Nanostructures for Drug Delivery

Nanostructures for Drug Delivery

Nanostructures in Therapeutic Medicine Series

Edited by

Ecaterina Andronescu

University Politehnica of Bucharest, Bucharest, Romania

Alexandru Mihai Grumezescu

University Politehnica of Bucharest, Bucharest, Romania

Table of Contents

Cover

Title page

Copyright

List of Contributors

Foreword of the Series

Preface

Chapter 1: Therapeutic nanomaterials: from a drug delivery perspective

Abstract

1. Introduction

2. General Methods of Synthesis of Nanomaterials

3. Characterization of Nanomaterials

4. Applications of Nanomaterials for Drug Delivery

5. Conclusions

Chapter 2: Core–shell drug carriers: liposomes, polymersomes, and niosomes

Abstract

1. Introduction

2. Self-Assembled Bilayers

3. Liposomes as Drug Carriers

4. Polymersomes as Drug Carriers

5. Niosomes as Drug Carriers

6. Biomedical Applications of Core–Shell Vesicular Drug Carriers

7. Discussion

8. Conclusions

Conflict of Interests

Chapter 3: The new nanocarriers based on graphene and graphene oxide for drug delivery applications

Abstract

1. Introduction

2. Chemistry of the Graphene Surface

3. Modification of Graphene Surface for Drug Delivery Applications

4. In Vitro Toxicology and Biosafety of Graphene Derivative

5. Conclusions

Chapter 4: Nanostructured nanoparticles for improved drug delivery

Abstract

Abbreviations

1. Introduction

2. The Core–Shell Nanostructure

3. The Capsule and Vesicle Nanostructure

4. Multicompartment Nanoparticles

5. Conclusions and Perspectives

Acknowledgments

Chapter 5: Design of functionalized materials for use in micronanoscale drug delivery devices and smart patches

Abstract

1. Introduction

2. Traditional Approaches to Drug Delivery

3. Compliance

4. Evolution of Smart Drug Delivery Devices

5. Electrochemical Approaches to Drug Release

6. Innovation and Application

7. Conclusions

Chapter 6: Niosomes: a novel approach in modern drug delivery systems

Abstract

1. Introduction

2. Factors Affecting the Formation of Niosomes

3. Types of Niosomes

4. Niosome Preparation

5. Characterization

6. Advantages of Niosomes

7. Limitation of Niosomal Drug Delivery System

8. Comparison of Niosomes Versus Liposomes

9. In-Vivo Behavