; Mohanpuria et al. 2008). Most of these soil and marine isolates are involved in biogeochemical metal cycles (Sweet et al. 2012). Certain bacteria detoxify metals by decreasing and/or precipitating inorganic ions (Narayan and Sakthivel 2010).

1.5.1

Fungi-Mediated Nanoparticle Synthesis

In recent years, researchers have focused on using fungus to make nanoparticles (Dhillon et al. 2012). The study of fungus is favored because of the myriad advantages it provides. The ability to generate vast amounts of enzymes is one of the advantages. Other advantages include their simplicity of processing, which enables biosynthesis of nanoparticles utilizing fungus fascinating. Due to their resistance and metal bioaccumulation capacity, fungi have dominated investigations on biological metallic nanoparticle formation (Sastry et al. 2003). Extracellular nanoparticle formation includes transporting ions into microbial cells using enzymes. Comparatively, intracellular nanoparticles are smaller than external ones. Size restriction is likely connected to particles nucleating in organisms. Extracellular nanoparticle synthesis has more potential than intracellular synthesis since it lacks cell components. Fungi create nanoparticles extracellularly due to their secretory components, which reduce and cap nanoparticles (Narayan and Sakthivel 2010). Fusarium oxysporum is used to produce nanoparticles. Even after a month, F. oxysporum produces 20–40 nm extracellular spherical or triangular gold nanoparticles (Mukherjee et al. 2002). F. oxysporum was treated with proteinstabilized H2PtCl6 to produce 5–30 nm platinum nanoparticles (PtNP) (Syed and Ahmad 2012). F. oxysporum produces spherical 42-nm ZnS nanoparticles (Mirzadeh et al. 2013). Fusarium species including F. acuminatum and

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F. semitectum were discovered to be involved (Basavaraja et al. 2008).

1.6

Characterization of Nanoparticles

Precise and accurate characterization of nanomaterials is required for further investigation of their distinctive and remarkable properties. This can be accomplished using various techniques that provide information on the created nanomaterial’s electrical, optical, morphological, and magnetic properties. There has been a lot of advancement in terms of technologies and characterization tools which have the advantage of characterizing materials without producing considerable alteration or damage to the nanoparticles under investigation. Nanostructure optical characteristics are determined via spectroscopy. UV/ visible spectroscopy, photoluminescence spectroscopy, surfaceenhanced Raman spectroscopy, atomic force microscopy (AFM), Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy, scanning, and transmission electron microscopy, dynamic light scattering, and powder X-ray diffractometry are used to characterize nanoparticles (Omran 2020a). These approaches resolve particle size, shape, crystallinity, fractal dimensions, pore size, and surface area and can determine nanoparticle orientation, intercalation, and dispersion in nanocomposites. In addition, these methods could be used to ascertain the intercalation, orientation, and dispersion of nanoparticles and nanotubes in nanocomposite materials (Elkhateeb et al. 2022). The usual characterization of nanoparticles mainly includes: (1) actual visualization of the nanoparticles for size, shape, and surface morphology, which is done using electron microscopy, which is among the most prominent common ways to find particle size and distribution (there are now a variety of electron microscopes with a wide range of resolutions and a variety of add-on instrumentation capable of determining, recording, and analyzing different essential features of the nanoparticles). Laser

diffraction techniques evaluate bulk materials in the solid phase, while scanning electron microscope (SEM) and transmission electron microscope (TEM) images quantify particles and agglomerations. Utilizing photon correlation spectroscopy and centrifugation, liquid phase particles are quantified. Because gaseous particle imaging is complex and irreversible, scanning mobility particle size (SMPS) is employed for faster and more exact observations. Apart from that, nanoparticle tracking techniques can be used to follow the Brownian motion, which is unique to nanoparticles due to their small size. (2) Dynamic light scattering (DLS) and zeta potential measurements are used to quantify a nanoparticle’s surface charge and dispersion stability. Differential mobility analyzers (DMA) determine the gaseous nanoparticle charge. (3) Crystallography studies atoms and molecules in solid crystals. X-ray diffraction measures nanoparticle crystal structure. The morphology of nanoparticles is determined using powder X-ray, electron, or neutron diffraction. Nanoparticle purity and efficacy depend on their chemical composition. Analyzing nanoparticles or nanostructures uses X-ray photoelectron spectroscopy and energy-dispersive X-ray spectroscopy. (4) Spectroscopic techniques like Fourier transform infrared spectroscopy (FTIR), matrixassisted laser desorption/ionization-time of flight mass spectrometry, MALDI-TOF MS, UV-visible spectroscopy, and Rutherford backscattering spectrometry; (5) dual polarization interferometry; and (6) nuclear magnetic resonance techniques are all examples of mass spectrometry techniques. Figure 1.3 depicts an outline summarizing all different techniques that can be utilized for the characterization of nanoparticles for biological applications. Since absorption or penetration through biological membranes is highly dependent on particle size, accurate particle size analysis and distribution are fundamental for applications, as a result, these methods play an important role in the characterization of nanoparticles (Pande and Bhaskarwar 2016).

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Fig. 1.3 Schematic outline summarizing all different techniques that can be utilized for the characterization of nanoparticles for biological applications

1.7 1.7.1

Characterization Techniques Scanning Electron Microscopy

Visualizing the sample’s crystalline structure and chemical composition is made possible via scanning electron microscopy (SEM). Aside from the benefits of morphology and size analyses, SEM gives little information regarding the distribution of particles and associated pores in terms of their sizes (Sundar et al. 2010). Carbon, gold, other metals, or alloys are often used to cover electrically insulating samples. For elemental analysis, carbon is the recommended conductive coating, whereas metal is superior for electron imaging with high resolution. It would appear that the main downsides of DLS and SEM are the time and resources they require and the frequent need for more data on size distribution (Pal et al. 2011). In the SEM pictures of ibuprofen-loaded nanoparticles, the uneven distribution, and

aggregation of the ibuprofen-loaded nanoparticles were fully evident (Ganesh and Lee 2013). According to a report ZnO NPs were synthesized via a biological route using Bacillus subtilis. They were nanorod-shaped structures with signs of agglomeration in bacterial biomass. Structures had 100–200 nm diameters and 1–2 m lengths. The structures were uniformly arranged and comparable. According to the studies of Raj et al., co-polymer of polylactic acid and polyethylene glycol (PLA-co-PEG) nanocapsules had open, straight channels in their SEM morphological evaluation. They looked to have a smooth, spherical form on their surface. Others made with gold nanoparticles were smooth, while those without gold nanoparticles were rough and had more holes (Raj et al. 2012).

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1.7.2

J. Swain et al.

Transmission Electron Microscopy (TEM)

The first TEM device was created by German scientist Ernst Ruska and electrical engineer Max Knoll (Auty et al. 2005). Later, additional TEM techniques were developed and modified to characterize nutraceutical delivery systems technically and analytically at the atomic and nanometer length scales, respectively (Tiede et al. 2009; Lorenz and Kulp 1982). It is a cuttingedge equipment with a resolution of 0.07 nm, though efforts are being made to improve it to 0.05 nm in the near future (Dudkiewicz et al. 2011). SEM and TEM work on separate principles, although the data they produce is frequently the same. The process of preparing samples for TEM requires a lot of time and effort. Researchers can learn about a thin sample’s surface by interacting with it as it moves through an electron beam (Sundar et al. 2010; Pal et al. 2011). In TEM studies, the resolution is highly reliant on sample thickness and electron beam acceleration voltage; a higher voltage results in a higher theoretical resolution. A voltage of >100 kV is ideal for studying food-related components that are susceptible to electron damage in TEM (Dudkiewicz et al. 2011; Williams and Carter 1996). TEM can regulate nanomaterial structure via contact with a gas/liquid/solid surface and detect phase impurities and crystalline flaws. High-quality TEM micrographs may demonstrate nanostructure distributions, orientation, exfoliation, and intercalation. TEM provides extensive information on the nanometric lattice structure; therefore it can show crystallinity, shape, particle size, and interparticle interaction at a high resolution (Wang 1998). This approach provides structural information on colloidal nanovesicles to validate encapsulation and bioactive entrapment (Petersson Nordén et al. 2001). Inability to view live specimens, grayscale micrographs, two-dimensional pictures, and extensive sample preparation processes are drawbacks of traditional TEM technologies. In this context, more accurate and artifact-free

micrographs may be obtained by cryo analytical TEMs, cryo-TEM, and freeze-fracture direct imaging; among these, cryo-TEM is the most extensively used technology for visualizing nanodelivery systems. Cryo-TEM devices have a bright future, and various efforts have been made to design innovative equipment that can produce high-quality 3D pictures and examine interactions between live cells and nano vehicles (Rostamabadi et al. 2020). TEM specimen preparation processes (freeze-fracture, negative staining, and plunge freezing) provide fundamental details concerning delivery methods on 1–100 nm scales (Meyer 2003). With suitable prep, this methodology can describe both solid and hydrated nano vehicles in delivery systems (Reimer 2013). The diameter of drug-capped gold nanoparticles was determined using TEM images. TEM examination of gold/drug-enclosed polymer nanocapsules showed that PLA-co-PEG molecules blocked nanocapsule coalescence (Raj et al. 2012).

1.7.3

Atomic Force Microscopy

The atomic force microscope (AFM) was created in 1985 by three inventors: Binnig, Quate, and Gerber. Diamond shards bonded to gold foil were the basis of their first AFM. Using interatomic van der Waals forces, the diamond’s tip met the surface directly. In order to detect the cantilever’s vertical movement, an STM was mounted above the cantilever and used as a second tip (Eaton and West 2010). When contrasted to TEM and SEM, AFM has a few benefits since it relies on force calculations between the particle surface and the probe tip. Simple sample preparation, quick picture capture, and appropriate resolution are the method’s distinguishing features (Sundar et al. 2010). Due to sedimentation, it is easy to immobilize bigger particles before seeing the examined particles. However, because of Brownian motion, immobilization is problematic for tiny particles. Dehydration may help cure the issue, but it may also lead to undesired modifications such as cluster formation, shrinkage, lipid crystallization, and much more (Kumar and Randhawa 2013). AFM

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can picture non-conducting objects without specific preparation, enabling imaging of cellular and polymeric nano- and microstructures (Dubes et al. 2003). This method depicts particle size and dispersion most accurately. There is no need for further mathematical methods in this case (Raut et al. 2018). Nanoparticle characterization may benefit from AFM’s high-resolution pictures and the ability to map a sample’s attributes, such as its capacity to resist deformation, in addition to its size (Garud et al. 2012).

1.7.4

High-Performance Liquid Chromatography

Mikhail S. Tswett, a Russian botanist, defined liquid chromatography (LC) in the early 1900s. These ground-breaking experiments focused on the separation of plant chemicals (leaf pigments) extracted by the solvent in a particle-filled column (Dong 2006). Prof. Csaba Horváth introduced the abbreviation HPLC to denote that high pressure was utilized to produce liquid chromatography flow in packed columns (Svec 2004). HPLC can separate complex molecular mixtures in biological and chemical systems. HPLC has exceptional selectivity, and it also has a high degree of accuracy. The choice of detection method in liquid chromatography is crucial to ensure that all components are identified. Photodiode array (PDA) and variable wavelength (VWD) detectors are among the most often utilized instruments. Using the PDA, a preprogrammed wavelength range may be applied to detect all of the substances that absorb within this range. Furthermore, the PDA detector may be used to analyze peak purity via the use of spectrum matching to identify Iloperidone in pharmaceutical technique development (Manjula and Ravi 2012). Alcohols, sugars, fatty acids, polysaccharides, and polymers have low or no UV absorption, hence the refractive index detector is used. Low noise is essential for ensuring good trace-detection performance. This detector is the least sensitive yet can be utilized at high analyte concentrations (Kunasekaran and Krishnamoorthy 2015).

1.7.5

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Liquid Chromatography-Mass Spectrometry

It is possible to combine the physical separation capabilities of liquid chromatography (e.g., HPLC) with the mass analysis capabilities of mass spectrometry (MS) in a high-sensitivity method (e.g., LC-MS). For example, it can be used to pinpoint compounds in complicated mixtures such as herbal substances, pure substances from a mix of intermediates, and so on (Jacob et al. 2014). It is used in many different ways to find new drugs, such as breaking down natural compounds, mapping peptides and glycoproteins, testing bioaffinity, testing drugs in living organisms, testing metabolic stability, and so on (Lee and Kerns 1999). LC-MS/MS was used to measure the concentration of paclitaxel in whole-cell culture medium and cell lysate samples. Methanol was used in the sample preparation process. Acids were used to prevent the breakdown of the drug paclitaxel and to recover over 80% from both samples spiked with the compound. Internally, docetaxel served as a benchmark. Using this approach, paclitaxel could be quantified within a linear range of 1–250 nm in culture medium and 5–250 nm in cell lysate; limit of quantification (LOQ) measured 0.2 pmol in cell culture media and 1 pmol in lysates (Baati et al. 2015). An LC-MS/MS technique for the direct estimation of curcumin in mouse plasma and brain tissue using salbutamol as an internal standard has been developed and validated. MRM was utilized to monitor the m/z transitions 369 > 285 for curcumin and 240 > 148 for salbutamol, which was detected by quadrupole mass detection. Both matrices have a lower limit of detection of 2.5 ng/ ml. To explore curcumin pharmacokinetics and brain distribution, researchers intravenously administered mice: free curcumin as well as solid lipid nanoparticles (SLNs) that contained curcumin (Ramalingam and Ko 2014). LC-MS/ MS has shown to be a viable way of targeted therapy, notably for neurological and carcinogenic illnesses in humans (Deng et al. 2009; Dang et al. 2014). New LC-MS/MS techniques

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have been established to conduct pretrial pharmacokinetic research in rats following intravenous injection; it was effectively applied (Dimer et al. 2014).

1.7.6

Matrix-Assisted Laser Desorption Ionization Time-of-Flight (MALDI-TOF) Mass Spectrometry (MS)

Small molecules produced by lyophilized microorganisms were discovered to produce discrete spectra for several bacterial taxonomic groups in 1975 (Anhalt and Fenselau 1975). To identify microorganisms, MALDI-TOF MS can be used to analyze whole microbial cells with no need for substantial pretreatment. This study uses intact or direct cell analysis. A bacterial or yeast colony is placed to a plate or slide with a sterile loop. To avoid the mass spectrometer being clogged with fibers, never use swabs in the instrument. Intact cell MALDI-TOF MS analysis requires 104–106 colony forming units (CFU) of the test microorganism (Wieser et al. 2012). The spotted bacteria are covered with soluble, tiny acid molecules. α-Cyano-4-hydroxycinnamic acid (HCCA) and 2,5-dihydroxybenzoic acid (DBA) are common matrix solutions. The microbe is embedded in the matrix as the matrix dries. Water, organic solvents, or strong acids lyse most intact microorganisms (Buchan and Ledeboer 2014; Clark et al. 2013; Patel 2013; Randell 2014; Wojewoda 2013). The target dish is put in the MALDI-TOF MS ionization chamber once the matrix and microbiological material are dry. Short bursts of light from a nitrogen laser sublimate the matrix and microbiological specimen from solid to gas, ionizing the sample. Electric charge accelerates ionized molecules via a vacuum tube to a detector. The mass-to-charge ratio (m/z) separates ionized molecules as they move. The instrument’s mass analyzer monitors the time each ion takes to reach the detector and generates a mass spectrum (Clark et al. 2013; Patel 2013). MALDI-TOF MS identifies numerous proteins, mostly ribosomal and cytosolic. Varied bacterial genera and species

have different protein compositions, producing unique spectra (Ryzhov and Fenselau 2001; Sun et al. 2006). The unknown microorganism’s spectrum is compared to a reference database (Bourassa and Butler-Wu 2015). Analytical characterization is essential for novel or developing materials. One such example is analysis of dendrimers using MALDI time-offlight mass spectrometry. Dendrimers are macromolecules used in cancer and biomedicine. Analyzing them as possible targeted treatments is crucial. Complex and diverse dendrimers make characterization difficult. MALDI-TOF mass spectrometry is one way to analyze these compounds (Ramalinga et al. 2011). MALDITOF MS may detect bacteria in blood, cerebrospinal fluid (CSF), and urine without previous culture or subculture. Thus, MALDI-TOF MS has the potential to enhance patient prognosis and lessen hospitalization and is recognized as a crucial technique in clinical microbiology (Tsuchida et al. 2020).

1.7.7

Scanning Electrochemical Microscopy (SECM)

Binnig and Rohrer invented the scanning tunneling microscope in the early 1980s, nearly simultaneously with the advent of ultramicroelectrodes (Sun et al. 2007). SECM highlighted the promise of acquiring fresh perspectives into biological structure-function interactions at its beginning, and the field has grown significantly since then. Essentially, SECM has progressed from an electrochemical specialized tool to a widely used electroanalytical surface technique in recent years, including interesting improvements for nanoscale electrochemical research. SECM research is usually multidisciplinary, including fields such as electrochemistry, nanotechnology, and materials science, as well as biomedical research (Izquierdo et al. 2018). It is a powerful method for probing local electrochemical current by scanning across the sample surface with a tip electrode, currently with a resolution of nm scale. A positioning device moves a UME (ultramicroelectrodes) as a local

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probe with respect to the sample in an SECM. As an amperometric mircoelectrode, the UME is coupled to a potentiostat, and the electrochemical cell is completed by a reference electrode and an auxiliary electrode. The sample to be investigated can be connected to a bipotentiostat as the second working electrode. SECM can photograph individual immobilized NPs with an nm-sized probe, providing spatially resolved data about NP morphology and evaluating electron transfer characteristics and catalytic activities. Furthermore, because they are prepared in solution and do not require transfer to the gas phase or vacuum, they can be used to make electrode measurements. In most cases, even at the 1-nm level, the measurements described in this paper can be performed without extensive searching for particles (Ma et al. 2017; Wittstock et al. 2007). The SECM can be operated in several ways. In tip generation/substrate collection (TG/SC), the tips form a reactant that is sensed at a substrate electrode, comparable to a rotating ring disc. At the tip, for instance, the reaction O + ne- → R occurs, whereas the reverse reaction occurs at the substrate. TG/SC is often used in the study of homogeneous chemical reactions, where the species R reacts with the substrate as it transits between tip and substrate, causing the substrate current to decrease. Whereas in the substrate generation/tip collection (SG/TC) mode, the substrate serves as a generator and the tip as a collector, and this mode is useful for studying reactions at a substrate surface (Bard et al. 2022; Bard and Mirkin 2001). Furthermore, SECM imaging investigations can be done in two modes: generation-collection (GC) and feedback (FB). SECM has become a popular approach for determining the kinetics and distribution of immobilized enzymes on surfaces, and it can be used to improve biochemical sensors, biochips, and enzyme support materials (membranes, foams, gels). In FB or GC mode, the activity of immobilized enzymes can be visualized. SECM has also been used to characterize a number of innovative, non-manual microstructured transducer immobilization techniques (Wittstock et al. 2007). Wei Ma et al. demonstrated the preparation of platinum

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nanoparticles (PtNP) with dimensions as small as 1 nm using electrode deposition on a carbon substrate. Electrochemical measurement and electrodeposition of PtNPs with the size measurement are demonstrated here. The size of the particle can be determined without discarding the electrode. Furthermore, the findings confirm that hydrogen bubble formation is responsible for the blocking effects on PtNPs. SECMs are used in this work, to serve as a way to prevent hydrogen bubbles from forming at high proton concentrations and to determine area and radius more precisely (Ma et al. 2017).

1.7.8

Surface Enhanced Raman Scattering (SERS)

SERS increases scattering on metal nanoparticles or rough surfaces. Initially identified in 1974 by Fleischmann et al., this effect has since been widely studied. A roughened silver electrode enhanced the pyridine Raman signal. In electromagnetic models, the molecule is a point dipole that responds to local fields on metal surfaces. In addition, these increased fields are created by roughness features connected to surface plasmons. Chemical models credit the SERS intensity to the alteration of molecular charge density by the metal, causing molecular resonances, as in resonance Raman scattering (Kumar et al. 2020). Because of their plasmonic properties in the UV spectrum, most metals, namely Al and Cu, can be used as SERS substrates. Au and Ag-based plasmonic nanostructures have been used the most because they have higher enhancement factors and plasmonic resonances in the visible and near-infrared ranges. Exosomes and viruses are among the biologically relevant NPs that can be detected by SERS. SERS is an excellent tool for exploring the intracellular environment, identifying biomolecule localization, delivering and monitoring medicines, and characterizing complicated cellular processes at the molecular level (Yaneva and Georgieva 2018; Kahraman et al. 2017).

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SERS can be used to observe the biomolecular diversity of exosomes (a kind of extracellular vesicle with a diameter of 30–200 nm). They form tumorigenic colon cells that displayed a higher RNA signal in an SERS spectrum than those from healthy cells. A SERS spectrum contains a vast quantity of information, i.e., peak intensities directly reflect analyte concentration. When materials are stressed, the frequency of a vibrational peak can shift, allowing for a stress-sensitive nanomechanical biosensor. Viruses are another possible target for SERSbased tests since they present in bodily fluids. HIV, influenza, and a slew of other diseases have had devastating consequences on people, both in terms of the population and the individual (Kahraman et al. 2017). Liquid interfacial plasmonics benefit tunable optical devices, sensors, and catalysis. SERS identifies trace drug compounds in human urine by assembling gold nanoparticle arrays at the cyclohexane/water interface. Dual-analyte detection proved the liquid interfacial SERS platform’s ability to detect aqueous and organic analytes (Yaneva and Georgieva 2018). A number of species and strains of bacteria were studied using SERS on unique gold nanoparticle (80 nm) covered SiO2 substrates excited at 785 nm. On these SERS active substrates, Gram-positive and Gramnegative bacteria show Raman cross-section increases of >104 per bacterium. At this excitation wavelength, bacteria’s SERS spectra are spectrally less congested and show stronger species differentiation than their non-SERS (bulk) Raman spectra. The surface enhancement effect allows for fast data gathering and visualization of Raman spectra of single bacterial cells excited at low incident energies. The SERS spectra of B. anthracis Sterne demonstrate this capability at the single-cell level (Premasiri et al. n.d.). A seedmediated synthesis method is used to synthesize starfruit-shaped gold nanostructures of different dimensions, which have good SERS activity as compared to similar sized smooth-surfaced rods. By using gold nanowires as a seed, starfruitshaped nanowires can be developed; the purity of the resulting nanorods depends on the concentration of gold in the growth fluid and the

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presence of silver ions (Vigderman and Zubarev 2012).

1.7.9

X-Ray Diffraction (XRD)

A study of X-ray diffraction (XRD) of crystals initiated by Laue, Friedrich, and Knipping in 1912 opened new avenues for the study of crystals, which is now one of the most widely used conventional methods of characterizing NPs (Epp 2016). The crystal lattice, lattice parameters, crystalline size, and phase nature are all determined by XRD, together with the crystallographic structure and morphology. X-ray diffraction is commonly used to determine nanocrystalline orientation, particle quantification, phase identification, average particle size, lattice distortion, and the amount of departure a given element has from its ideal composition. Diffraction of X-rays varies from element to element and from atomic configuration to atomic configuration. Size and shape of particles with translational symmetry can be determined from the positions of the peaks, while the intensity of the peaks can be used to determine the positions and densities of atoms within the unit cell. For amorphous materials, this approach is ineffective, whereas the XRD peaks produced by materials and particles less than 3 nm are too broad (Omran 2020a). In X-ray crystallography, Bragg’s law is the cornerstone (XRD). Crystallization rates can be measured, spark elements in nanoparticles and nanoclays can be identified, and “unit cell size analysis” may be performed with XRD. Grinding and homogenizing the sample is necessary for XRD analysis. In 1915, Bragg and Nishikawa distinguished between the orthorhombic, cubic, hexagonal, tetrahedral, octahedral, and polymorphic crystal forms of iron oxide. When X-rays are projected on a crystal, diffracted beams typically originate from the powder specimen themselves and hence accurately reflect the structural physicochemical features of the material. X-ray diffraction (XRD) can be used to investigate a wide variety of materials, including inorganic catalysts and superconductors as well as biomolecules,

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glasses, and polymers. Each substance has its own unique diffraction beam, and this can be used to characterize and identify it by crossreferencing it against the Joint Committee on Powder Diffraction Standards (JCPDS) database. Analyzing diffracted patterns helps detect sample purity or contamination (Zhang et al. 2016). A sol-gel combustion methodology was used to make ZnO-NPs. At calcination temperatures of 650 °C and 750 °C, the XRD confirmed that the Wurtzite structure ZnO-NPs were devoid of any pyrochlore phase. The reduced crystallite size and lattice strain caused the line broadening of ZnO-NPs calcined at this temperature range. The Scherrer formul, modified forms of W-H analysis, and the size-strain plot approach were used to investigate this broadening. As the calcination temperature was increased, the strain value fell but the particle size enhanced, according to the results (Zak et al. 2011). Without employing any chemical components, we have been able to produce TiO2 nanoparticles successfully at room temperature in a versatile, non-toxic, and bio-safe manner. The produced particles’ tetragonal anatase phase TiO2 and nanosize were validated by XRD studies. Their various characteristics, including specific surface area, dislocation density, and morphological index, were also examined using XRD. It has a specific surface area of 19.16 m2 g-1 and a diameter of 74 nm. The link between particle size and specific surface area is explained by the morphology index (MI), which is calculated from the full width at half maximum (FWHM) of XRD data. MI has a direct association with particle size and an inverse relationship with specific surface area, according to the findings (Theivasanthi and Alagar 2013).

1.7.10

Dynamic Light Scattering (DLS)

DLS, also known as quasi-elastic light scattering (QELS) or photon correlation spectroscopy, is a potent technique for customizing the average particle size of nanoparticles. Hydrodynamic diameter is defined as the diameter of a solid sphere equal to the hydrodynamic friction of the molecule of interest; dynamic light scattering (DLS) is

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a method for analyzing the size and dispersion of hydrodynamic particles. One of the quickest and popular tools for assessing particle sizes in the 1 nm to 1 μm range at the moment is DLS. DLS is a quick analyzer, saves money and time, and offers information on the aggregation status of nanoparticles (Naganthran et al. 2022). DLS is cost-effective, fast, and provides information on nanoparticle aggregation. The method determines a particle’s velocity relying on the Doppler effect of light scattering in a suspension. Nanoparticle suspension, scattering angle, and shape affect particle size distribution. Light scattering is correlated to particle radius, which assist to detect microscopic aggregates. This approach is faster and cheaper than microscopy for sizing nanomaterials (Mageswari et al. 2016). Brownian motion is the basic working principle and hydrodynamic diameter is the deciding factor, affected by the size and shape of macromolecules behind DLS. According to Brownian motion study, particles in move in a random zigzag manner and has shown that larger particles move more slowly, travel shorter distances, and reflect more light than smaller particles. Furthermore small numbers of dust particles can cause the particle size distribution to shift to a higher value (Omran 2020a; Naganthran et al. 2022). DLS also offers information regarding the state of nanoparticle agglomeration (Omran 2020a). This technology is very useful in the repurposing of nanoparticles because the samples can be utilized for other purposes (Mageswari et al. 2016). Basically particle size less than a nanometer can be measured using the technique in general, and is best suited for submicron particles. The distinction between a molecule (like a protein or macromolecule) and a particle (like nanogold) and even a second liquid phase (such as an emulsion) blurs in this size regime (microns to nanometers) and size measurement (but not thermodynamics). It can also be used to investigate complex fluids like concentrated solutions (Sandhu et al. 2018). Elamawi et al. reported the DLS results of filtered AgNPs made from Trichoderma longibrachiatum; 10 g of fungal biomass and 15 g of fungal biomass, respectively, showed three peaks and two peaks with the

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presence of 39.3, 4.4, 1.5 nm, 41.7 and 4.9 nm, indicating that 10 g of fungal biomass at 20% dilution without filtration, using DLS, produced good results. In addition, the T. longibrachiatum produced AgNPs were generally monodisperse, having diameters varying from 5 to 30 nm, highlighting the importance of filtering for aggregate removal (Elamawi et al. 2018). Trichoderma harzianum (AgNP-TS) and Sclerotinia sclerotiorum were studied without enzymatic activation (AgNP-T). Mohanta et al. reported AgNP-TS and AgNP-T NPs synthesized by Trichoderma harzianum representing hydrodynamic diameters of 57.02 ± 1.75 and 81.84 ± 0.67 nm, respectively. NPs synthesized using Trichoderma harzianum (AgNP-TS) whereas without enzymatic stimulation (AgNP-T) by the cell wall of Sclerotinia sclerotiorum. The AgNPs synthesized by Enicostemma axillare leaf extract showed 25 to 80 nm in size and dispersity index (PDI) of 0.412 (Naganthran et al. 2022).

1.7.11

X-Ray Photoelectron Spectroscopy (XPS)

Heinrich Hertz first discovered the photoelectric effect in 1887, paving the way for XPS (Stevie and Donley 2020). XPS, or electron spectroscopy for chemical analysis (ESCA), is a quantitative spectroscopic surface chemical analysis technique for estimating empirical equations, elemental composition in ppt units, and the elements’ internal chemical and electrical states. XPS is carried out in a high-vacuum environment. XPS spectra are created by irradiating a sample with an X-ray beam while simultaneously measuring the kinetic energy and quantity of electrons that escape from the top 0–10 nm of the material under investigation. Kinetic energy can be used to compute binding energy. This approach could be used to quantify and reliably describe nanocrystal interior structures. XPS can identify starburst macromolecules such as P=S, aromatic rings, C–O, and C=O (Zak et al. 2011). XPS and static time-of-flight secondary ion mass spectrometry were used to study the architectures of chitosan/tripolyphosphate

nanoparticles and assess their physicochemical properties. Using dipalmitoylphosphatidylcholine as well as dimiristoylphosphatidylglycerol, nanoparticles can be completely coated with lipids, as shown by zeta potential, XPS, and static time-of-flight secondary ion mass spectrometry. The technique gave the lipid film a significant negative charge, which made it easier for it to interact with the positively charged nanoparticles (Kahraman et al. 2017). By using oleylamine and oleic acid as co-surfactants, Fe3O4 nanoparticles including an average crystallite size of 5 nm were solvothermally synthesized. Excess oleylamine (x = 0.59) reduced the Fe3O4 nanoparticle surface but produced magnetite-like Fe 2p XPS spectra (Wilson and Langell 2014). The CdS–Ag2S core and shell nanoparticles were made utilizing an AOT/n-heptane/water microemulsion system and a post-core and partial microemulsions addition approach. Core-shell particle size and surface composition were determined using X-ray photoelectron spectroscopy. Based on measurements of core-shell nanoparticles made with XPS, the Ag/Cd ratios for post-core and partial microemulsion methods are (~5) and (~10), respectively. This study provides evidence that core-shell nanoparticles, consisting of CdS nanoparticles encased in a layer of Ag2S atoms, are synthesized. The organic AOT developing in the macroscopic phase surrounds the inorganic crystalline CdS core, preventing agglomeration during nanoparticle production. Binding energy peaks for metal sulfide are 161.5 and 168.8 eV, respectively, while those for the highly oxidized form of sulfur in the AOT molecule are greater (Hota et al. 2007).

1.8

Conclusion and Future Perspectives

Nanotechnology, as a cutting-edge branch of developing sciences, has the potential to profoundly transform our lives. Different types of nanomaterials have a unique set of features and the potential to be employed in various fields. Advances in nanotechnology are expected to

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Fundamentals and Analytical Techniques for Biological Applications of Nanomaterials

bring several breakthroughs and new opportunities for the global economy over the next 20 years. However, in order to cut costs, numerous synthetic techniques can be employed to make the nanoparticles, which can then be used in a variety of nanomedical and biological applications. This chapter mainly outlined the role of numerous distinct methodologies in the characterization of nanoscale materials and a summary of various new characterization techniques for determining the microscopic structure and properties of the interface was presented; also new characterization methods and procedures are continually being developed into the bargain. We highlighted the usage of every method, emphasizing their benefits and limits, as well as illustrating how they can be successfully coupled and complement one another, through this complete overview of NP characterization methods. Our evaluation will serve as a comprehensive resource, assisting the scientific community in better understanding the discussed topic by explaining the role of each technique in a comparable manner (Mourdikoudis et al. 2018b). In particular, atomic force microscopy has revolutionized the field of nanocomposites in recent decades, permitting imaging and interpretation of interface structures on much smaller scales than previously available, resulting in an improvement in knowledge of why distinct nanomaterial interfaces display various bulk properties and behaviors. Understanding the crucial function of the interface, developing accurate nano-mechanics-based models, elucidating the interactions at the interface, and acquiring an understanding about the relationship among nanocomposite properties and interfacial optimization will be necessary to effectively tackle the issues connected with interfacial properties. With new fundamental findings being produced on a regular basis, there has never been a better amazing prospect to be active in the area. This review is expected to assist in some little way to the growth of this burgeoning field and to stoke new research passion in order to enrich the content of an increasingly intriguing science (Chen et al. 2019).

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Questionnaire Multiple Choice Questions (MCQs) 1. Chemical solution deposition is also called (a) Sol-gel (b) CVD (c) Plasma-spraying (d) Laser pyrolysis 2. Typical precursor used in sol-gel are (a) Metal-oxides (b) Metal-dioxides (c) Metal-alkoxides (d) Metal fluorides 3. The measurement range of electron microscopy is around _____________ meters? (a) 1 m (b) 1 nm (c) 100 micro (d) 12 mm 4. In which one of the following the number of constituting particles are from two to several thousand? (a) Atom/molecules (b) Nanomaterials (c) Bulk-materials (d) None of the above 5. The increased signal in SERS is due to (a) Surface (b) Solvent (c) Sample molecule (d) None of these 6. XPS is responsible for the determination of (a) Solvation energy of the solvent (b) Binding energy of the element (c) Intermolecular forces (d) Potential energy of molecules 7. What is the typical range of operation for XPS techniques? (a) 0–10 nm (b) 10–100 nm (c) 100–200 nm (d) 200–300 nm Short Type Questions 1. Which methods can be used to measure nanoparticles in a simple, basic manner? 2. Does the size of a metal nanoparticle responsible for the UV-vis behavior?

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3. What is the difference between dynamic light scattering (DLS) and zeta potential? 4. How DLS is used for measuring zeta potential? 5. How to Characterize nanoparticle surface morphology and monodispersity? 6. What are nanomaterials? What is the size range of nanomaterials? 7. How chemical properties are dependent on the changes of size of NPs? 8. What are the different modes of SECM operations? 9. Can SECM be used to distinguish the number of electrons transported during an electrochemical reaction? 10. What are the important surface techniques used to characterized nanoparticles? 11. What are the fundamental differences between SEM and AFM in context of material characterization? 12. Which materials properties can be determined by XRD? 13. What is the fundamental difference between STM and SECM?

Long Type Questions 1. What are the different types of methods used for the synthesis of nanoparticles? 2. What are the different surface techniques are used for Nano particles characterisation? 3. Explain in detail how XRD analysis is important in nanomaterial characterisation? 4. Explain in detail size and surface, morphological analysis of nanostructures using SEM? 5. What are the differences between biological synthesis and chemical synthesis for nanoparticle preparation? 6. Discuss the working principle and mechanism of SECM techniques? 7. What is MALDI-TOF? Discuss its mechanism?

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Emerging Applications of Nanotechnology in Human Welfare with Special Reference to Biomedical Issues Tanishq Meena, Yogesh Singh, V. S. Sharan Rathnam, Tanmay Vyas, Abhijeet Joshi, and Avinash Sonawane

Abstract

Nanotechnology has attracted researchers from diverse fields due to its outstanding potential in providing solutions to current-day problems. It deals with structures that are typically less than 100 nm at least in one of the dimensions. The special focus is due to its unique electrical, magnetic, and chemical properties. Their biological performance is highly dependent on their physical and chemical characteristics such as size, shape, surface charge, surface area, and polarity. Their small size and flexible physicochemical properties make them advantageous in terms of improved drug delivery, targeted therapy, and non-invasive diagnosis, with minimal side effects. In the current chapter, we tried to focus on the applications of nanotechnology in various sections of healthcare such as drug delivery, therapeutics, tissue engineering, and diagnostics. The emphasis was given to the role of the properties of different kinds of nanostructures in their medicinal applications. We also covered the other applications of nanotechnology in the environmental and agricultural sectors. Several nanoparticles are

T. Meena · Y. Singh · V. S. Sharan Rathnam · T. Vyas · A. Joshi (✉) · A. Sonawane Department of Biosciences and Biomedical Engineering, Indian Institute of Technology (IIT), Indore, Madhya Pradesh, India e-mail: [email protected]

successful in the removal of pollutants such as pesticides, heavy metals, and dyes. Nano fertilizers are known to improve crop yield, by responding to the plant signaling stimulus and releasing nutrients. They also improve plant metabolism and prevent nutrient loss. Overall, the involvement of nanotechnology is evident in almost every domain of science and engineering. However, some differences in their properties could be responsible for the detrimental effects on the ecosystem. Hence, there is a need to address several challenges for a better future. Keywords

Nanoparticles · Drug delivery · Diagnosis · Tissue engineering · Heavy metal · Nanofertilizers · Agriculture · Environment · Pollution

Highlights • Nanotechnology has plunged into providing deep insights and solutions to modern-day problems associated with diverse fields of science and engineering. • Physicochemical properties of nanoparticles (NPs) such as size, surface charge, composition, and chemistry govern their biological and environmental applications. • Chemical modification of nanomaterials with receptor ligands and photodynamic and

# The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 B. Sarkar, A. Sonawane (eds.), Biological Applications of Nanoparticles, https://doi.org/10.1007/978-981-99-3629-8_2

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photothermal approaches are some of the strategies to improve their drug delivery applications. Nanomaterials are also used as nanofillers, to mimic the mechanical properties of native extracellular matrix (ECM) for tissue regeneration. Upconversion nanoparticle-based near infrared (NIR) bioimaging and metallic nanoparticle-based MRI imaging are the prominently used diagnostic tools. Metal oxide nano adsorbents are highly effective in the removal of dyes, pesticides, and volatile organic compounds compared to their micro counterparts. Smart nano fertilizers and nano pesticides have been designed which are stimuli-responsive to light, temperature, pH, and other factors and act in a time-dependent manner.

• Nanotechnology aids in the improvement of aquacultures and further the attainment of the “Zero huger” goal of UN.

2.1

Introduction

The idea to consider studying something that requires more than just the naked eye originated historically from the mind of a curious man, Richard Feynman. In one of his lectures at Caltech in 1959, Feynman invited the scientific community to attempt the manipulation of matter at the atomistic scale, using the words “There’s plenty of room at the bottom,” envisioning the atomic scale. His idea was taken forward by an American engineer named K. Eric Dexler who published his work talking about nanotechnology. However, the credit of coining the term

Fig. 2.1 Lengths of various biological materials for a size-comparison perspective

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Fig. 2.2 Applications of nanotechnology in wide domains of biological sciences and environment

“nanotechnology” lies with Japanese scientist Norio Taniguchi who first used it to describe the manipulation of materials by one atom or one molecule (Taniguchi 1983). Structures behave very differently at the nanoscale from what they behave in their bulk form. Figure 2.1 helps put things of various lengths into perspective. Nanotechnology relates to the study, design, and application of nano-sized structures, materials, particles, and sheets. These structures are considered to be nano if at least one of their dimensions falls in the size range of 1–100 nm. They are known for their unique physical, chemical, and biological properties. The idea and growth of nanotechnology have come up by learning from the fact that there are enormous interactions among several biomolecules in a single living cell which function at high precision at a nanometer level (Sindhwani and Chan 2021). The research on nanotechnology aims in providing promising solutions for a wide variety of problems that are encountered in day-to-day life. The design of nanomaterials is flexible, which means that their physicochemical and biological properties could be tuned. Therefore, nanotechnology platforms are useful in applications in various domains of science and engineering (Fig. 2.2). Here, in this chapter, we tried to specially emphasize on the applications of nanotechnology in the fields of medicine and the environment.

2.2

Nanotechnology in Medicine and Healthcare

The application of nanotechnology in the field of medicine is termed nanomedicine. It specifically aims at the prevention, diagnosis, and treatment of diseases. These fall into five sub-sections, i.e., (1) sensing tools for the diagnosis, (2) therapeutics in treating cancer and other diseases, (3) delivery of drugs, genes, protein/growth factors, (4) tissue regeneration, and (5) treating bacterial/viral infections.

2.2.1

Physicochemical Properties of Nanomaterials for Medicine

The nanostructures possess special characteristics compared to their original components making them unique from a biological point of view. The physicochemical properties of the nanomaterials play a crucial role in deciding their behavior with the biological systems and a few of the roles of physicochemical characteristics of nanostructures have been discussed from biological applications perspective (Fig. 2.3). Nanoparticles (NPs) also possess a tendency to induce toxicity on biological specimens, hence there is a necessity to tune their physicochemical properties accordingly to meet their demands in applications.

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Fig. 2.3 Different physicochemical characteristics of nanomaterials which influence their biological and environmental applications

2.2.1.1 Size and Surface Area It plays a vital role in interaction with biological entities, since lesser size of the particles results in an increase in surface area than its volume leading to more reactivity. Generally, it is observed that, the smaller the size of the particles, the more the pulmonary toxicity even if the material is inert (Sharifi et al. 2012). It has reported earlier that the structures between 10 and 20 nm get accumulated in the alveolar area. The ultrasmall particles which have the similar size to that of the globular proteins and DNA helices have the tendency to even enter the cell organelles (Sukhanova et al. 2018). Huo et al. reported that the gold nanoparticles with 6 nm that could enter the nucleus are more toxic compared to the larger gold nanoparticle counterparts that could not enter the nucleus (Huo et al. 2014). The specific surface area (total surface area per unit mass) also influences the size-dependent toxicity of NPs. The TiO2 NPs with the size range of 10–30 nm produced high reactive oxygen species (ROS) per unit surface area compared with that of the NPs with the size less than 10 nm and greater than 30 nm (Huang et al. 2017).

2.2.1.2 Shape The shapes of the NPs affect its toxicity and also their subject to membrane wrapping processes in vivo during endocytosis or phagocytosis. It has been observed that the elements with higher aspect ratios are more toxic than lower ones, e.g., TiO2 fibers are more toxic if they are of 15 nm but lesser toxic when of size 5 mm and becomes the initiator of generating inflammatory response in macrophage of mice. Breza showed that rod-like shaped rutile nanoparticles were more cytotoxic than that of sphere shaped, which may be attributed to high electron density transfer in the former case (Breza and Šimon 2020). 2.2.1.3 Surface Charge The surface charge of nanomaterials is also an important parameter which influences their interaction with the cellular membranes and other biomolecules. It could affect the colloidal stability, plasma protein binding, and transmembrane permeability. In several studies it has been found out that the cellular uptake of positively charged surface particles is higher with respect to that of the negatively charged or neutral NPs and hence it

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Table 2.1 Table depicting different nanostructures under each category Type of nanostructures Polymerbased nanomaterials Non-polymerbased nanomaterials

Examples Dendrimers, micelles, nanogels, drug conjugates, protein nanoparticles Carbon nanotubes, graphene derivatives Nanodiamonds, quantum dots

Lipid-based nanomaterials Metal basednanoparticles

Silica, bio glass, nanoceramics Liposomes, exosomes, solidlipid particles Gold nanorods, iron oxide, and silver nanoparticles

Principal applications in healthcare Drug delivery

Drug delivery, photothermal and photodynamic therapy Biosensing Tissue engineering Drug delivery Photothermal therapy; antimicrobial

determines the toxicity (Huang et al. 2017). It was reported that the iron oxide NPs, treated with carbon and oleic acid had different surface charges and displayed different levels of toxicity despite having similar size. The high positive charge caused higher toxicity (Kai et al. 2011). Weiss et al. demonstrated the effect of surface charge density on the toxicity by examining five different cationic carbon NPs. The NPs with highest surface charge densities induced oxidative stress and mitochondrial dysfunction in THP-1 monocytes (Weiss et al. 2021). Similarly, the rod-shaped cerium oxide NPs resulted in the lactate dehydrogenase (LDH) release and production of tumor necrosis factor (TNF) alpha in RAW 264.7 macrophages, which was not observed when treated with cube or octahedron particles (Forest et al. 2017).

2.2.1.4 Composition and Chemistry In a study with zebrafishes, algae the soluble form of nanocopper and nanosilver particles caused toxicity while it was not observed with TiO2 despite having same dimensions. Crystal structure also affects the various characteristics and toxicity as per the findings in several studies that rutile TiO2 nanoparticles cause oxidative DNA damage, lipid peroxidation, and micronuclei formation in absence of light while anatase

References Hao et al. (2022), Gao et al. (2020), Abedi et al. (2021), Kalimuthu et al. (2018), Wang et al. (2013) Chen et al. (2020), Jiang et al. (2020)

Morales-Zavala et al. (2018), Mohammadi et al. (2022) Wu et al. (2018), Wang et al. (2017a), Mei et al. (2022) Lai et al. (2019), Vázquez-Ríos et al. (2019) Gong et al. (2021), Armijo et al. (2020), Nudelman et al. (2021)

nanoparticles were not found impacting the same. The other properties like surface coatings, roughness, clump-forming aggregation, and solvent media also affect the nanostructures’ particular characteristics altering its toxicity and interactions with the biomolecules. There are different types of nanostructures, categorized based on the aforementioned physicochemical properties. Table 2.1 shows the types of nanostructures used in medicine and healthcare with their respective examples.

2.2.2

Drug Delivery

On a recent note, the incidence of cancer-related deaths has increased significantly worldwide. The goal of the therapy is to ultimately remove the tumors in a long-lasting manner. An ideal drugdelivery platform is attributed to two elements. Firstly, the ability to control the release of the drug and secondly the ability to target the delivery site (Sim and Wong 2021). The drug molecules show less efficacy in vivo compared to in vitro due to the additional interactions with the physiological fluids, leading to poor pharmacokinetics. Such examples include adsorption over the surface of serum proteins, excretion of the drugs below renal filtration cutoff (i.e., below 6.5 nm)

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and exposure to degrading enzymes like endonucleases. Liver also reduces the number of active drug molecules by metabolizing them further. Secondary lymphoid organs can also sequester the drug molecules further reducing their activity. In this regard, nanotechnology is very useful in overcoming these challenging aspects. This could be done by certain modifications in their designs making them suitable to work as an excellent drug delivery vehicle protecting efficacy of the drug in vivo as well. The nanoparticles ease the permeability for the drug molecule to move across any kind of biological structure due to their small size and tunable surface characteristics such as surface charge, polarity, shape. There are various kinds of nanostructures which are preferred in therapeutics and are characterized in multiple forms depending on their chemical composition. In general, either of the three following ways is chosen to load drug to any nanoparticle, i.e., encapsulation inside nanoparticles, integrated to the matrix, or coating over the surface. The method chosen to load depends on the interaction between drug molecules, nanoparticle material, and the specific target of that particular drug molecule. There are four fundamental reasons for the drug to be loaded on to the nanoparticles. Firstly, for improving the bioavailability by enhancing aqueous solubility, to increase resistance time in the body (by increasing half-life and reducing the adsorption of serum proteins), to target the drug to specific site of action (Mudshinge et al. 2011), and finally to protect the drug from the immune rejection post intravenous injection to inhibit degradation (Carissimi et al. 2021). Chemical modifications of nanostructures are achieved by treating them with polymers. One of the commonly used approaches is the modification of the surface with poly ethylene glycol (PEG). It increases the specificity of drug uptake, targeting ability. It further reduces the chance of detection of nanoparticles as foreign objects by the body’s immune system, which allows them to circulate in the bloodstream until they reach the tumor (Sim and Wong 2021). The advantages of using nanoparticle-based drug delivery systems are

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many. They have the unique property of a high surface area to volume ratio, due to which they possess high adsorption capacities for the drugs. Among them graphene-based nanomaterials are predominant due to their two-dimensional structures (Jampilek and Kralova 2021). It was reported that etoposide loaded on to carboxylated graphene oxide (GO) resulted in the higher toxicity of hepatocarcinoma cells compared to free etoposide, via upregulation of seven apoptotic genes (Gholami et al. 2020). These nanomaterials are also used in combination with other materials to reduce its direct toxicity and also to enhance the loading properties. In one such study, it was shown that GO foams functionalized with alanine results in sustainable release against breast and liver cancer cell lines, due to larger pore volume (Ezzati et al. 2020). The nanoparticles have the ability to penetrate within the body due to their small size and minimized irritant reactions due to controlled drug release. Considering their ultrasmall size, the metallic nanoparticles are well explored in this category. They are known for their biocompatibility, high colloidal stability, and they also minimize the usage of organic solvents for their production (Klębowski et al. 2018). Among them, gold NPs are one of the most widely used, with varying sizes in the order of 10–100 nm. They also possess different shapes such as rods, spheres, cages, and bipyramids (Chen et al. 2008). Several reports suggest surface modification of Au NPs to change its toxicity and biodistribution. Active passage is a mechanism in which the nanoparticles are generally coated with some specific binder biomolecules such as monoclonal antibodies, ligands, substrates, and peptides which could lead the drug molecule to its particular target site by binding with their specific receptors present on the target surface with the help of receptor-ligand interactions. In one such study, it was shown that Au NPs were conjugated galactose targeting ligand-enabled delivery to the asialoglycoprotein receptor and assisted in the treatment of hepatocellular carcinoma (Bergen et al. 2006). Folic acid is one of the commonly used ligands since its receptor is overexpressed in several cancer types (Fernández

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et al. 2018). For example, Qu et al. showed that the folic acid conjugation improved the uptake of topotecan-loaded mesoporous silica NPs by retinoblastoma cells and resulted in significant cytotoxicity. It was also consistent in reducing the tumor volume in mice model (Qu et al. 2018). Metallic nanoparticles are also synthesized from biological sources. Singh et al. reported the synthesis of Ag NPs from the leaf extract of Morus alba and used for the treatment of hepatocellular ailments (Singh et al. 2018a). The blood brain barrier (BBB) is a highly selective membrane, whose permeability is limited to a very few molecules that are hydrophobic and smaller in size. Hence, it is very challenging to transport any kind of drugs through it (Dong 2018). In this regard, carbon nanotubes (CNTs) are promising candidates considering their minute size. They are one-dimensional, elongated carbon allotropes, which are highly hydrophobic in nature (Xu et al. 2019). For this reason, they interact through hydrophobic interactions and pi-pi stacking with the various kinds of aromatic therapeutic compounds, which assist in their loading (Chen and Mitra 2019). CNTs are also functionalized with polymers like PEG to enhance its hydrophilicity. Kafa et al. demonstrated that the amine-functionalized multi-walled CNTs were able to pass the BBB and their presence was confirmed in brain capillaries and parenchyma fractions post intravenous injection mice model (Kafa et al. 2015). The earlier studies also show that the dual loading and delivery of hydrophobic and hydrophilic drugs is highly inducing cytotoxicity against tumor cell lines (Espanol et al. 2016). In this context, liposomes offer promising strategy. These are vesicular in nature which consists of phospholipid one or bilayers, with the size ranging from 25 nm to even 2.5 μm (Akbarzadeh et al. 2013). There are two unique advantages of liposome-based drug delivery. The liposomal lipid layers possess hydrophobic and hydrophilic ends, due to which simultaneous loading of polar, hydrophobic and amphiphilic drugs can be achieved (Zacheo et al. 2020) for anti-cancer, antibacterial and antifungal therapy (Alavi et al.

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2017). Liposomes have been proven to be effective in the drug delivery against cardiovascular diseases. Prostaglandin E-1 possesses unique properties of inhibition of platelet aggregation and anti-inflammatory effect for the inhibition of platelet aggregation and thrombosis. Liposomalbased delivery of PGE-1 had been tested for the treatment of cardiovascular diseases like restenosis following angioplasty (Bulbake et al. 2017). Polymeric drug delivery systems have greatly developed in recent years, due to their high biocompatibility and biodegradability. Polymeric hydrogels, micelles, polymer-drug conjugates are used for the controlled release of a wide range of anti-cancer and antimicrobial drugs. It is well known that the tumor microenvironment is acidic (Feng et al. 2018) due to the higher production of lactic acid. In this regard, pH responsive drug delivery platforms have been exploited. Polymers which possess imidazole groups or poly(β-amino ester) have been exploited which are responsive to tumoral low pH (Yoshida et al. 2013). In a similar fashion, Gao demonstrated that a pH responsive delivery of insulin was carried out through carboxy methyl cellulose/poly acrylic acid hybrid hydrogels into the small intestine (Gao et al. 2014). Temperature-sensitive polymers such as N-isopropylacrylamide (NIPAAM) are stimuli responsive, consisting of amide and propyl moieties. PNIPAAm has lower critical solution temperature (LCST) of approximately 32 °C (Sarwan et al. 2020). Cao et al. had developed reversible thermos-responsive pNIPAAm-peptide hydrogels for controlled drug delivery (Cao et al. 2019). Apart from the delivery of drugs, various nanomaterials have been reported to deliver gene and proteins to the target site (Giannaccini et al. 2017; Jeevanandam et al. 2019).

2.2.3

Therapeutics

Apart from the delivery of drug molecules to the target site, the nanomaterials also have been used in direct therapeutic applications, especially for

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Fig. 2.4 Schematics depicting (1) NIR-induced photodynamic therapy through-ROS production via release of photosensitizers; (2) NIR-induced combined photothermal

and chemotherapy through heat and drug release, inducing necrosis and apoptosis, respectively

cancer treatment. Photosensitizers (PSs) are the type of materials which absorb light from specific wavelength and transfer the energy to a nearby material. Hence, in the biological context, these molecules have the potential to generate ROS upon excitation with specific energy of light (de Freitas and Hamblin 2016). The produced ROS is utilized in the disruption of cell structures of disease-causing microorganisms and tumor cells by induction of apoptosis, necrosis, or autophagy (Shang et al. 2021) (Fig. 2.4). This kind of treatment strategy is known as photodynamic therapy (PDT). For this purpose, a variety of materials have been in use, among them porfimer sodium is one of the earliest firstgeneration PSs, which is well reported for the destruction of tumors and can also be formulated in water for intravenous administration (Hosokawa et al. 2020). The encapsulation of PSs in NPs increases their solubility and stability, which avoids self-quenching and thereby increases 1O2 yield (Liu et al. 2019a). The NPs also assist in delivering oxygen, to minimize tumor hypoxia, for the better PDT effect (Day et al. 2017). The efficacy of many

photosensitizers gets limited due to their pure stability and short half-life. To overcome this problem, Liu et al. have designed an encapsulation system for indocyanine green. To stabilize and increase the half-life of the photosensitizer, PEG4000, human serum albumin and nuclear targeting peptide transactivator of transcription (TAT) were used. The nanoparticle-based system enabled higher cellular uptake. It has also enabled tumor growth suppression in mice model (Liu et al. 2021). In another report, a PDT system was designed with the help of hemoglobin (Hb)-linked conjugated polymer nanoparticles (CPNs). Here, Hb aids in the activation of luminol; further, its chemiluminescence would be absorbed by the polymer nanoparticles which can sensitize the oxygen supplied by Hb and finally produce reactive oxygen species to kill the cancer cells. This system possesses three main advantages. Firstly, it could be used for the controlled release, secondly, it does not need an external light source, and finally it overcomes the oxygen insufficiency under hypoxia, to enhance PDT (Jiang et al. 2019). The interactions between the PSs and

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polymeric nanoparticles lead to aggregation. Hence to improve the quantum yield of singlet oxygen generation, tetraphenyl porphyrin derivatives were used for the preparation of nanoparticles. It increased phototoxicity, retention time, and efficacy against tumor in mice model (Zheng et al. 2019). Another interesting feature of nanoparticles is the display of photothermal effects. This property is because of the surface plasmon resonance due to which the materials undergo photoacoustic and photothermal changes and also affect their molecular vibrational energy. This results in the generation of hyperthermia (Ali et al. 2019). These elevated temperatures are exploited for the killing of cancer tissues and microorganisms (Fig. 2.3). This mechanism is known as photothermal therapy (PTT). Among them, gold nanoparticles of different shapes are extensively explored. There are several advantages of using gold nanoparticles, i.e., they minimize non-specific distribution by localizing into the tumor site, they get excited with near-infrared (NIR) irradiation, which have high penetration ability, they can also be tuned to create multifaceted PTT and drug delivery (Vines et al. 2019). In another study, it was shown that the incorporation of gold nanorods in the hydroxyapatite/gelatin hydrogels resulted in the photothermal treatment of postoperative tumors in tibia osteosarcoma mice model (Liao et al. 2021). Gold nanorods are also used in the hyperthermal therapy to viral infections. An aptamer-conjugated rabies virus glycoproteingold nanorod formulation was used for the enhanced delivery to the central nervous system. It resulted in a more than 100-fold decrease in the viral load, with nanorod mediated PTT (Ren et al. 2021). Apart from these, graphene and its derivatives such as graphene oxide and reduced graphene oxide were also utilized in PTT of cancer (Dash et al. 2021). Graphene has high amount conjugated π bonds, due to which electrons of various π-π transitions get excited at about every wavelength in UV, visible, and NIR region. Hence, it has strong absorption in the entire solar spectrum. Additionally, large surface area available for the absorption and its efficiency in the photothermal conversion makes it an ideal

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photothermal material (Li et al. 2021). There are also polymers which exhibit photothermal effect such as polydopamine, polyaniline, and acrylamide derivatives and utilized in the PTT (Yu et al. 2020). The recent emerging technology involves the usage of two or more of these strategies for combined therapy for cancer. Yang et al. had developed a single platform that displayed the photodynamic and photothermal properties. The platinum nanozyme system was able to catalyze production of oxygen for an efficient PDT, and also enhanced intrinsic photothermal properties of carbon nanozyme which combination resulted in tumor inhibition in vivo (Yang et al. 2020). Chitosan-functionalized copper iron sulfide nanoplates resulted in NIR-mediated photo ablation of tumors in vivo. The same platform was used to load and deliver cis-platinum pro drug, which was facilitated due to the released heat. The system displayed a synergistic effect (Ding et al. 2017).

2.2.4

Antibacterial/Antiviral Therapy

An excessive use of antibiotics had led to an increase in the number of drug-resistant strains of disease-causing agents. These are known as superbugs, which are harder to treat through normal medication (Wang et al. 2017b). It had been presented that all forms of nanomaterials have the potential to exhibit antibacterial properties, i.e., zero-dimensional Ag and silica-based nanoparticles, one-dimensional carbon nanotubes, silver nanowires, two-dimensional graphene nanosheets, and three-dimensional silver sulfide nanocubes, polyacrylic acid scaffolds (Hu et al. 2021). Further, the usage of nanostructures for the antimicrobial growth has a unique advantage. There are many simultaneous mechanisms of action exhibited by NPs against bacteria, hence simultaneous mutations are needed in the same cell to develop a resistance against NPs; which makes them difficult to become resistant against NPs (Wang et al. 2017b). Silver nanoparticles are one of the most well explored. They are known to inhibit both

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Gram-negative and Gram-positive bacteria and also multidrug resistant strains. They exhibit several simultaneous mechanisms and also display synergistic effects when used in combination with antibiotics (Bruna et al. 2021). The advantages of using ZnO nanoparticles are its efficiency even at low concentrations against a wide variety of strains and also operate at relatively low cost (Gudkov et al. 2021). These nanoparticles work by disrupting cell membranes (Sirelkhatim et al. 2015), binding to cellular proteins, and production of ROS (Saha et al. 2020). The biofilm is the deposition of extracellular polymeric substances by the bacteria. It is difficult for the drug molecules to surpass the biofilm and hence aid in reducing the efficacy of the drugs. In this regard, graphene-based nanomaterials offer remarkable abilities to inhibit biofilm synthesis. The graphene coating on the titanium implants reduces the formation of biofilms of enterococcus and pseudomonas species (Srimaneepong et al. 2022). Graphene is also reported to enhance the attachment of cells and induce osteogenic differentiation, and at the same time maintaining its antibacterial abilities (Gu et al. 2018). Apart from these the nanoparticles also have the capability to interact with viral particles and inhibit their growth. Silver nanoparticles exhibited antiviral properties against SARSCoV-2 (Seifi and Kamali 2021). Further, Fe3O4 nanoparticles were able to reduce the ability of SARS-CoV-2 virus to attach to the host cell receptors (Abo-Zeid et al. 2020).

2.2.5

Tissue Regeneration

Besides the use of nanostructures in delivering therapeutic compounds, involvement in cancer and antimicrobial therapy, they are also used as inducers of tissue regeneration. Because of the high surface area to volume ratio, these are used as substrates for cell adhesion, spreading proliferation, and migration. It has been shown that graphene serves as a platform for the adhesion of human mesenchymal stem cells (hMSCs) and aids in the proliferation. Nanoparticles also

facilitate the differentiation of stem cells toward osteogenic, chondrogenic, and cardiomyogenic lineages. The size of the nanoparticles could also affect the fate of the differentiation of stem cells. For example, TiO2 nanotubes of about 15 nm was observed to regulate the adhesion and differentiation of human hematopoietic stem cells, whereas higher dimensions around 50 and 100 nm enabled osteogenic differentiation both in vitro and in vivo (Wei et al. 2017). It is responsible for inducing epigenetic changes at histone H3 for regulating the differentiation of hMSCs. Na+/K+ transporting adenosine triphosphatases (ATPases) such as ATP1A2 and ATP1A3 are involved in the osteogenic differentiation of stromal cells in the presence of TiO2. Nanomaterialinduced physical stimulation such as mechanical stimulation and electrical stimulation are used to induce the differentiation of tissues. The former is used for the differentiation of muscle, whereas the latter in the case of neuron differentiation. Materials such as carbon nanotubes and fullerenes possess extraordinary electrical conductivity, due to which they are used in the electrical stimulation (ES) of the cells to undergo differentiation. ES is highly beneficial in ES influences the direction of alignment of cells and migration of cells. In order to minimize the effect of field gradient across the cell, few cells such as cardiac adipose-derived progenitor cells align perpendicular to the direction of the electric field vectors. On the other hand, few cells such as ventricular monocytes align parallel to the field vectors because of the cytoskeleton of the cells (Chen et al. 2019). One important feature that a scaffold should possess to be used as a supportive material for tissue regeneration is its ability to mimic the mechanical properties of the ECM of the native tissues. In this regard, several nanomaterials are used to enhance the mechanical properties of scaffolds, hydrogels, and thin films. They are used as nanofillers and used in tuning the mechanical strength by imparting reinforcement (Fathi-Achachelouei et al. 2019). These include the tuning of the compressive strength, tensile strength, and Young’s modulus of the hydrogels and fibers. The mimicked mechanical strength is

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used for enhancing its interactions with cells and biomolecules. The incorporation of graphene oxide increased the mechanical stiffness of polycaprolactone nanofibers which aided in the adhesion, proliferation, and differentiation of neural stem cells (Kim et al. 2015).

2.2.6

Diagnosis

Early and accurate diagnosis is one of the crucial steps in establishing treatment for any kind of disease. Nanoparticles could be used in diagnostics that aim to visualize or sense pathologies and also help in understanding patho-physiological principles underlying diseases and developing their treatment options (Baetke et al. 2015). One of the principal categories in this section is the detection of cancer as biosensors. Conventionally, low-dose computed tomography is the widely accepted tool for the detection. However, there are several risks and challenges associated with it. They include excessive cost, exposure risk due to radiation, and also sometimes false positive results. Therefore, the detection of circulating nucleic acids (miRNAs) would provide important information regarding the outcome of lung cancer, especially at the earlier stage. Smaller size, sequence homology between species, low concentration, and stability are some of the major challenges involved in characterization and specific detection of miRNAs. To circumvent these problems, the usage of sage of quantum dot-based biosensors might be sensitive, specific, and also economical in the detection of miRNAs. They possess high quantum yields due to their wide range of excitation and emission spectra and could detect multiple targets using fluorescence resonance energy transfer (FRET). They detect miRNAs by mitigating its challenges of low concentration, small size, and stability (Singh et al. 2018b). Near infrared fluorescence (NIRF) imaging is a non-invasive method which gives a microscopic imaging of the pathology (Han et al. 2019). The penetration depth of NIR is higher than that of visible light. Upconversion nanoparticles are the

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materials that absorb NIR and can emit light at lower wavelengths such as in the visible and UV spectrum (Mokoena et al. 2017). Mostly, lanthanides make up the composition of upconversion nanoparticles. Generally, these materials are biocompatible and also photostable and display high quantum yields. These are mostly hydrophobic in nature; however, they are coated with hydrophilic components to ease their usage in the biological systems. Nanomaterials are also used as contrast agents in MRI for diagnosis. Among them, superparamagnetic iron oxide is widely used. In this the predominant components are either Fe3O4 or Fe2O3. The nanomaterial-based MRI imaging enables its use even at gene/protein and cellular level. In the case of active targeting, ligands or antibodies are used for biodistribution of nanoparticles and for the diagnosis.

2.3 2.3.1

Other Applications Environment

2.3.1.1 Water Purification One of the most prominent uses of nanotechnology in the environment is the removal of contaminants from the polluted water. This could be from the drinking water source such as rivers and lakes or from the effluent discharged water. Novel and innovative technologies are necessary to ensure supply of safe drinking water and also reduce global water pollution. The nanomaterials act as absorbents in the removal of pollutants. They are involved in adsorption of pollutants, catalysis, and censoring with higher efficiency, and affordability (Khan et al. 2019). Due to their high specific surface area, these nano adsorbents possess greater adsorption rates for organic materials compared to that of activated carbon. The presence of heavy metals is considered to be one of the serious threats to the human and aquatic life. New engineering strategies have been in use in immobilizing nanomaterials on carriers and organic membranes for the efficient removal of heavy metals from water (Liu et al.

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Fig. 2.5 Schematics showing different adsorbents used in the removal of pollutants and purification of water

2019b). One such example is illustrated in Fig. 2.5. Several semiconducting nanoparticles such as SnO2 are effectively involved in the detection of cadmium, lead, mercury, and copper ions from drinking water (Wei et al. 2012). The nanoparticles are also used as composites with conducting polymers for the betterment of electrochemical stability and sensitivity of heavy metal ions. On the other hand, quantum dots which display high quantum yields are more sensitive and selective in the detection of metal ions such as lead, arsenic, chromium, and cobalt (Torres et al. 2022). Dyes are used in commonly used items such as paper and clothing. The textile industry is one of the major contributors of contaminating the nearby water reserves through the discharge of dyes. Most of the dyes are aromatic organic compounds and are considered as carcinogenic. They are also chemical and thermal resistant making them difficult to remove from the water sources (Osagie et al. 2021). In this regard, nanotechnology aims for the efficient removal of dyes due to their controlled parameters and surface area. Examples include titanium dioxide, iron oxide, zinc oxide, and aluminum oxide nanoparticles. The nano-adsorbents are about five times more efficient in this regard, to remove pollutants compared to that of their micron-size counterparts. As a part of less toxic and eco-friendly point of view, several plant and

microbial extract nanoparticles have been explored in this case. Such example includes the removal of bromophenol blue through potato peel extract silver nanoparticles (Akpomie and Conradie 2020). Additionally, various nanomaterials have been explored for the removal of volatile organic compounds (Weon et al. 2019) and pesticides (Taghizade Firozjaee et al. 2018) from the industrial effluents.

2.3.1.2 Soil Remediation Soil provides 99% of our daily food requirements (Ur Rahim et al. 2021). It is the most valuable resource and is also non-renewable. The repeated exposure of pollutants to the soil by human activities specially driven by industrial revolution has gradually resulted in irreversible degradation. These pollutants could be either organic (plastics, microplastics, pesticides, or fertilizers) or inorganic (heavy metals), resulting in a persistent poisoning of the environment. Hence, careful measures have to be taken in order to conserve the richness, integrity, and nutritional value of the soil. There are certain limitations of conventional approaches for the bioremediation of soil, such as sensitivity, longer time for remediation, and by-products might be toxic (Bioremediation 2013). The newer approaches to remove pollutants mostly revolve around adsorption of contaminants with the use of materials, such as

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carbon (biochar, activated charcoal, carbon nanotubes, and graphene), metal oxides (TiO2, MnOs, FeO, MgO), minerals, and chemical reducing materials (nano-zerovalent iron, FeS, S2O32-, MoS2, Mn, Zn, H2O2) (Ur Rahim et al. 2021). The mobility and toxicity of soil pollutants can be dealt with by making certain changes in the soil. These changes can either be (1) addition of mobilizing agents that enhance the bioavailability of soil pollutants to facilitate their increased removal and (2) addition of immobilizing agents that bind to pollutants in the soil and prevent their entry into the food chain (Usman et al. 2020). Use of recyclable nanomaterials (NMs) is a smart approach to manage remediation costs. Nanotechnology and bio-remediation can also be performed in tandem to deal with organic pollutants. NMs make the pollutants more readily available and less toxic to the bioagents working to remedy the soil (Gong et al. 2018). Apart from the many beneficial effects of NMs on plants, some studies also indicate their phytotoxicity. However, effects, whether positive or negative, depend on size, nature, and dose of the NMs, and the duration and conditions of exposure. Smaller nanostructures were found to be more toxic.

2.3.2

Agriculture

Currently, owing to the growing human population, the agriculture and related industries are facing tremendous pressure to fulfill the growing nutritional needs (United Nations 2022). The UN plans to reach its goal of achieving “Zero Hunger” by 2030, which would take intricate planning both to manage available reserves of food and to develop newer and more efficient technologies to produce food which could sufficiently meet the global nutritional demand. In the constant battle against population, production of ample food is facilitated by resources like fertilizers, pesticides, water, and energy. Normally, chemical fertilizers are used for the purpose of making enough nutrients available to plants. However, these come with limitations such as limited nutrient content, potential for

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pollution (Wurtsbaugh et al. 2019), and other undesired outcomes like the changing of the soil pH over time, which need to be applied frequently. Similarly, pesticides, while protecting plants from pests, weeds, or diseases, are also associated with damage to human health and to the environment. Therefore, there is a need for alternative methods to serve these purposes. In that regard, nanotechnology has been found to be a promising option. Nanofertilizers can be made where nanoparticles themselves serve as nutrients. An important feature is that they can be tuned according to the need, i.e., controlled release of fertilizers (Usman et al. 2020). Nanofertilizers also report an increase in efficacy of nutrient uptake, compared to conventional fertilizers (Ur Rahim et al. 2021). Biofertilizers can also be integrated with nanostructures to improve their overall efficiency, and shelf life protecting them against desiccation, heat, and UV inactivation. Nanofertilizers have also been shown to improve plant metabolism and uptake of nutrients. One way to improve the fertilizer efficiency and curb nutrient loss is through the use of slowrelease fertilizers. There are certain kinds of nanofertilizers which can release nutrients as and when required by the plant, guided by plant signaling. Nanoparticles respond to stimuli which are characteristic of plant needs. These structures are aimed at modifying the internal root signals closely associated with some form of nitrogen or phosphorus deficiency (ethylene production and acidification of the rhizosphere) (Usman et al. 2020). Elements that have been used for formulating nanofertilizers include Iron, Zinc, Boron, Selenium, Nitrogen, Phosphorus and Potassium, Calcium, Vermicompost, TiO2 (Servin et al. 2012), Carbon, and biofertilizers (Djaya et al. 2019). Apart from the useful aspects of nanofertilizers, they carry some drawbacks. The high reactivity of nanomaterials is a health concern for the farmers who may get exposed to them. Thus, each NP must get evaluated for their toxicity and bioaccumulation. Nano pesticide systems are slow delivery systems that use nanomaterials as carriers for integration with classical pesticides (a term that

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encapsulates herbicides/weedicides, insecticides, and bactericides) to observe improved stability, biodegradability, and targeted delivery. Nanopesticides are associated with high efficiency of uptake, increased deposition on leaves (owing to small size), increased pest–pesticide interaction, reduced pesticide-related waste, and improved water retention (Ur Rahim et al. 2021). Nano Herbicides have some advantages, such as they increase the affinity for the target by providing a larger surface area and they reduce splash losses. Nano herbicides work on targeting the underground receptors in the weed roots, entering the roots and inhibiting the glycolytic pathway there, essentially killing the weed (Altman 2018). Nano herbicides also show a high detoxification rate. Metallic oxide-based NPs were reported to be successful regulators of soil-borne diseases (Shenashen et al. 2017) and in keeping the size and composition of soil microbial communities in check. One way to ensure the desired slowrelease of pesticides is the application of stimuliresponsive nanopesticides. These can be made to respond to changes in pH, temperature, endogenous living factors like antioxidants and enzymes, and to light.

2.3.3

Aquaculture and Fisheries

Foods based on aquatic animals have been rich sources of many nutritional components that benefit the human diet. These include ω-3 long chain polyunsaturated fatty acids (LCPUFAs), selenium, iodine, potassium, vitamins A, D, E, B12, and taurine (Oehlenschläger 2012). Aquaculture refers to the farming and husbandry of fish and other species of aquatic living organisms for the purposes of food preservation, among others. Aquaculture contributes majorly to global food supply, with 143.8 million tons of seafood consumed by humans every year. Aquaculture has now started to play a vital role in supporting the UN’s goal of achieving Zero Hunger. While there is enough significance of aquaculture in terms of a food source, there still exists a huge gap in terms of disease treatment, water quality management, better fish breeding

(through introduction of efficient maturation and spawning agents), culture time reduction, and effective vaccine (Aklakur et al. 2016). Among many approaches, nanotechnology has come out to a fast-emerging platform for advancement in aquaculture. The idea behind replacing existing aquacultural practices with nanotechnology is to bypass the harmful effects that the former causes. Such practices include excessive use of antibiotics, administration of synthetic growth regulators. Adverse effects arising from these practices can be as severe as impairment of growth and reproduction, undesirable biochemical changes in the fish, and even death. Nanotechnology has been successfully applied for the purposes of water purification, water quality monitoring, seafood processing and preservation. Delivery of vaccines and nutrients and pathogen detection and bioimaging. Vaccines are indispensable tools to help fish fight against aquatic pathogens. Traditional methods of vaccine preparation that involve oil/water formulations occasionally lead to fish mortality. Alternative delivery methods for vaccines developed to overcome this problem revolve around the encapsulation of the drug. Several materials serve as encapsulating agents including alginate, chitosan, poly(lactic-coglycolic acid) (PLGA), and liposomes (Irie et al. 2005). These methods make excellent encapsulating agents due to properties like biodegradability, biocompatibility, biostability, mucoadhesion, and low or non-toxicity. All of these were shown to successfully contribute positively toward fish survival, growth, and reproduction. Conjoining gene modulation with nanoparticles is a novel approach which is being used to improve metabolic conversion of dietary molecules. This is an example where nanoparticles were used to serve more than just carrier vehicles. Encapsulation ensures protection of enclosed materials against physical and chemical degradation. Upon entry of the cell, the vaccine can be stimulated to release from the NP by means like pH, infrared, or ultrasound. When applied to detection, nanotechnology provides an advantage in point-of-care use in complex matrices like water. Different types

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of nanoparticles exhibit different kinds of properties which can be put either to use to detect bioanalytes themselves or to improve the sensing abilities of existing biosensors (Li et al. 2017). Literature also backs the use of nanotechnology in delivery of nutrients to fish. Such systems work to make the nutrients more soluble and more stable within the gut of the fish. Different nanoformulations, ranging from nanoencapsulated-6-coumarin (Trapani et al. 2015) and nano-selenium to NPs based on gold, MnO, and copper, to even those based on Aloe vera extract and ginger (Korni and Khalil 2017).

2.4

Challenges and Future Perspectives of Nanotechnology

There are few issues associated with the development of nanoparticulate-based nanomedicines in a clinical perspective. These are toxicity, bulk manufacturing, reproducibility, minimizing cost of production, intellectual property, and other safety issues. In the environmental perspective, nanomaterials have the potential to migrate into ground waters and also contaminate the soil. The nanoparticles used in effluent and solid waste treatment could be transported to water bodies via wind or rainwater flow. Hence, to overcome these challenges there is a necessity for a combined effort. The future goals should be the translational success of usage of nanotechnology that requires the involvement of active collaboration of experts from different stages of its development, toxicology, and clinical studies.

2.5

Conclusion

Nanotechnology deals with the design, study and applications of the materials which are ultrasmall in the order of nanometer range. Currently, it has paved the way for the development of remedies for the present-day challenges. It addresses the diagnosis, predicting, and treating of illness and helps in modulating human frameworks at the cellular level. Nanoparticles such as metallic and

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polymer based are used in targeted chemotherapy against various tumors. Graphene and CNT derivatives are known to exhibit photoresponsive and thermal responsive therapeutic abilities. Apart from these, several nanomaterials induce tissue regeneration. Bioimaging and sensing are used for the early and accurate detection of outcomes of several cancers. Further, nanoparticles are used in wastewater treatment by the removal of heavy metals, industrial effluents, dyes, and pesticides. They are also utilized in aquaculture and fisheries and also to improve plant nutrient uptake and crop yield. Besides these potential applications, they still lack their practical utilization to the fullest. There is a necessity for their controlled physical and chemical behavior for each application and collaboration of experts is needed from diverse fields to assess their development to the final usage for a sustainable and better future. Questionnaire Multiple Choice Questions 1. Which of the following is credited with coming up with the term “nanotechnology”? (a) Richard Feynman (b) Harry Kroto (c) Eric Drexler (d) Norio Taniguchi 2. Which of the following properties is not influenced by the charge on nanoparticles, in the case of interaction with cellular membranes? (a) Plasma protein binding (b) Adhesion (c) Transmembrane permeability (d) Colloidal stability 3. How are the surface area of a nanoparticle and its reactivity related? (a) Linearly (b) Inversely (c) No correlation 4. Nanoparticles aid in targeted drug delivery by (a) Increasing the interaction with biofluids (b) Increasing the drug’s metabolism by the liver

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(c) Increasing the drug’s cellular uptake (d) Reducing the interaction with biofluids 5. Which of the following properties of used nanoparticles is most crucial for nanotechnology-assisted drug delivery? (a) Size and shape (b) Surface charge (c) Chemical reactivity (d) Drug to be delivered 6. Which of the following is NOT true regarding textile dyes? (a) Most are aromatic organic compounds (b) They are carcinogenic (c) They are biodegradable (d) They are heat-resistant

1. Why is there a need to remediate water? Give examples how nanotechnology has been used for this purpose. 2. Why is nanotechnology replacing conventional aquaculture practices? Give two areas where such application can be seen. 3. Explain in detail the various physicochemical properties of nanoparticles and how they affect the use of nanotechnology in medicine. 4. Shed light on how nanotechnology helps in realizing the UN’s goal of “Zero Hunger.” 5. Explain the different types of nanomaterials that have been used in healthcare and medicine.

Short Answer Type Questions 1. Explain why loading a drug onto a carrier nanoparticle is the ideal way of delivering said drug. 2. Explain how treating chemical modification of a nanoparticle affect drug delivery using that nanoparticle. 3. Expand the following: (a) ROS (b) LDH (c) FRET (d) TNF (e) PTT (f) NIRF (g) CNT (h) NIPAAM 4. Which nanomaterials have been used to electrically induce the regeneration potential of tissues? 5. Briefly explain the mechanism of photothermal therapy. Give an example showing the application of nanotechnology in PTT. 6. Write the advantages of using ZnO NPs in antimicrobial therapy. 7. Nanomaterials have been finding application in water purification. Explain the basis of this application. Give examples to support your answer. 8. Explain why liposome-based drug delivery is preferred over other methods of drug delivery. Long Answer Type Questions

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3

Role of Biogenic Inorganic Nanomaterials as Drug Delivery Systems Hira Ateeq , Afaf Zia and Mohd Sajid Khan

Abstract

Nanotechnology has emerged as a twentyfirst-century discipline that has piqued the interest of the community of the scientific circle worldwide due to its ground-breaking inventions and prosecution in various fields. Nanomaterials have exemplary catalytic and biochemical qualities, among others, that distinguish them as materials. Characteristics such as the small size and high surface-areato-volume ratio, strong reactive nature, the usability of nanoparticles (NPs) etc. improve their effectiveness for various applications, including biological applications. The ultimate goal of research interest in nanotechnology is to create therapeutically applicable NPs with improved drug kinetics and dynamics in a biological system that can contain the ideal dosage of a targeted drug. To increase safety and efficacy, NPs stimulate transport across membranes, enhance the stability and solubility of encapsulated drugs and lengthen circulation periods. Cancer immunotherapies have not yet produced encouraging outcomes, despite tremendous success. By increasing the efficiency of immunotherapy, NPs

, Qayyum Husain

,

represent a novel and sensible approach to cancer treatment. Biogenic nanoparticles exhibit excellent immunogenicity and modifiability and coherently regulate the immune system to kill or inhibit cancer cell proliferation, thus presenting an efficient immunotherapeutic approach. Keywords

Inorganic nanoparticles · Drug delivery · Biogenic nanoparticles · Targeted therapy · Green inorganic nanoparticles

Highlights • Inorganic nanoparticles are tuneable and multivalent in nature for effective drug delivery. • The mechanism of action of nanomedicine is always associated with reactive oxygen species (ROS) generation. • Internalization of nanomaterials is charge dependent. Different types of nanomaterials follow different mechanism of internalization. • Delivery directly to the nucleus is highly effective through anionic nanomaterials.

H. Ateeq · Q. Husain · M. S. Khan (✉) Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, India

3.1

A. Zia Dr. Ziauddin Ahmad Dental College, Aligarh Muslim University, Aligarh, India

Nanotechnology has sparked a lot of attention in recent decades. Different definitions of nanotechnology have developed over time. The creation of

Introduction

# The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 B. Sarkar, A. Sonawane (eds.), Biological Applications of Nanoparticles, https://doi.org/10.1007/978-981-99-3629-8_3

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a single atom or molecule to submicron dimensions systems for chemical, physical and biological applications, as well as the incorporation of the resulting nanostructures into larger systems, are all included in the field of nanotechnology. Nanotechnology is best described as technology at the nanoscale. Dramatic changes take place in the properties of a material when its dimensions are shrunk to 100 nm. The most desirable properties can be reached at the nanoscale due to the supremacy of size confinement, distribution and morphology, interfacial processes and quantum effects. Additionally, it is not always possible to predict how materials would behave at the nanoscale in terms of what can be distinguished at the macroscale. It will someday be feasible to use novel chemical, physical and biological features of systems that are intermediate in size to develop innovative features and offer better performance (Kopeckova et al. 2019). Nanoparticles (NPs) fall under synthetic novel particles with at least one dimension less than 100 nm. Rearranging the atoms to create various nanostructures and nanodevices constitutes two approaches, atomic-scale fabrication representing the bottom-up approach. The top-down approach relies on assembling structures by manipulating parts of much bigger devices using monolithic processing, which is easier to do with present technology. This strategy has been applied to semiconductor devices used in consumer electronics with astounding success. On the other hand, the bottom-up method, which involves arranging atoms or molecules in nanostructures, entails the systematic self-assembly of molecules, atoms, or other fundamental building blocks of matter in order to create device structures. Due to their unparalleled intrinsic features, NPs offer a variety of purposes in medicine, agriculture, food preservation and cosmetics, which has prompted researchers to expand their studies. Because NPs are smaller than biological organelles and have the same proportions as biological macromolecules, they add additional elements to translational research. The ability of nanotechnology to change the pharmacokinetics of a drug has attracted interest in its usage in numerous

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biomedical applications, including drug administration (Mitchell et al. 2021). Biological synthesis is a more environmentally friendly technique of producing metal NPs than traditional physical and chemical processes, including using hazardous and expensive reagents and an excruciating reaction environment. Various reductase enzymes enable some bacteria to collect and detoxify heavy metals by converting metal salts into metal NPs with a specific size range. Because of this, microbes have enormous promise as environmentally safe and economically advantageous tools for biologically synthesizing NPs, as opposed to using harsh chemicals and requiring a lot of energy. Microorganisms can produce NPs intracellularly or extracellularly as part of the biological synthesis process. Extracellular synthesis is practical and cost-feasible as other processing steps such as sonication, centrifugation and washing are not needed post-synthesis for purification. Additionally, proteins, secretary peptides, reducing enzymes, cofactors and organic components are essential in synthesizing NPs, which reduce and cap the NPs. Notably, such capping avoids NP aggregation and aids in their long-term stability (Khan et al. 2020). Traditional drug delivery affects normal body cells and has limited specificity, uncontrolled biodistribution and risks of intracellular trafficking. In contrast, the conjugation of drugs with NPs targets specific cells and increases specificity. Interactions between NPs and biomolecules are inescapable once delivered into the body, either orally or through injections before the NPs reach the relevant areas via the bloodstream. Because of their interaction with serum opsonin proteins, the biodistribution, therapeutic efficacy and biocompatibility of NPs are influenced by forming a protein layer known as the protein corona. A nanoscale drug carrier functions as a single unit in terms of characteristics and transport. Novel pharmacological therapies that target the illness site and assist in lowering the cost and toxicity of the active component in health care are predicted to be enabled by nanotechnologyenhanced drug delivery vehicles. Once the functionalized NPs are close to the target cells,

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Role of Biogenic Inorganic Nanomaterials as Drug Delivery Systems

they ultimately detect the surface receptors and bind them (Bahrami et al. 2017). Therefore, a nano-drug delivery system employing NPs as a drug delivery vehicle for drugs to reach target cells such as cancer cells is required. To overcome the challenges of traditional drug delivery, the development of nanotechnology has resulted in more potent drug delivery systems with increased effectiveness of the drug and fewer adverse effects (Zhang et al. 2018).

3.2

Complementary Characteristics of Inorganic NPs as Effective Drug Delivery Vehicles

Among the currently available engineered nanomaterials, inorganic NPs have proven to be one of the most effective drug delivery strategies. Inorganic NPs have unique material and sizedependent properties in addition to a high surface area volume ratio and versatile surfaces which can be easily functionalized for drug delivery and targeting. They are capable of targeted and regulated distribution and are readily available for absorption, depict low toxic potential, enhanced functional properties and biocompatibility. Inorganic NPs are chemically stable; thus, they maintain their integrity during the entire delivery process and do not biodegrade in the plasma membrane or cytoplasm of the human body. In contrast to organic NPs, the stability and distinguished optical, magnetic and other physical properties of inorganic NPs provide them with an edge (Yoon et al. 2017). Standard inorganic NPs are prepared from noble metals such as gold (Au) and silver (Ag). Metals such as nickel (Ni), cobalt (Co), iron (Fe), magnetite (Fe3O4) and iron-platinum (FePt) are used to design magnetic NPs with supra-magnetic properties in a magnetic field. Fluorescent NPs include quantum dots, silicon dioxide (SiO2) etc. (Paul and Sharma 2019). Inorganic NPs have also received apprehension as possible disease regulators and drug delivery methods due to their stability and resistance to microbial attack, which can be imparted to their shallow toxicity profile, biocompatibility and hydrophilic nature. In biomedical science,

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inorganic NPs are favoured over organic NPs because they can build up in cells undetected by P-glycoprotein (P-gp) and they promote controlled drug release. P-gp is a multidrug-resistant (MDR) protein that is a member of the ABC family of efflux transporters and plays an important role in the study of cancer and the administration of drugs. Cross-resistance developed by malignant cells to potent chemotherapy medications, or MDR, is a substantial factor in therapeutic failure. Normal expression of P-gp can be seen in the colon, kidney, liver, breast and brain, but it is overexpressed in malignant cells. P-gp hinders the effectiveness of therapy by hastening tumour growth (Xu et al. 2012). Due to unexpectedly low selectivity, poor inhibitory activity and accumulating hazardous plasma concentrations that cause adverse effects in patients, the proposed P-gp inhibitors have demonstrated disappointing outcomes over time. Different drug delivery methods, including NPs and liposomes, have demonstrated a potential capacity to circumvent P-gp-mediated drug efflux and enhance intracellular concentration with little to no change in the pharmacokinetics of the co-administered anticancer treatment. Drug efflux transporters are typically avoided by nanocarrier systems by effectively eluding MDR (Singh and Lamprecht 2016). Other favourable properties offered by inorganic NPs are easy and efficient uptake by cells, excellent gene delivery without generating an immune response and low toxicity. Additionally, inorganic NPs have electron-rich surfaces due to high surface area-to-volume ratios. High surface energies facilitate the easy exchange of outer electrons and surface valances with electron acceptors and donors in biological systems. In a compromised cellular environment such as a tumour, inorganic NPs increase reactive oxygen species (ROS) production caused by intermediary metabolism of nanomaterials through enzyme or metal-catalysed chemical reactions (Khan et al. 2015). In terms of diameter, the tuneable properties of porous inorganic NPs allow the transport of many different types of small drugs to large proteins or oligonucleotide strands. Modifying the surface of inorganic NPs helps in targeted drug delivery and

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keeps track of drug release. Drug-conjugated inorganic NPs provide a versatile platform for image diagnostic and therapeutic applications. Metallic NPs and inorganic nanomaterials such as graphene, silica and silicon are rigid and resistant. Still, they can be easily modified chemically and mechanically, facilitating more accessible transport into tumour cells but encountering hampered penetration due to limited flexibility. Organic nanocarriers such as liposomes can easily penetrate tumours due to their soft nature but present premature drug release. Inorganic NPs have revolutionized the biomedical field—nano biosensors have aided in cellular tracking, imaging and disease diagnosis. Luminescent nanodevices have contributed substantially to nano diagnosis in identifying diseases at the cellular or molecular level. Nanotherapy involving nanocarrier systems to target the disease site with increased accuracy and enhanced drug efficacy and minimum side effects has garnered tremendous success. Another important branch of biomedicine that has received attention is regenerative medicine-nanotechnology. Tools and techniques such as gene and cell therapy remove or replace damaged tissues and organs. Under dosage therapy, nanotechnology tools such as bio-regenerative tissue engineering are used to treat injured tissue or replace damaged tissue or organ (Probst et al. 2012). On interaction with biomolecules, the free NPs generate radical and non-radical ROS due to their unique surface characteristics. Therefore the inorganic NPs are encapsulated with a nontoxic, biocompatible layer. Encapsulation with another metal forms core/shell NPs and complements properties such as quantum yield and photoluminescence. The non-radiative combination sites are passivated, providing air stability and reduced surface defects. Encapsulated NPs are transported between cells by either endocytosis or exocytosis. Endocytosis-mediated transport is caveolin or clathrin proteins dependent or independent and plays a decisive role in the cellular internalization of NPs (Oh and Park 2014). The environmentally friendly production of metallic NPs using biological components, i.e., green synthesis, has gained much attention.

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Biomass, plant extracts, microbes and a range of additional reductants are used in green synthesis. Green nanotechnology refers to the green synthesis of NPs using plants and microorganisms such as bacteria, fungi and green algae. The advantages of green synthesis over chemical and physical methods are enhanced bioactivity, reduced toxicity, easy synthesis at room temperature and pressure, eco-friendly and costeffectiveness. Green systems release proteins and enzymes that act as reducing agents, converting bulk metal salts into NPs and capping agents that provide NP stability and make them biocompatible for various biological uses (El-Seedi et al. 2019). Based on their research outcomes, the researchers have proposed a variety of mechanisms for the biogenic synthesis of NPs. One of the most extensively researched methods for the biosynthesis of NPs is the reduction of aqueous metal ions by donating an electron by various biomolecules and metabolite composition present extracellularly in the extract of a biological system. These substances are crucial for transferring electrons to aqueous metal ions to make up the deficit and reduce them to their neutral form, commonly referred to as a nano form or NPs (Hietzschold et al. 2019). Bacterial synthesis of NPs can be either intracellular or extracellular. Metal ions are mainly reduced in the bacterial cell wall. Reportedly proteins and sugars present in the cell wall participate in capturing the metal ions. Positively charged metal ions and negatively charged cell walls, in particular the negatively charged carboxylate groups on the cell wall, may interact electrostatically to enhance the trapping and transit of metal ions in bacterial cells. Extracellular synthesis of metal ions takes place by various metabolites secreted in the surrounding medium by bacteria, such as sulphur-containing proteins and reduced nicotinamide adenine dinucleotide (NADH)-reductase, as well as amino acids such as arginine, cysteine lysine, as reported in the case of AuNPs. Peptides containing disulphide bonds are also known to reduce metal ions to NPs. One of the hypotheses is that bacteria produce metal NPs as a by-product during the detoxification process, in which a range of hazardous metal ions are absorbed via

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cationic membrane transport systems that typically carry metabolically significant cations. An excessive buildup of harmful metals is prevented by the particular mechanism to oppose this type of absorption (Guilger-Casagrande and de Lima 2021).

3.3

Mechanism of ROS Production by NPs and NPs-Mediated Toxicity

In biomedicine, NPs have become favoured material for drug delivery, targeted gene knockdown, delivery of siRNA and as biofilling medical materials. The ability of NPs to cause ROS burst contributes to their cytotoxicity and can also be attributed to their antibacterial activity. ROS is produced in organelles like the mitochondria, endoplasmic reticulum and peroxisome as a general response to normal oxygen metabolism. ROS is essential for various signalling cascades, including those involving the epidermal growth factor receptor, NF kappa B, mitogen-activated protein kinase (MAPK) and others. ROS are chemically reactive oxygen-containing particles, such as reactive superoxide anion radicals (O2-) and hydrogen peroxide (H2O2). ROS are involved in cellular growth, proliferation, differentiation and are also essentially involved in innate immunity (Lee et al. 2014). The structures as well as size of NPs, which affect their propensity to cause the production of ROS, define their hazardous potential. Excessive ROS production may result in many physiopathologic effects, including genotoxicity, apoptotic events, necrosis, inflammatory response, fibrosis, metaplasia, hypertrophy and carcinogenesis. Furthermore, it has been shown that the toxicity of NPs induces the secretion of pro-inflammatory cytokines and activates inflammatory cells like macrophages, both of which help to produce ROS. It has also been demonstrated that the increased production of ROS after exposure to NPs causes the regulation of cellular activities, sometimes with lethal outcomes. Therefore it is imperative to understand the original mechanisms of ROS production

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by NPs to reduce their toxicity to normal cells (Song et al. 2012). The primary mechanistic theories for ROS bursts state that metal ions produced by NPs encourage ROS overexpression by compromising mitochondrial respiration. Through the Fenton reaction, it has been demonstrated that the metal ions produced by NPs can combine with redox cycling and chemocatalysis [H2O2 + Fe2+ → Fe3+ + HO- + •OH] or Fentonlike reaction [Ag + H2O2 + H+ = Ag+ + • OH + H2O]. In addition to deactivating cellular enzymes, disrupting membrane structure along with the electron-shuttling process, depleting redox potential levels and reducing mitochondrial membrane potentials (MMP), the dissociated metal ion (i.e., Ag+) also contributes to the accumulation of intracellular ROS. By deranging the electron transfer mechanism, raising the nicotinamide adenine dinucleotide phosphate +/reduced nicotinamide adenine dinucleotide phosphate (NADP+/NADPH) ratio and interfering with mitochondrial activity, NPs have also been shown to induce intracellular ROS buildup. Additionally, oxidative stress-associated genes like soxS, soxR, oxyR and ahpC, antioxidant genes like sod1 and gpx1and the gene met9 connected to NADPH synthesis are all affected by NPs. The elevated level of intracellular ROS is established due to the inhibition of the expression of genes involved in oxidative and antioxidant defence after interacting with the gene expression machinery (Yu et al. 2020). Once the NPs get adsorbed onto the cell surface, ROS production leads to the peroxidation of lipids present in the outer membrane. It alters the fatty acid content, which further enhances the membrane permeability. Cellular injury is also brought on by the unregulated transport of NPs into the cell from the extracellular environment. The increased ROS results in oxidative modification of various biomacromolecules, such as carbohydrates, proteins and amino acids, which damages nucleic acids. Irreversible cellular damage occurs, such as the organellar membrane rupturing, leading to leakage of organellar content into the cytoplasm, inactivation of various cellular receptors, the release of lactate dehydrogenase

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etc. ROS attacks the hydrophobic amino acid residues, causing peptide bonds to break and impairing the ability of these proteins to function. Additionally, the process of carbonylation damages proteins, causing them to permanently lose their ability to perform because the aggregates they produce are chemically irreversible and cannot be destroyed by proteasomes. NPs, due to their genotoxic potential, induce ROS, cause DNA breaks in single and double strands and alter chromosomal structures (Zuberek and Grzelak 2018). Due to its low redox potential, ROS interacts and modifies nucleic acids such as DNA and RNA, thus affecting the normal functioning, growth and development of cells. Gene miscoding, aneuploidy, polyploidy and the induction of mutagenesis in cells exposed to NPs are all primarily caused by an increase in ROS production. The DNA damage brought on by the ROS production by NPs leads to mutagenicity, oncogenesis, MDR, ageing and immunological escape. It has been demonstrated that NP-induced DNA damage inhibits the amino acid synthesis and replication and results in an abnormal buildup of the proteins p53 and Rab51. DNA damage can also cause a cell to partially or completely stop functioning and lose its ability to grow and multiply, which could eventually lead to cell death (Yu et al. 2020). Oxidative stress, endogenous ROS generation and the depletion of intracellular antioxidant reserves are all factors for NP cytotoxicity. Amplified oxidative stress causes biomacromolecules to sustain oxidative damage, which further impairs cellular function and aids in the onset and progression of numerous diseases. NPs disrupt membranes and speed up their entry into the cytoplasm. Lysosomes, mitochondria and the nucleus are where NPs congregate, which has disastrous effects on the cell. NPs can disrupt lysosomes, decrease adenosine triphosphate (ATP) production, deplete glutathione, cause protein mistranslation and prevent the ribosomal subunit from binding (tRNA). The essential biological mechanism in the cell collapse as a result of these cellular activities, which also

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significantly reduce cell viability (Aioub et al. 2017) (Fig. 3.1). NPs cause both extracellular and intracellular ROS production. (1) Radiation, contaminants and nanomaterial exposure are variables that cause extracellular ROS to generate. (2) NPs interact with cell membrane NADPH oxidase to produce a variety of oxides and superoxides; this leads to intracellular ROS generated by NPs that further contribute to lipid peroxidation and cell membrane damage. The Fenton reaction plays a key role in the creation of hydroxyl radicals and the toxicity of NP. NPs can enter a cell by either (a) endocytosis or (b) diffusion. Through endocytosis mediated by caveolae formation, the cationic NPs enter the cell. Further, the cavoeosomes reach the endoplasmic reticulum and generate ROS. Once the negatively charged NPs have been internalized by endocytosis, endocytic vesicles are formed, and the NPs are then released into the cytoplasm. Endosomes are the entry point for NPs into lysosomes, and the lysosomal enzymes housed inside cause the acidic environment that makes NPs unstable. NPs break down the lysosomal membrane, allowing their contents to escape. Additionally, the NPs interact with mitochondria, where they depolarize the mitochondrial membrane and obstruct the electron transport chain by activating enzymes associated to NADPH. NPs boost ROS production while decreasing ATP synthesis. When NPs interact with mitochondria, the potential of the mitochondrial membrane is diminished, which is followed by Ca2+ ion leakage and the stimulation of Ca2+associated enzymes. The enzymes that have been activated eventually result in powerful oxidizing and nitrating non-radical species. Cyt-c is released, and caspase-mediated apoptosis is started. Other signalling channels are further deactivated by the ROS burst. (c) The ROS generated by NPs causes DNA and proteins to polymerize, which leads in DNA mutations. Additionally, the generated ROS leads to RNA mistranslation and hinders tRNA from attaching to ribosomes. The nuclear contents are released as a result of a rupture of the nuclear membrane.

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Fig. 3.1 Schematic representation of ROS production by NPs

(d) The NPs also serve as nanozymes because of their inherent characteristics and functionalization.

3.4 3.4.1

Biogenic Gold NPs (AuNPs) Characteristics

AuNPs have a long history in medicine. For instance, in the early sixteenth century, a Swiss physician and chemist by the name of von

Hohenheim produced and administered AuNPs to patients suffering from specific ailments. A Flemish glassmaker by the name of John Utynam was granted a patent in England in 1449 for creating stained glass that contained AuNPs (Nasrollahzadeh et al. 2019). Due to their unique amalgamation of physical, chemical, electrical and optical properties, the useful qualities of Au have been investigated in various applications and have drawn substantial attention in targeted medication administration,

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illness diagnostics and monitoring surgical procedures. Au can be formed into monodisperse nanostructures with high specificity, chemical inertness and functionalized with a wide variety of ligand species and other chemical moieties. Since the primary purpose of nanomedicine is to achieve targeted delivery, AuNPs have emerged as a promising candidate for delivering a variety of payloads to the desired location. AuNPs have a large surface-to-volume ratio, which allows them to transport multiple drug molecules. Small drug molecules and large macromolecules like DNA, RNA and proteins can be easily transported (Seo et al. 2015). Some pharmaceutical compounds can be directly conjugated with AuNPs through physical absorption and ionic or covalent bonding without requiring modification of a monolayer of AuNPs for administration. The electrons in the conduction band of metal NPs resonate with light intensity in the electromagnetic field, causing light absorption; this process is known as surface plasmon resonance (SPR). The optical behaviour of AuNPs less than 2 nm is based on plasmonic characteristics, which allows AuNPs to absorb and scatter light with incredible efficiency. Plasmonic features can be tailored to absorb specific wavelengths based on form and aspect ratio. AuNPs have been described as superior to most absorbing and scattering organic molecular dyes with far higher absorption and scattering intensity that make them effective contrast agents in imaging. Heat is produced as a result of the interaction of electron-photon and photon-photon when AuNPs are subjected to near-infrared (NIR) light (650–900 nm). Due to minimal absorption by blood and water in this region of the wavelength spectrum, NIR light only penetrates human tissue by a few centimetres to a few millimetres (cm) (Tinajero-Diaz et al. 2021). Au nanoshells, nanocages and nanorods prepared using various chemical and electrochemical synthesis methods absorb light in the NIR range and transfer heat to the surrounding tissue. They have been widely used and investigated for tumour imaging and ablation. AuNPs with a core size of mid-to-large differ from ultrasmall counterparts in various respects, the most significant of which is efficient light-to-

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heat conversion. This feature of AuNPs was first employed in photothermal treatment to eliminate malignant tissue by converting NIR irradiation into heat. Photothermal therapy with AuNPs can be combined with other therapeutic techniques, allowing for multimodal cancer treatment. However, this method has problems such as high irradiation power density and low selectivity. The photothermal properties of AuNPs nanoshells are also being investigated for prostate cancer treatment (Hammami and Alabdallah 2021). Another parameter essential for the coherent delivery of therapeutic agents via AuNPs is the efficient release of the drug. Internal stimuli such as glutathione, enzymes and pH and external stimuli such as light affect the release of play loads from AuNPs. Covalent cargo attachment to the NPs presents challenges, such as early detachment before reaching the target site; therefore, non-covalent encapsulation is a good alternative. AuNPs are coated with polyethylene glycol (PEG)-(PEGylation NPs), oligonucleotides or conjugated with amino acid and peptides to deliver other payloads. PEGlyation alters the size of NPs and protects them from recognition by enzymes and antibodies. Thus coated NPs evade rapid degradation and secretion from the body. However, the coating does not prevent wide recognition by macrophages or other immune cells. When formed in higher concentrations in response to PEGlyation NPs, the anti-PEG antibodies can lead to rapid clearance of NPs from the body. Hydrophobic pockets of PEGylated AuNPs provide enhanced loading capacity (Sen et al. 2020). The ligand monolayer on AuNPs also allows for drug encapsulation and delivery. For delivery to cancer cells, a hydrophobic small molecular anticancer drug can be put into a monolayer of 2 nm core AuNPs. AuNPs are conjugated with PEG alone or in the presence of another molecule during the PEGylation process to improve cellular absorption of AuNPs. Biotin, peptides and oligonucleotides are examples of these molecules. Because of their capacity to bind to cell membranes, these functionalized AuNPs are employed for targeted drug administration. The production of AuNPs functionalized with lectin,

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lactose, biotin and PEG has been studied (Nitica et al. 2018).

3.4.2

Potential Role of AuNPs in Enhanced Drug Delivery Vehicles

Delivery systems mediated by NPs have a number of notable benefits. In a typical drug administration, drug molecules circulate through the bloodstream and affect both the target cell and nonspecific cells without showing any preference for the targeted cells. In contrast, the surface fictionalization of the NPs controls the driving factors for transfection in drug delivery systems using NPs. Additionally, site-specific transport of NPs into cells is made possible by grafting particular biomolecules onto NPs. Since many medications are needed at extremely high concentrations in the human body and thus have hazardous effects, nanoconjugates also assist in lowering the dose of specific medications. Only if the precise quantity of the conjugated drug is known can the precise action of the conjugated drug be predicted. AuNPs have become a promising candidate for delivering different biomolecules to their intended destinations. AuNPs can also be utilized as adjuvants to boost the efficiency of radiation therapy and as contrast agents for a variety of uses in therapeutic and diagnostic applications. AuNPs can efficiently carry and unload drugs in cellular systems thanks to their special chemical and physical features. Additionally, the photophysical qualities of Au could cause medication release in far-off locations. Particularly AuNPs are a great intracellular targeting vector because they can be designed into appropriate sizes, surfaces and functions. Although AuNPs are widely distributed throughout the human body, the internalization of AuNPs is dependent on the kind of cell (Medici et al. 2021). The presence of AuNPs may contribute to the development of an oxidative environment, impact the control of cellular

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stress response mechanisms and simultaneously trigger the formation of autophagosomes, which may serve to shield the cell from the damaging effects of oxidative stress. The zeta potential of biomolecules is improved by surface-modified AuNPs and the adverse effects are decreased by limiting nonspecific contact. It is interesting to note that most modifiers offer excellent defence against plasma enzymes breaking down biomolecules, largely because of the steric effect and electrostatic repulsion from the modifiers (Coulter et al. 2012). Drugs, including gentamycin, ampicillin, amphotericin B, anticancer antibodies and many others, have all been shown to be highly effective when transported in nanocarriers. In a two-step process, Khan et al. (2015) created AuNPs with human serum albumin (HSA) encapsulation and then bioconjugated them with secnidazole. Because of its acidic nature and wide pH solubility range, HSA has been used as a capping agent and linker between drugs and NPs. HSA is a good drug delivery system since it is easily accessible, biodegradable, toxic-free and lacks immunogenicity. Additionally, by drastically lowering nonspecific interactions, which increases system stability and effectiveness, it safeguards drugs. This AuNPs bioconjugated secnidazole (Au-HSA-Snd) drug delivery system was successful in improving the stability and therapeutic efficacy of secnidazole while minimizing its negative effects and resulting in a decrease in the quantity of drug dosage needed. Compared to pure secnidazole, this system was found to be much more effective against Bacillus cereus and Klebsiella pneumonia. Nevertheless, depending on the antibiotic, they were found to be 12–40% more active when combined with colloidal Au than when the antibiotic was taken alone. It was thus established that AuNPs increased the antibacterial activity of antibiotics. However, to significantly boost the antibacterial activity, stable conjugates of NPs coated with antibiotic molecules are required. Additionally, it has been established that after being injected intravenously, AuNPs conjugated

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with drugs rapidly accumulate in cells with defects but are undetectable in cells from the liver, spleen and other healthy organs (Khan et al. 2015).

3.5 3.5.1

scale production of AgNPs, which is made possible by the presence of a significant amount of extracellular protein in the filtrate. Additionally, compared to other systems, downstream processing of fungal biomass is much simpler (Rai et al. 2021).

Biogenic Silver NPs (AgNPs) Characteristics

AgNPs are of economic significance because of the many ways in which they can be used to harness powerful antibacterial characteristics in a variety of fields. The vast antimicrobial potential of AgNPs, which includes antibacterial, antifungal, antiviral and antiprotozoal actions, has been proven to have a wide range of uses, particularly in biomedicine. Biogenic AgNPs have thus attracted a lot of interest. Fabricating AgNPs using microorganisms or plant extracts is known as biological synthesis, an environmentally benign approach to metal NP synthesis. Because of its simple, cost-effective and high-yielding nature, it has various advantages over chemical and physical procedures. Extracellular synthesis and intracellular synthesis are two types of biological synthesis. NPs are generated inside cells in intracellular synthesis, while cell-free fungal extract is employed in extracellular synthesis (Rozhin et al. 2021). Bacterial species such as Shewanella sp. ARY1 and Citrobacter freundii have been used for the biosynthesis of AgNPs (Mondal et al. 2020). Mycosynthesis is a process for synthesizing metal NPs from fungi. Remarkably, the fungal extracts are metal-tolerant and the biomass is easy to regulate. The biomolecules found in fungal extracts allow for efficient metal ion reduction while also ensuring the stability of NPs. The fungal system can be used for both intracellular and extracellular biosynthesis and produces AgNPs in a single step. The mycelial mass of fungi can resist increased pressure and agitation, making it suitable for use in large-scale biogenic synthesis. The advantage of the fungal system over the bacterial and plant systems is the large-

3.5.2

Anticancer and Theranostic Application of Biogenic AgNPs

Biogenics AgNPs can serve as an alternative to conventional anticancer drugs due to their enhanced anticancer activities and mitochondrial-dependent and caspase-dependent apoptosis by the NPs. According to earlier research, AgNPs make up about 65% of all NPs employed worldwide in biological applications. Additionally, due to their nanoscale size, these particles can easily penetrate biological membranes and affect cellular physiology. Their penetration and effectiveness are directly impacted by the increase in contact surface as the diameter decreases (Wypij et al. 2021). Plant-mediated synthesis is simple, affordable, secure, quick and doesn’t require stabilizing and reducing chemicals. Environmental and natural resources can be significantly preserved through biological NP production, lowering the threat to humans, the environment and the ecosystem. Two of the most crucial medical issues are the prevention and treatment of cancer. Recently, the medicinal potential of numerous natural compounds has been studied. Identification of plants with various therapeutic characteristics and chemicals produced from plants that may be useful in the treatment or prevention of cancer is continuously being pursued. Numerous bioactive substances found in plants have antioxidant, antiinflammatory and anti-tumour properties. An innovative approach and viewpoint for the prevention and treatment of several diseases, including cancer, have been made possible by greensynthesized AgNPs. Other benefits of using plants in the production of NPs include their safety and excellent capabilities to other

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Role of Biogenic Inorganic Nanomaterials as Drug Delivery Systems

biological processes, as well as the fact that they are more stable and healthier than bacteria, fungi and yeast. Additionally, by attaching the plant molecules to the surface of the NPs during biosynthesis, the anticancerous properties of NPs are enhanced. Several researchers have been interested in using plants as a sustainable source of biocompatible NPs in recent years. Plant phenolic acids, flavonoids, alkaloids and terpenes, among other primary and secondary metabolites, significantly reduce metal ions to generate NPs. These substances reduce, cap and stabilize NPs during biosynthesis (Ratan et al. 2020). Mousavi et al. (2018) produced AgNPs and examined their cytotoxic and anticancer potential using Artimesia turcomanica leaf extract. Gastric cancer cell lines L-929 and AGS demonstrated an inhibiting effect of the biogenic AgNPs on cellular proliferation. Compared to pure NPs, extracts from different species have a higher IC50 value. The produced AgNPs are more efficient at stopping the proliferation of cancer cells than the plant extracts alone, according to an analysis of the IC50 values of the Artemisia extract alone and the extract used to make the AgNPs. Functionalized NPs act as drug carriers or antibacterial agents (Mousavi et al. 2018). Plants produce both primary and secondary metabolites, such as phenolic acid. A great supply of proteins, dietary fibre, enzymes, flavonoids, phenolic acids, sugars, C-glycoside and trace minerals can be found in the mature fruits of Benincasa hispida. Terpenes, flavonoids like quercetin and rutin, alkaloids, glycoside (arbutin), coumarin (umbelliferone), vitamins (A, B1, B3, C) and amino acids like tryptophan, tyrosine and phenylalanine are also abundant in them. The fruit contains diuretic, immunomodulatory, antimicrobial, antiangiogenic, anti-inflammatory and antioxidant effects. Using the pulp protein extract from B. hispida, Baker et al. (2021) produced AgNPs. The proteins functioned as reducing and capping agents and imparted stability to the AgNPs. Due to their large size, proteins enclose the NPs and provide them stability. In addition to size, the native charge of proteins also plays a vital role in the stability of nanoemulsions by giving particles a certain charge and determining

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their internalization mechanism, which is crucial in drug delivery systems. The fruit protein extract contains a variety of proteins as well as reducing enzymes such as serine proteases and angiotensin-converting enzyme (ACE) that work synergistically to reduce AgNO3 to Ag. During the synthesis of NPs, a rapid exchange of electrons occurs between the metal ions and proteins, causing conformational changes in protein, reportedly restored after forming neutral Ag0 from Ag+ ions. The synthesized AgNPs showed antibacterial activity, antibiofilm and apoptotic properties against Staphylococcus aureus, Salmonella enterica, Staphylococcus epidermidis. The AgNPs showed concentration-dependent anticancer activity against A549 cells and were nontoxic to normal cell lines up to 200 μM concentration. The internalized AgNPs caused severe damage to the cells by generating ROS (Baker et al. 2021).

3.5.3

Antimicrobial and Antibiofilm Potential of AgNPs

The global cosmetic industry is expanding at a rate of 4.3% between 2016 and 2022 and is expected to reach $429.8 billion by 2022. Cosmetic products (CPs) are contaminated once exposed to microorganisms or atmospheric oxygen. To prevent contamination, many preservatives are added, including parabens, triclosan, imidazolidinyl urea and diazolidinyl urea, all of which have been linked to adverse effects in humans, including DNA damage, antiandrogenic activity, estrogenicity, endocrine disruption, impact on human lymphocytes that are cytotoxic and genotoxic, increased risk of cancer in humans. Owing to this, some of the conventional preservation methods are currently under scrutiny, leading to the search for novel compounds with biocidal activity or chemicals that deter the growth of microbes. Due to its unique physicochemical features, nanomaterials offer a new and intriguing alternative to conventional and toxic substances in CPs. AgNPs have excellent biocidal properties and are therefore implemented in the food, medicine and health care sectors. Iris tuberosa has been used as a folk treatment for

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acne, skin care and for dandruff. Biogenic AgNPs prepared from waterleaf extract of I. tuberosa showed exemplary antimicrobial activity against various pathogens found in cosmetic products such as Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans and Aspergillus brasiliensis. The as-synthesized biogenic AgNPs were found to be an effective and eco-friendly chemical preservative. In addition, to antimicrobial properties, the synthesized AgNPs also showed antioxidant activity, thus showing favourable characteristics to be incorporated as a preservative in the cosmetic industry (Mondejar-Lopez et al. 2021). It is universally believed that oxidative stress arises from the attachment of AgNPs to the cell wall and membrane and the intracellular damage brought on by AgNPs and Ag ions. An increase in ROS concentration can be attributable to the disturbance in the scavenging pathways. These pathways contribute to the antibacterial effects and cause cellular inactivation of microorganisms by the NPs. Ag ions in the AgNPs bind to the thiol groups of the bacterial cell wall, disrupting the cell wall and membrane and obstructing the process of respiration. The AgNPs enter the bacterial cell membrane and damage the DNA and proteins by subsequent enhanced production of ROS and completely disrupting the electron transport chain and finally killing the microorganism (Behravan et al. 2019). Nanotechnology emerged as a promising approach to design antimicrobial and drug delivery systems able to penetrate biofilms and kill MDR bacteria. The shape and size of NPs affect their distinctive capacity to penetrate biofilm. NPs can interact with bacterial cell walls, cross microbe membranes, obstruct metabolic pathways, alter the structure and function of membranes and interact with microbial cellular machinery to inhibit enzymes, deactivate proteins, cause oxidative stress and electrolyte imbalances, or change gene expression levels. Understanding the mechanisms underlying the bactericidal activity of NPs is crucial, given their huge therapeutic potential. Nanotechnology breakthroughs can be a great tool in this regard. Another crucial aspect of the antibacterial properties of AgNPs is their capacity to prevent

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or reduce the growth of microbial biofilms, which is a critical virulence component in many localized chronic illnesses. Before releasing Ag+ ions, AgNPs demonstrated the ability to diffuse toward the interior of the biofilm. This penetration effectively kills the biofilm-forming microorganisms. One of the most notable features of emergent biofilms is the ability of adhering bacteria to embed themselves in a self-produced matrix of extracellular polymeric substances (EPS), which is composed of proteins, polysaccharides, humic acids and DNA. The EPS matrix serves as the binding agent for the bacterial biofilms, securing them against extrinsic dangers to their survival and growth, such as host immune systems and environmental hazards (Shkodenko et al. 2020). Consequently, by preventing antibiotic penetration inside the biofilm, the polymeric matrix plays a crucial role in antimicrobial resistance. Even though the EPS-matrix contains water-filled channels necessary for transferring nutrients and metabolic waste products with their environment, most antimicrobials have trouble penetrating it. This is due to size restrictions, ready adsorption onto the EPS matrix or negatively charged bacterial cell surfaces that become increasingly positively charged with a decrease in pH inside a biofilm. These methods encourage the survival of inner biofilm cells and highlight the drawbacks of conventional molecular methods for eradicating biofilm (Koo et al. 2017).

3.6

Characteristics and Prospects of Nano Drug Delivery Systems

Disease diagnosis is fundamental to health care because it improves the efficacy of medical therapy and can save lives in cases where early diagnosis is essential. Early diagnosis, however, frequently calls for very advanced biological equipment or better methods. In the field of biomedical engineering, the use of NPs has ushered in a new era for the creation of novel contrast media and drug delivery systems, which have the potential to revolutionize the medical industry. Because of recent developments in the

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application of new nanomaterials in this field, the idealistic concept of a single platform for drug delivery to its monitoring of drug-release appears to be attainable in the near future. The adaptability of NPs has been used in a number of studies relating to disease diagnostics, early detection research and superior contrast agents for enhanced imaging techniques. Because of enhanced bio- and cytocompatibility and longer circulation times, the development of innovative drug delivery systems has not only lowered the payload of the medications but also increased their efficacy in the body. Thus, the development of NPs has had an impact on all areas of medical biotechnology and biomedical engineering, strengthening and upgrading already-existing approaches as well as exploring new and cutting-edge methods for drug delivery and monitoring. Research is currently concentrated on more advanced drug delivery techniques that can be created to route themselves discretely and to their site of action with a high level of specificity, evading the immune system until their intended purpose is served. This introduces us to the concept of “targeted drug delivery,” in which the drug is concentrated on certain tissues while its relative concentration is decreased in others. Drugs have recently become more specialized and effective to particularly address a physiological imbalance in a more localized manner thanks to many breakthrough discoveries in medical research and engineering. The majority of medications on the market today rely on the circulatory system of the body to get them to the area where they work, which results in a high rate of dilution, decreased efficacy and subsequently higher adverse effects. Sometimes, these negative effects outweigh the benefits of the medication. For instance, during chemotherapy, both healthy and cancerous cells sustain significant collateral damage (Sohail et al. 2021). Given that the drugs currently being applied in cancer has a very low therapeutic index (the ratio of therapeutic efficacy to side effects, which causes frequent relapse or severe health deterioration), the majority of targeted drug delivery research is focused in areas of cancer therapy and treatment of static tumours. Therefore, it is

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crucial to focus the efficacy of these drugs solely on the dysfunction of the affected cells. Diabetes and cardiovascular disorders, which all result from the malfunctioning of specific tissue regions or cells, are the next in line in terms of contemporary medical importance after cancer therapy. Pancreatic cell dysfunction is a factor in diabetes. Therefore, a precise and long-lasting remedy could be achieved and the issue may be permanently resolved by targeting these cells specifically with drug therapy (Castillo et al. 2018). The two types of traditional targeted drug delivery are (1) active targeting and (2) passive targeting. Antibodies are employed in active targeting because they are naturally selective and do not require extra targeting equipment. The second method of passive or enhanced permeability and retention effect (EPR)-dependent drug targeting, which does involve immunoglobulins, is more significant and technically challenging. As defective endothelial cells, tumour cells frequently exhibit the EPR, which manifests as cell aggregates with aberrant lymphatic-blood vascular dynamics and cell shape. Due to their rapid growth, these cells cause the development of new blood vessels and subsequently rely on the neovasculature for their oxygen and nutrient needs, resulting in the creation of a local microenvironment. In these tissues, NPs can easily collect and are maintained longer than in healthy tissues. As a result, NPs constitute a key component of the reasoning for building new targeted medications, with EPR serving as their guiding principle (Aghebati-Maleki et al. 2020). Although targeting strategies vary, they are typically based on biomarkers and their interactions with appropriate tags on the drug carriers through ligand-receptor binding. Due to the difficulty of integrating so many different types of materials (drug, adjuvant, carrier, targeting and other molecules), macro systems of delivery become complex and nonspecific and thus have limited efficacy. Additionally, payload delivery and drug-carrying capacity are still modest and unpredictable. Nanovectors with a diameter of 400 nm are more easily able to enter the tumour tissue due to the EPR effect. Therefore, various pathophysiological characteristics of

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tumour tissue, such as aberrant vasculature, temperature, pH and surface charge of tumour cells, influence passive targeting. It is clear that certain physicochemical characteristics of nanocarriers, including size, surface charge, molecular weight and hydrophobic or hydrophilic features, are essential for passive targeting. Although passive targeting is an intriguing strategy, it has major drawbacks, including ineffective drug diffusion into tumour cells, random targeting and the absence of the EPR effect in some cancers (Bae and Park 2011). The drug delivery system employs safe and effective technologies to deliver therapeutic substances into a biological system to achieve desired results while minimizing adverse effects. The physicochemical properties of a drug determine the delivery media, drug release kinetics and mechanism. An in vitro drug release experiment is followed by an in vivo pharmacokinetics investigation in animals and humans to establish the suitability of a formulation for clinical use. The quantity of the drug-loaded and the duration of the presence of a drug in the body are the two most common variables used to evaluate how efficient the drug delivery system is. As a result, the chemical formulation of the drug, its route of administration, the amount of dosage and the usage of auxiliary medical equipment are considered when designing drug delivery systems. NP-based drug delivery systems provide a platform for transporting large and diverse cargos, including hydrophobic and amphiphilic drugs and genes, to tumour cells. The strategy of the targeted delivery system is that the directed drug is released in a regulated manner over a period of time and is only active in the targeted location of the body. The potential of an NP-based nano-drug delivery system is determined by several parameters, including the production method, surface features and administration route. These NP-based methods improve therapeutic efficacy by increasing targeted distributions and lowering off-target systemic toxicity (Nikezic et al. 2020). After intravenous (IV) administration, the systemic transport of NPs to solid tumours is never straightforward; it entails numerous significant

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biological barriers at all levels, from organs to tissues to cells. Five biological barriers exist between the injection site and the site of action for NPs: (1) the binding of serum opsonin proteins to their surfaces, (2) interactions with the immune system, (3) selective extravasation at tumour sites, (4) penetration into solid tumours and (5) internalization of NPs by tumour cells. The mechanical property of NPs, in addition to size, shape and surface chemistry, has only recently been acknowledged as being crucial in controlling their biological function. This is partly motivated by the fact that many cells, including viruses, can change their mechanical characteristics to perform certain biological roles. The nanometre size range can significantly modify the physical, chemical and biological aspects of a substance. Various compounds, including polysaccharides, proteins and polymers, can be used to change the surface properties of NPs. For certain medications, the size and surface qualities of NPs can be tuned. This opportunity permits many different therapies to be reformulated into new pharmaceutical products with greater activity and lower toxicity. Different functional and chemical structures of NPs can be used to encapsulate active substances. This enables the creation of a wide range of NP-based delivery systems with specific features tailored to their intended purpose. The use of NP drug encapsulation has a number of benefits for developing efficient methods of medication delivery and localization. Effective NP delivery systems are made possible by NP characteristics such as particle size, surface charge and shape, which work through a variety of methods (Kumari et al. 2014).

3.6.1

Surface Charge, Size and Shape of Nano Drug Delivery Systems

NP morphology has depicted distinct biological behaviour and thus is a determining factor during synthesis for effective drug delivery. Before NPs penetrate the nucleus, they must pass through multiple cellular barriers. The simplest example

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of these barriers is getting through the plasma membrane, avoiding endosomes or lysosomes and getting across the nuclear envelope. The effectiveness of the transportation of drugs attached to the NPs to the intended site in the cell is determined by the various mechanisms and efficacies that different NPs can use to overcome these barriers. The surface charge size and shape of the NPs determine their capability to internalize and transportation inside the cellular machinery (Yuan et al. 2022). The size of the delivery vehicles determines the biodistribution of the desired therapeutic molecule. For many NPs, size characteristics are expected to have a key influence in regulating cell contact and adhesion. The size of NPs has a big impact on their cellular absorption. In the degradation and removal of NPs, size can also play an important role. Colloidal NPs smaller than 10 nm are quickly excreted by the kidneys, while bigger NPs are removed via the reticuloendothelial system (RES) of the liver. It is crucial to keep in mind that clearance and NP size have been connected. The rate of clearance increases as the size of the NPs grows. Toxicity is caused by NPs greater than 300 nm accumulating in the liver. However, no single geometry is ideal for every stage of delivery or transportation (Rizvi and Saleh 2018). There are two types of drug release mechanisms: active targeting and passive targeting. Active targeting is the method by which cells take up NPs via the endocytosis mechanisms. NPs are coated with specific ligands in this scenario. The uptake process of cells in passive targeting is EPR. In this type of targeting, neither the receptor nor the targeted ligands are present. The EPR effect is considered to cause NPs to concentrate in cancerous cells. The primary purpose of some NP systems is to avoid the RES, which is responsible for destroying foreign bodies. Total blood circulation time and bioavailability are increased by avoiding this process. NPs easily evade the mononuclear phagocytic system (MPS) with hydrophilic surfaces and particle sizes less than 100 nm. MPS is a crucial part of physiological methods for eliminating external pollutants from the body. Opsonin proteins expressed in blood serum can effectively tag

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larger NPs for MPS degradation. Small-particlediameter NPs with hydrophilic properties can prevent opsonization and MPS degradation, allowing for total blood circulation duration (Yao et al. 2020). The charge of the NPs affects both the activity and effectiveness of their dispersion to and through cellular membranes. The stability of an NP system is aided by the amount of surface charge on NPs. In a highly charged system, the attraction between like-charged particles is noticeably stronger. This overall repulsive force prevents the accumulation of NPs. More pronounced surface charges in NPs have been shown to stabilize NP suspension and inhibit particle aggregation. Highly positive NPs can interact with mucus’ anionic polyelectrolyte qualities to increase mucoadhesion and retention; the amount of absorption depends on the surface charge characteristics of NPs. There are membranes with a negative charge in many biological structures. In NPs manufactured with known anionic polymers or surfactants, net negative surface charge will be higher. The enhanced negative surface charge of the NP will cause it to resist cell membranes when it comes into touch with them. The effect of this repulsive force is a reduction in cellular adhesion and cellular absorption. Positively charged NPs have polarized effects. By encouraging membrane attraction and adhesion, the cationic NP creates favourable conditions for cellular uptake by endocytosis or other mechanisms (Mitchell et al. 2021). The ability of NPs to internalize well and how they respond to the challenge of passing through various cellular barriers can both be influenced by their shape. Most frequently, high aspect ratio NPs like rods and tubes exhibit better drug delivery and cellular absorption than spheres. Dominantly rod-shaped NPs have been seen to internalize more rapidly than equivalently sized spheres. Rod-shaped NPs have a longer retention time inside cells than spherical ones, which is one reason why they may be better for drug delivery than spherical ones. Because non-spherical particles are more effective at leaving organelles than spherical ones, they spend longer time inside cells. Second, contrary to spheres of comparable

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diameter, some studies demonstrate that rod-shaped NPs with a width of less than 40 nm can enter the nuclear envelope through the nuclear pore complex and transport more cargo into the nucleus where it is needed (Wang et al. 2019). Rod-shaped AuNP-based complexes synthesized by Zhang et al. in 2017 showed enhanced internalization compared to spherical AuNP-based complexes (Zhang et al. 2017). However, contrary results have been reported in other studies, but this does not limit the fact that NP shape affects their internalization and drug delivery efficiency.

3.6.2

Efficient Drug Loading and Release Characteristics of Nano Drug Delivery Systems

The main characteristics to contemplate during developing nano-drug delivery systems are drug loading and encapsulation efficiency. Drug molecules can be conjugated to the surface of NPs via various chemistries. The pharmacological treatment of disease pivot abundantly on the mechanism of nano-drug carrier production. When creating the formulation, several aspects of nanoconjugates are taken into account, including size, shape, surface charge, stability, dispersity, solubility and availability to the biological system. The synthesis technique has an impact on the release characteristics of drug carriers. The nanocarrier should be able to carry a high dosage of the intended drug, which will limit the amount of matrix material needed for dispensing the drug. The synthesis can be carried out in two ways: physically or chemically (Patra et al. 2018). The physical method involves incubating the nanocarrier with a concentrated drug solution and allowing the drug to absorb across the surface of NPs. Part of the chemical method is covalently attaching the end functional group of the drug to the charge on the surface of the NPs. Direct drug molecules attached to the surface of NPs might cause major problems since the drug can dissociate from the nanocarrier and be delivered in an unintended location. The rate at which the drug is released from the carrier is also affected by the

breakdown of the bond between the carrier and the drug molecule and the degradation of the nanocarrier. As a result, drug leakage during transportation may rise, lowering effective concentration and efficiency at the target site. Several different approaches and crosslinkers can be used to create covalent bonds. Inorganic NPs have a large surface area, which increases the loading capacity. Loading and encapsulation efficiency can be affected by how well the drug sticks to the NPs, how stable the drug molecule is in the solvent, the physical state of the NPs, and the molecular weight of the drug molecule (Cooper et al. 2014). The overall functionality of NP-based drug delivery systems is critically determined by their capability to release the entrapped drug, which requires a thorough understanding of drug release properties to create drug delivery vehicles for biomedical applications. Researchers can appropriately study new NP system behaviour and evaluate their probable effectiveness in clinical applications by measuring NP release kinetics. There are three ways for NPs to release drugs: desorption from the surface, erosion of the polymer matrix and diffusion. Matrix diffusion or erosion are primary routes for the release of a drug, while in many NP formulations, rapid burst release is seen for the desorption of the surface-bound drug, which is either unbound or weakly bound. The overall amount of drug release in cells or animal models is evaluated using chromatographic techniques. So far, no standard method for determining drug release qualities has been developed (Lee and Yeo 2015). Numerous procedures have been created by researchers, including turbidimetry and voltammetry, as well as continuous flow, dialysis membrane, sample and separation. Every approach has its own set of benefits, drawbacks and obstacles for setup and sampling. The rate of release can be affected by the type of drug, how well it dissolves, how much of it is used, the size of the particles and how crystallized they are. Controlled release of the drug includes extended and pulsatile release. Based on nanotechnology, a pH-dependent, temperature-sensitive or photosensitive drug delivery mechanism can release

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the drug at the target site. In the case of nanospheres, the drug usually is uniformly deposited throughout the surface and the drug is released through a diffusion process. The burst release mechanism releases unbound or weakly bound drugs. The NP and drug molecule conjugation approach impacts the release profile. When a drug is put together with strong bonds, it slowly gets out of the nanocarrier. This is called sustained release. The drug is released through the polymer matrix if a biodegradable polymer is wrapped around drug-coupled NPs. Most of the time, the dialysis membrane technique is used to study NP release. This technique measures how much drug is released as a function of how quickly it moves across the membrane (Son et al. 2017).

3.6.3

Efficient Cellular Uptake and Transport of Nano Drug Delivery Systems

NPs can have a wide range of toxicological consequences and can cause biological reactions like inflammation and immunological responses. They can enter the body by a variety of different pathways, such as the skin, lungs or intestinal system. The cellular uptake of NPs is highly dependent on various intrinsic and extrinsic properties. Different intrinsic, physiochemical properties of NPs, such as size, surface charge and chemistry, influence their uptake and interaction in a biological system. NPs with a positive surface charge have shown higher cellular uptake but higher toxicity than NPs with a negative surface charge which are more efficiently transported. When placed outside the cell, NPs can interact with cellular plasma membranes and enter the cell by passive diffusion or endocytosis. Traditional oral or intravascular drug delivery methods disperse therapeutic agents throughout the body, with little of the drug actually reaching the tumour location. Targeted drug delivery that is specifically aimed at the tumour results in drug buildup in the tumour area and reduces drug leakage into other healthy tissues. This strategy

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lessens side effects while improving therapeutic effectiveness (Zhao and Stenzel 2018). Active (also known as ligand-based) and passive targeting are two main methods of drug delivery. Nanovectors with a diameter of 400 nm are more easily able to enter the tumour tissue due to the EPR effect. Therefore, various pathophysiological characteristics of tumour tissue, such as aberrant vasculature, temperature, pH and surface charge of tumour cells, influence passive targeting. It is clear that certain physicochemical characteristics of nanocarriers, including size, surface charge, molecular weight and hydrophobic or hydrophilic features, are essential for passive targeting. Although passive targeting is an intriguing strategy, it has major drawbacks, including ineffective drug diffusion into tumour cells, random targeting and the absence of the EPR effect in some cancers (Kou et al. 2018).

3.7

Competence of Biogenic Inorganic NPs in Immunomodulating Cancer Environment

Cancer is the major cause of death in developed economies and the second largest in emerging ones. For a long time, intravenous chemotherapeutic drug treatments were the most common health treatment for cancer. The rapid discovery of several cancer vaccines has resulted from new and improved perspectives on cancer research and numerous vaccination regimens are currently being evaluated. Vaccines are now used to treat a number of cancers, including lung, breast, pancreatic and colorectal cancers. However, traditional cytotoxic chemotherapy is still the go-to therapy for many cancers. The only anticancer vaccines being given clinically are Sipuleucel-T (Provenge) and the advanced melanoma vaccination Talimogene laherparepvec (T-VEC). Phase II/III clinical studies for several novel vaccinations are underway. At this stage, finding an anticancer vaccine that enables the immune system to identify and destroy cancer cells or depletes cancer cell proliferation is crucial (Cheng et al. 2020). To maintain their cells

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developing at a fast rate, solid tumours require a lot of nutrition. As a result, blood vessels are forced to form in order to irrigate the neoplastic tissue. The specific blood arterial architecture observed in solid tumours leads to EPR. The EPR effect has long been assumed to be the primary mechanism that causes NPs to accumulate in tumour tissues rather than in normal tissues. These new vessels are manufactured rapidly and feature a number of faults, like high tortuosity and wide inter-endothelial junctions, which result in massive fenestrations of a few hundred nanometres in size. NP-based drug delivery systems have been designed to deliver therapeutic drugs precisely to solid tumours, improving anticancer efficacy while limiting systemic toxicity (Fang et al. 2012). Biogenic NPs are among the various carriers examined for their ability to act as cancer antigens. These particles are created by spontaneous vacuolation of bacterial (outer membrane vesicles, OMVs), eukaryotic (exosomes) or viral structural proteins. Biogenic NPs have the ability to modulate the immune system and are effective in tumour immunotherapy. In vivo biodistribution is aided by the nanoscale size, huge surface-tovolume ratios and surface functionalization capacity. Furthermore, multifunctional nanocarrier systems can be used to deliver chemotherapeutic agents to specific locations. Through active mechanisms, the NPs are functionalized and directed to the cancerous cell. When NPs are combined with biomolecules or a ligand that acts as a receptor, the distribution of the NPs to cancerous cells can sometimes be enhanced without harming healthy cells (Naskar et al. 2021). Lung cancer is the most significant cause of cancer-related death, accounting for 23% of fatalities globally, more than the total deaths from colon, breast and prostate cancer. Lung cancer is fatal due to a lack of efficient chemotherapeutic treatments and diagnostic procedures for early detection. Cisplatin is a highly effective cancer therapy, including lung cancer and osteosarcoma, that is now widely available, although its use is restricted due to its numerous side effects. In Scientific Report, Iram et al. (2019)

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used bromelain, a pineapple-based cysteine protease, as a reducing and surface functionalizing agent to manufacture monodispersed AuNPs. Cisplatin was conjugated with AuNPs in this study to distribute it selectively on the directed site delivery with high patient compliance. Due to their enormous size, AuNPs preferentially aggregate at tumour sites and in inflamed tissues. Enzyme-mediated synthesis of NPs has been reported to enhance the adequacy of the medication; bromelain acts as a capping agent to improve therapeutic efficacy and overcome constraints. Bromelain is hydrophilic in nature and has numerous polar functional groups on its surface and NPs with a hydrophilic surface can resist identification by RES (Bagga et al. 2016; Iram et al. 2019). Additionally, due to the EPR effect, NPs circulate in the circulatory compartment for a longer period of time and are able to accumulate in solid tumours. Bioconjugation also prevents the functional groups in charge of nonspecific binding since these groups are engaged in the covalent interactions between the drug and NPs. The protease component of bromelain is primarily responsible for its anticancer properties. Due to the synergistic effect of bromelain, the synthesized Cisplatin bioconjugated bromelain encapsulated AuNPs were efficacious against lung cancer and osteosarcoma even at low concentrations. The secondary structure of NPs was lost due to encapsulation, while the tertiary structure was preserved, improving the anticancer potential as previously reported (Iram et al. 2019).

3.8

Conclusion

The physicochemical properties of NPs combined with a well-coordinated set of biological events to help them overcome biological barriers at the target delivery location is the foundation of NP-based drug delivery. Despite the substantial effort, the inconsistency between mechanical and physicochemical parameters like shape, size and surface modification has led to contradictory outcomes in most NP-based drug delivery experiments. This necessitates carefully

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elucidating paired investigations on manipulating mechanical and other characteristics of nano-bio interactions. NP systems with a wide variety of mechanical properties should be employed to obtain similar results and their mechanical characteristics should be evaluated using established methodologies. More focus should be paid to other significant factors, such as how the mechanical properties of NPs regulate their ejection from tumour vessels and confinement at tumour tissues due to the EPR effect, as well as how these factors interact with the extracellular matrix, tumour-accompanying cells and stromal tumour cells, which are all components of the tumour microenvironment. Other crucial elements, including the effects of NP mechanical characteristics on protein corona formation and cell signalling pathways using new omics techniques, that affect NP cellular uptake, should be further investigated (Ali et al. 2017). Manipulating the characteristics of NPs that can be delivered directly to the blood has made significant progress in providing most of the medicine to the target site. After all, the capacity of drug delivery systems to reach their intended targets is critical to the efficacy of tumour treatment as well as gene therapy, among other things. Despite widespread primacy, the translational gap between animal and human investigations keeps nanomedicine access to patients far below expectations. This discrepancy stems from a lack of knowledge about the physiological and pathological distinctions between animal model species and humans and how these variations affect the response and modes of action of nanomedicines in the body. One of the reasons limiting clinical translation is the differences between species. This is partly due to the underappreciated variability found in both the biological foundations of diseases and across patients, which affects NP efficacy by altering NP distribution and functionality due to the development of diseased tissue, structure and physiology (Thanusha et al. 2018). Despite the fact that all NP drug delivery systems outperformed shrinking the tumour size in small animal models, none of the NP formulations has

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been successfully converted into clinical applications. NPs are essential players in developing new medicinal and imaging agents because of their synergy between size, structure and physical properties. Nanotechnology can significantly contribute to the expansion of cutting-edge techniques used to develop new products, replace outdated production machinery and reconstitute novel materials and chemicals for improved potency leading to abridged material and energy consumption, lessening environmental harm and environmental remediation. Although reducing material and energy use is good for the environment, nanotechnology offers the exciting prospect of solving issues in a more environmentally friendly manner. The development of solutions to present environmental problems as well as steps to solve issues arising from interactions between energy and material and the environment, are examples of how nanotechnology is being used in the environmental field and the potential hazards linked to nanotechnology. Questionnaire Multiple Choice Questions 1. Which metal nanoparticles show SPR? (a) Iron (b) Nickle (c) Copper (d) Terbium 2. The size of Quantum dots should be less than. . . . (a) 20 nm (b) 15 nm (c) 12 nm (d) 10 nm 3. Maximum amount of internalization of nanoparticles takes place via. . . (a) Diffusion (b) Osmosis (c) Endocytosis (d) Pinocytosis 4. Toxicity of nanomaterials is due to the. . . (a) ROS (b) Caspases (c) ER

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(d) Golgi body Short Answer Type Questions 1. Why is surface plasma resonance (SPR) in gold nanoparticles (AuNPs) so prominent? 2. How does the size of nanoparticles help in delivering drug at much low effective concentration? 3. Which types of particles are used to deliver drugs to the nucleus directly? 4. How do AgNPs work against bacteria? Long Answer Type Questions 1. Explain the mechanism of generation of GNP-mediated ROS in the cell. 2. How does the internalization of anionic nanoparticles take place in a eukaryotic cell? 3. How does inorganic nanoparticles-mediated drug delivery lower the effective dosages of drugs? 4. How is nano-emulsion stable at low zeta potential? Acknowledgements The authors are thankful to the Chairman, Department of Biochemistry, Faculty of Life Science, Aligarh Muslim University, for kind support. Conflicts of Interest The authors declare no conflict of interest.

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Modeling of Nanorobots and Its Application Toward Medical Technology Koena Mukherjee and Anup Kumar Sharma

Abstract

Highlights

Recent advances in the development of micro and nanosensors have led researchers to develop nanorobots (nanobots) that would be able to detect and deliver drugs to defective cells. These nanorobots include sensors to detect defective cells or tissues and can be easily programmed for the detection and treatment of various important diseases like cancer. Here we discuss some recent advancement of nanobots in biomedicine field with particular emphasis on targeted drug delivery, sensing of biologic targets, detoxification, and precision surgery using nanorobots, locomotion, and power supply requirements of bio-nanorobots. The future success of bio-nanorobot technology can be achieved through close collaboration between nanotechnology, robotics, and biomedical experts.

• Nanorobots are the answer to targeted drug delivery for curing varied medical problems which require precise drug delivery. • Nanorobots constitute sensors, communication devices, and actuators for manipulation of payload in nano dimension. • Sensors based on nanomaterials are low cost, light weight, highly sensitive, selective, and small in size. • Nanosensors are sensing devices with a dimension of less than or equal to 100 nm.

Keywords

Nanorobot · Non-Newtonian blood flow model · Nanosensor

K. Mukherjee (✉) · A. K. Sharma EIE Department, NIT Silchar, Silchar, Assam, India e-mail: [email protected]

4.1

Introduction

Robots are programmable machines for performing repetitive, specialized tasks. Scaling down the size of a robot by a billionth of a meter gives a nanorobot or a nanobot (Berger et al. 2016;Cavalcanti et al. 2003). The development of nanobot unlike any other robot is a multidisciplinary research area involving nanosensors, nanomotors, nanoactuators and fabrication in nanoscale using machines with size of a molecular cell in human body. Generally, in a single dimension if a particle size is less than 100 nm, then it is considered to be of nanoscale. Various applications like environmental monitoring, sanitization of a closed arena through destruction of infectious diseases are prevalent for a nanorobot. However, the driving force behind the advent of

# The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 B. Sarkar, A. Sonawane (eds.), Biological Applications of Nanoparticles, https://doi.org/10.1007/978-981-99-3629-8_4

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K. Mukherjee and A. K. Sharma

nanobots has always been the domain of medical technology and these nanobots are popularly known as bio-nanorobots. Research and product development for bio-nanorobotics area need multidiscipline oriented groups and novel-technical processes for material-synthesis, characterization, and applications. Nanobots for the advancement of medical technology are the most ambitious but emerging research area. Till now, a complete functional nanobot has not been constructed yet but the scientists from various research areas are working together to find a breakthrough in bio-nanorobotics. A series of computer simulations and modeling provide promising future for these nanobots. Diseases such as thrombocytopenia, various heart-related diseases, HIV, identification of cancer cells, and subsequent eradication of the targeted cancer cell are some of the few applications where bio-nanobots have shown promising future as indicated in Warkentin (2009) and Rajesh et al. (2018). The researchers believe that bio-nanobots will be able to deliver small but precise medication to the patients suffering from cancer and finally eradicate cancer from the human body. In general, Li et al. (2017) discussed that four potential applications of bio-nanorobots can be identified, such as targeted drug-delivery, de-toxification, precision-surgery, and bio-signal sensing.

4.1.1

Targeted Drug Delivery

Wu et al. (2013) have demonstrated the application of a polymeric-nanomotor in targeted drug delivery near the vicinity of the cancer cells. Anticancer drug doxorubicin is encapsulated inside the nanomotor.

4.1.2

Sensing of Biological Targets and Detoxification

Thrombocytopenia (Warkentin 2009) refers to a medical condition of the human body when the platelet count has reduced drastically, typically less than 150,000 per liter. Due to less platelet,

these types of patients suffer from bleeding problems like nose bleeding, menstrual bleeding, etc. However, in case of an accident, huge blood loss leads to shock, paralysis. Platelet transfusion is one of the many ways to treat thrombocytopenia. During platelet transfusion, due to less longevity of the platelets, a patient requires two to three transfusions within a month. But, this process is costly and after a few transfusions, the host body refuses the foreign platelet due to developed immunity. Therefore, a futuristic idea of therapy for thrombocytopenia is to inject nanorobots in bloodstream to develop own platelets through targeted stimuli delivery or injection of artificial platelets. Another application of bio-nanorobots can be found in case of detection and destruction of cancer cells in Rajesh et al. The cancer cells can be identified through the pH value in blood. The bio-nanorobots are injected into the blood vessels and small blood vessels like arterioles are used as carrier to these nanorobots. They reach the targeted area using controlled motion and administer precise medication to the cancer affected cells while leaving the healthy human cells unaffected which is not possible in case of traditional chemotherapy or radiation.

4.1.3

Precision Surgery

Precise and minimally invasive surgery in human body can only be achieved through robotic surgery. Nowadays, robotic manipulation with or without assistance of human surgeons are established. Several examples of eye and neurological surgeries are present in medical journals. These robotic surgeries are performed through robot manipulators and they are actuated using external power supply through wires. However, this poses a great challenge to the researchers working in the domain of nanorobotic surgery in terms of biocompatibility of power sources Therefore, researchers have been working on various areas of external power source, e.g. magnetically powered sources and ultrasound generated propulsion of nanorobots. In order to perform nanosurgeries, Leong et al. (2009) and

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Modeling of Nanorobots and Its Application Toward Medical Technology

Breger et al. (2015) have extensively studied tools like microgripper and nanodrillers. However, unlike conventional robotic manipulators, tethers attached to this type of nanotools pose movement restriction inside arteries. Therefore, to overcome such problem, Breger et al. have reported selffolding actuation mechanism which is triggered by biochemical compounds like pH, temperature, and enzymes. Although, irrespective of the several promising results from the initial simulation studies, when the scientists and researchers will deal with nanoscale or molecular scale fabrication they have to face problems associated with their physical, chemical, biological and mechanical properties at nanoscale Therefore, an equal blend of quantum mechanics, nanomechanics, and bioinformatics-based molecular simulation can only lead to successful development of the bio-nanorobots.

4.2

What Is Nanorobot

In Hamdi and Ferreira (2007), Hamdi et al. reported, a nanorobot is a robotic device fabricated at nanoscale typically the size varies between 0.1 and 100 nm (1 nm = 10-9 m) to perform highly precise and specialized tasks. Unlike any other robotic device, these nanorobots also have sensors, actuators, communication module, source of power supply, and manipulators wherever required. Nanorobots find their application mainly in the field of medical technology and generally they are known as bio-nanorobots.

4.2.1

Nanosensors

With the advent of nanotechnology, it will be possible to design and develop sensors with smaller dimensions. Sensors based on nanomaterials are low cost, light weight, highly sensitive, selective, and small in size. Nanomaterial-based sensors have found their application in various fields such as medical technology, defense, security, space applications and

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many more. In biomedical field, sensors important to measure the physical parameters like temperature, pressure, and flow are required for basic and routine clinical care and research. In addition, sensors are needed to detect certain bacteria, ions, proteins, DNA, viruses and other important chemical compounds even at the molecular level, which will help in the diagnosis of many diseases like diabetes, cancer, etc. Urban (2009) has reported that for the use in biomedical field, nanosensors can be designed to interact with cells and tissues at molecular level for the measurement and detection of specific measurand. Sensors for the biomedical field are developed based on measurand, measurement sites, and transit principles. Table 4.1 gives the idea about various biological and physiological measurands, systems, and measurement sites under investigation (Rolfe 2012). Mousavi et al. (2018) have reported that nanosensors are the devices with one dimension is of the order of 100 nm. The choice of material and design of the nanosensor depends on how the sensor is going to interact with the measurement site. Measurement sites can be broadly classified as invasive measurements, non-invasive measurements, and ex vivo and in vitro measurements depending on where the nanosensors are positioned. Sensors under invasive measurement are positioned within tissues or intravascular spaces to produce the useful information. On the other hand, sensors under non-invasive measurement are placed at a position nearer to living tissue surface. Yao et al. (2020) observed that flexible and skin-attached sensors are now being developed for continuous monitoring of glucose under the non-invasive measurement category. After removal of samples from living-organism, they can be analyzed later in an analytical room. For example, lab on a chiptype analysis of samples taken from a subject or organism. In this, blood samples will be drawn from the patient and inserted into a channel that directs the blood sample into contact with several sensors. Thick film sensors are utilized to detect blood-gases level (such as O2, CO2) and pH measurement. Sensors based on semiconductors (such as ion-sensitive field-effect transistor, ISFET) are

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Table 4.1 List of biological and physiological measurands, systems, and measurement sites under investigation Sr. No. 1. 2. 3.

Type of measurand Physicalmeasurand Chemicalmeasurand Electricalmeasurand

Physical parameter Temperature, distance, pressure, etc.

Measurement site Cardiac system, respiratory system, gastrointestinal

Oxygen, carbon dioxide, nitric oxide. Glucose, urea, viruses, etc. Electrocardiogram, electromyogram, electroencephalogram

Intravascular system, renal, hepatic, tissue, non-invasive measurement from urine and saliva Cardiac, cerebral, muscles, ocular

now utilized in Lab on chip device for the detection of analytes such as DNA, viruses, hormones, etc. Biological type of nanosensors will consist of a bio-receptor and a transducer. An antibody, an enzyme, a protein or a DNA strain can be used as a receptor. An electrochemical detector, an optical transducer, or an amperometric, voltaic, or magnetic detector may be used for the transduction principle. An electrochemical bio-nanosensor works on the simple principle that the analytes (a substance whose chemical constituents are being identified and measured) binds itself to the receptor which will cause a change in some electrical signals. For example, Chaniotakis and Fouskaki (2014) have reported that a specific antigen has the tendency to bind itself to an antibody modified gate terminal of field-effect transistor (FET). The reported transduction principle looks simple but the decision to select a particular receptor for a particular analysis while maintaining high accuracy and fast response time is often very difficult. With exceptional features such as autonomous motion, highly selective for target analytics, fast response time, simple surface functionalization process, nanobots have shown remarkable performance in various biosensing applications for diagnosis of many diseases. Micro/nanorobot sensing strategy depends on different bioreceptors attached to its surface. Gradilla et al. (2013) have described bioreceptor functionalized nanobots that carry powerful binding and transport features that will open new ways to detect and identify biological traits such as proteins, nucleic acids and cancer cells in unprocessed body fluids. Chen et al. (2016) have pointed out that these growing technologies

have fueled the development of nanorobotic sensor networks (NSNs) to identify and locate regions of interest in the in vivo environment, such as the internal parts of the human body.

4.2.2

Locomotion for Bio-Nanorobot

Locomotion, meaning the ability to change position, is coordination between skeletons, neurons, and muscles in the case of a human body. Kim et al. (2022) are studying for a long time about this coordination to mimic the same for application in a bipedal robot. However, the challenge starts when the same has to be mimicked in a nanoscaled environment as mentioned in Xu et al. (2017), Purcell et al. (1976) and Wang et al. (2013); they have mentioned that the presence of low Reynolds number of the blood and completely random locomotion technique (characterized by Brownian motion), the modeling and control of nanoscaled biorobots pose even greater challenge. Blood being the only carrier of biological and chemical components inside the human body, an obvious choice for the researchers was to utilize the blood flow for identification of infected cells as well as for targeted drug delivery. However, in order to control the motion of artificial bio-nanorobots within the blood flow, we require a complete model of blood flow in a rigid pipe, i.e. arteries/ arterioles considering blood to be non-Newtonian in nature. In Jiansheng Xu (2013), vascular nanorobot was designed where artificial flagellum was used for modeling of kinematic motion and was driven by the external magnetic field. The robot consists of two parts, an ellipsoid head and the other is artificial flagellum tail.

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Modeling of Nanorobots and Its Application Toward Medical Technology

4.2.2.1

Modeling of Blood Flow in Arteries for Diagnostic Application of Bio-Nanorobot In the micro (nano) field, low Reynolds number is experienced and as a result the viscous behavior of the blood grows largely. Arteriole, a small diameter (5–100 μm) blood vessel in the complete blood circulatory system can be considered as the carrier of nanorobots and also nanorobots can perform manipulation. The blood flow in an arteriole can be characterized as non-Newtonian fluid which exhibits deformation rate of dependency, viscoelasticity, yield stress, and thixotropy. Different types of non-Newtonian fluid can be visualized in Fig. 4.1. Human blood becomes less viscous at high shear rates. Therefore, blood can be aptly catagorized as shear thinning fluid. But as the heart pumps, blood exhibits timedependent oscillatory flow characteristics along with the time independent part. Three types of non-Newtonian fluids are referred by Chabra and Richardson (2008), timedependent, time-independent, and viscoplastic fluid. During blood flow characterization, the researchers have divided the blood flow into two separate categories of time-dependent and timeindependent for heart pumping and for the viscous nature of the blood, respectively. However, further detailed study has revealed that the time independent non-Newtonian fluids can be further classified into three separate class of fluid.

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1. Shear-thinning 2. Shear-thickening 3. Viscoplastic The existence of yield stress characterizes viscoplastic fluid. The viscoplastic fluids can be categorized as Bingham plastic model, HerschelBulkley (H-B) fluid model, and Casson fluid model. Lida (1978) reported that H-B fluid model fits appropriately when the diameter of the blood vessel is less than 0.065 mm. The H-B model captures the shear thinning behavior when the shear stress exceeds the yield stress and mathematically it can be represented as in Trihirun et al. (2013)

Vz =

nR τw nþ1 m -

1=n

τy r R τw

1ðnþ1Þ=n

τy τw

ðnþ1Þ=n

ð4:1Þ



where τ is the shear stress, τy is the yield stress, τw is the shear stress at the wall, m is the consistency index, n is the power law index (n < 0). In the plug core region the velocity is constant and equal to Vz  T  r = Rp. The plug core velocity is calculated and written as Vp =

nR τw nþ1 m

1=m

1-

τy τw

ðnþ1Þ=n

ð4:2Þ

The time-dependent part of the blood-flow velocity can be written as Vϕ =

A1 J 0 ðλr Þ - 1 eiωt iρw J 0 ðλRÞ

ð4:3Þ

where A1 is the amplitude of the oscillating component, ρ is the blood density, J0 is the Bessel function zero order of the first kind, ω is the angular velocity. The total velocity can be considered as V = Vϕ þ Vz

Fig. 4.1 Relation between shear stress and shear rate for different fluids

ð4:4Þ

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K. Mukherjee and A. K. Sharma

4.2.2.2

Motion Control of Bio-Nanorobot for Targeted Disease Cure Matsumoto et al. (2010) have discussed about magnetic control of nanorobots considering nanorobots to be in the shape of bacterial flagella. Using three iron core coils, the magnetic field was set up. In order to control the motion of nanorobots using magnetic field, nickel was plated by vacuum vapor deposition on the nanorobot. Therefore, the nanorobots can then be aligned along the direction of the applied magnetic field. The nanorobots were inserted into the bloodstream using popular method of DNA injection or lipofection method. After the DNAs covered with lipid layer contact the cell, they are drawn into the cell using cell’s endocytosis method.

magneto aerotactic bacteria in a tumor was studied under a focalized directional magnetic field. Mautshumo et al. have discussed about magnetic control of nanorobots considering nanorobots to be in the shape of bacterial flagella. Similarly, using ultrasound powered micromotors deep tissue penetration has been reported in literature which gives promising results in the domain of ultrasound-related power supply.

4.2.3.2 Internal Source Literature survey shows that a controlled payload release can be achieved through the use of pH. Several tests in a mouse confirm the theory and thereby pave the way for a chemically powered bio-nanorobot.

4.2.4 4.2.3

Communication with Nanorobot

Power Supply to Bio-Nanorobot

The most challenging task for motion control lies with the power supply to these artificial bio-nanorobots inside human body. The batteries and fuel cells used for actuation in a traditional robot are not applicable for bio-nanorobots due to the biocompatibility and the size issue. Therefore, scientists have employed a variety of locomotion techniques as well as their source of power supply to the nanorobots as mentioned in Peyer et al. (2013), Abdelmohsen et al. (2014), Guix et al. (2014), Palagi et al. (2016), Mei et al. (2011), Duan et al. (2015), Vikram Singh and Sitti (2016), Sánchezet al. (2015), Wang and Pumera (2015), Kim et al. (2015), Lin et al. (2016). Typically, the power supply to the bio-nanorobots rely on either conversion of chemicals present inside the body, e.g. glucose and O2, or externally powered magnetic and ultrasound energies to drive the bio-nanorobots.

4.2.3.1 External Source Servant et al. (2015) reported a weak rotating magnetic field to magnetically power certain micro swimmers and finally they tested a mouse. Again in Felfoul et al. (2016), migration of

Nanorobots need to coordinate among themselves for the sensors to send signal to the actuators and communication among themselves. The nanorobots can use a macro transponder for accurate positioning. But this type of system would require externally placed beacons fixed outside skin. Therefore, the organ inlet where the medicine is to be administered becomes a well-known location for the nanorobots. A communication technology using chemicals were proposed by Cavalcanti et al. (2007). To identify the tumor cells, same method can be used by the nanorobots. Sonar communication in the nanoscale was developed by the researchers which consumes less than 20 μW. Acoustic communication capabilities for nanorobots were described by Cavalcanti et al. (2007). The researchers found out at which spectrum band the communication between nanorobots will be a success and simultaneously the tissue cells will not get damaged.

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Modeling of Nanorobots and Its Application Toward Medical Technology

4.3

Gaps and Future Scope of Nanorobots in Medical Field

In the recent years, a whole new domain of research has been introduced along with a new terminology of “medical technology.” The medical technology refers to the application of micro/ nanorobots in medicine. However, to achieve satisfactory success in this domain, the roboticists need to work hand in hand with the medical practitioners. The doctors understand the physical difficulties faced by a patient which needs to be conveyed to the roboticists for proper solution. Moreover, after the development of the bio-nanorobots, the medical practitioners are required to study the issues like biocompatibility, toxicity, and efficacy of the robot. Therefore, the idea of bio-nanorobots will come to clinical use only if the roboticists join hands with medical researchers. Recent medical reports on ophthalmic surgeries have been quite promising and therefore it is only a matter of time when the horizon of nanorobots will expand in the medical field. Questionnaire MCQ Type Questions 1. Nanomaterials can be defined as the materials with at least one dimension measuring less than ___________ (a) 100 nm (b) 1000 nm (c) 500 nm (d) 10 nm 2. What is graphene? (a) A new material made from carbon nanotubes (b) A one-atom thick sheet of carbon (c) Thin film made from fullerenes (d) A software tool to measure and graphically represent nanoparticles 3. Which of the following is a use for nanobots in medicine? (a) Targeted delivery of drugs (b) Constructing new bones during repair

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(c) Synthesizing insulin for diabetics (d) Increasing muscle tone and structure Short Answer Type Questions 1. What are nano-particles, nano-tubes, and nano-films? 2. What is Nanotechnology?

Long Answer Type Questions 1. Briefly explain how nanomaterials would be useful in medicine and clinical care. 2. Briefly describe nanosensors.

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72 propelled magnetically guided nanomotors: toward practical biomedical applications. ACS Nano 7(10): 9232–9240 Guix M, Mayorga-Martinez CC, Merkoçi A (2014) Nano/ micromotors in (bio) chemical science applications. Chem Rev 114(12):6285–6322 Hamdi M, Ferreira A (2007) Multiscale design and modeling of nanorobots. In: Proceedings of the 2007 IEEE/RSJ international conference on intelligent robots and systems, San Diego, 29 Oct–2 Nov. Kim K, Guo J, Xu X, Fan DL (2015) Recent progress on man-made inorganic nanomachines. Small 11(33): 4037–4057 Kim D, Zhao Y, Thomas G, Fernandez BR, Sentis L (2022) Stabilizing series-elastic point-foot bipeds using whole-body operational space control. IEEE Trans Robot 32(6):1362–1379 Leong TG, Randall CL, Benson BR, Bassik N, Sterna GM, Gracias DH (2009) Tetherless thermobiochemically actuated microgrippers. Proc Natl Acad Sci U S A 106:703–708 Li J, de Ávila Berta EF, Gao W, Zhang L, Wang J (2017) Micro/nanorobots for biomedicine: delivery, surgery, sensing, and detoxification. Sci Robot 2(14):eaam6431 Lida N (1978) Influence of plasma layer on steady blood flow in micro vessels. Jpn J Appl Phys 17:203–214 Lin X, Wu Z, Wu Y, Xuan M, He Q (2016) Self-propelled micro-/nanomotors based on controlled assembled architectures. Adv Mater 28:1060–1072 Matsumoto T, Hoshino T, Akiyama Y, Morishima K (2010) Magnetically control of nano-structures for intracellular nano-robots. In: 2010 International symposium on micro-NanoMechatronics and human science, pp 109–114 Mei Y, Solovev AA, Sanchez S, Schmidt OG (2011) Rolled-up nanotech on polymers: from basic perception to self-propelled catalytic microengines. Chem Soc Rev 40(5):2109–2119 Mousavi SM, Hashemi SA, Zarei M, Amani AM, Babapoor A (2018) Nanosensors for chemical and biological and medical applications. Med Chem (Los Angeles) 8(8):205–217 Palagi S, Mark AG, Reigh SY, Melde K, Qiu T, Zeng H, Parmeggiani C, Martella D, Sanchez-Castillo A, Kapernaum N, Giesselmann F (2016) Structured light enables biomimetic swimming and versatile locomotion of photoresponsive soft microrobots. Nat Mater 15(6):647–653 Peyer KE, Zhang L, Nelson BJ (2013) Bio-inspired magnetic swimming microrobots for biomedical applications. Nanoscale 5(4):1259–1272

K. Mukherjee and A. K. Sharma Purcell EM (1976) Life at low Reynolds number. Am J Phys 45:3–11 Rajesh J, Pavithra G, Manjunath TC (2018) Design & development of nanobots for cancer cure applications in bio-medical engineering. Int J Eng Res Technol 6(13):1–7 Rolfe P (2012) Micro- and nanosensors for medical and biological measurement. Sens Mater 24(6):275–302 Sánchez S, Soler L, Katuri J (2015) Chemically powered micro-and nanomotors. Angew Chem Int Ed Engl 54(5):1414–1444 Servant A, Qiu F, Mazza M, Kostarelos K, Nelson BJ (2015) Controlled in vivo swimming of a swarm of bacteria-like microrobotic flagella. Adv Mater 27(19): 2981–2988 Trihirun S, Achalakul T, Kaewkamnerdpong B (2013) Modeling nanorobot control for blood vessel repair: a non-Newtonian blood model. In: The 6th 2013 biomedical engineering international conference, pp 1–5 Urban GA (2009) Micro-and nanosensors for medical applications. In: World congress on medical physics and biomedical engineering, Munich, 7–12 Sept 2009. Springer, Berlin, p 310 Vikram Singh A, Sitti M (2016) Targeted drug delivery and imaging using mobile milli/microrobots: a promising future towards theranostic pharmaceutical design. Curr Pharm Des 22(11):1418–1428 Wang J (2013) Nanomachines: fundamentals and applications. Wiley-VCH, Weinheim Wang H, Pumera M (2015) Fabrication of micro/nanoscale motors. Chem Rev 115(16):8704–8735 Warkentin TE (2009) Thrombocytopenia due to platelet destruction and hypersplenism in hematology: basic principles and practice, 5th edn. Churchill Livingstone Elsevier, Philadelphia, pp 2113–2131 Wu Z, Wu Y, He W, Lin X, Sun J, He Q (2013) Selfpropelled polymer-based multilayer nanorockets for transportation and drug release. Angew Chem Int Ed 52:7000–7003 Xu J (2013) Motion simulation of an artificial flagellum nanorobot. In: Proceedings of the 13th IEEE international conference on nanotechnology, Beijing, 5–8 Aug 2013 Xu T, Li-Ping X, Zhang X (2017) Ultrasound propulsion of micro /nanomotor. Appl Mater Today 9:493–503 Yao S, Ren P, Song R, Liu Y, Huang Q, Dong J, O’Connor BT, Zhu Y (2020) Nanomaterial-enabled flexible and stretchable sensing systems: processing, integration, and applications. Adv Mater 32(15):e1902343

5

Polymer Nanoparticles and Their Biomedical Applications Monika Singh and Pradip Paik

Abstract

The polymer nanoparticles (PNPs) have a number of important implications in the field of biomedical applications. To be a part of healthcare, all NPs must qualify certain criteria such as shape, size and nature to deliver drugs into biological system. In this context, biocompatibility and biodegradability are two most important and necessary parameters. In this chapter, a summary of the state of the art of synthesis of various PNPs, polymer nanocomposites (PNC) and their bioavailability, stability and insertion are discussed in detail. The mode of delivery, pathway and mechanism are also highlighted here. Their applications toward cancer, wound healing, dentistry and antimicrobial polymers are defined precisely with their future scope. Keywords

Polymer nanoparticles · Bioavailability · Biocompatibility · Healthcare · Cancer

M. Singh · P. Paik (✉) School of Biomedical Engineering, Indian Institute of Technology-(BHU), Varanasi, UP, India e-mail: [email protected]; paik.bme@iitbhu. ac.in

5.1

What Is Polymeric Nanoparticles?

Polymeric nanoparticles (PNPs) are of nano sized (10 to 1000 nm) colloidal particles, mostly organic in nature made with C, H, O, N etc. These nanoparticles can contain active biomolecules or medicine within the polymeric network structure. Theses polymers further are ubiquitous in nature and can be natural, synthetic and semi synthetic. The dispersion of performed polymers permits for an extensive diversity of probable structures and characteristic properties. PNPs have exceptional properties compared to the bulk masses due to their reduced size and possess higher surface area to volume ratio (Nasir et al. 2015). They can be easily formulated to facilitate defined control of numerous nanoparticles with various features (NPs) such as shape, size and surface characteristics. PNPs are always considered as a good delivery vehicle due its biocompatibility and superior drug release control by diffusion through poly-matrix or by matrix degradation (Vasile 2018). Broadly, PNPs can be categorized into “nanocapsules” (hollows enclosed by a polymeric membrane or shell) or “nanospheres” (solid matrix system) (Fig. 5.1) (Mitchell et al. 2021). In a polymeric matrix, drugs can be physically entrapped, covalently coupled or adsorbed to the constitutive network. It totally depends upon the synthesis method of PNPs (Vasile 2018). PNPs have countless advantages including drug

# The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 B. Sarkar, A. Sonawane (eds.), Biological Applications of Nanoparticles, https://doi.org/10.1007/978-981-99-3629-8_5

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Shape of PNPs This is also considered for the drug to be loaded and delivered to the target cell. Nanospheres and nanocapsules, both the structures have the tendency to absorb or encapsulate the drug molecules itself (Anagnostou et al. 2020). Consequently, diverse morphologies or shape and their function can have miscellaneous solubilization aptitude, bio-distribution, blood circulation time, cellular uptake, intracellular destiny and toxicity (Elsabahy and Wooley 2012).

Fig. 5.1 Schematic of nanosphere and nanocapsule of PNPs

delivery, cancer therapy, wound healing, dentistry and many more in medical biotechnology.

5.2

Distinctive Features of PNPs

Size, shape, internal morphology and external surface characteristics of nanomaterial can modulate the polymer’s chemical, physical and biological properties. Size and surface character can be altered to get desired properties. These properties amplified the surface area of PNPs. Size is an important parameter during the engineered nanoparticles (NPs) or PNPs design and it is directly related to its clearance from the body. Although, PNPs of 10 nm from the liver and reticuloendothelial system, but 50 nm PNPs cannot be cleared from the renal system (Vasile 2018). However,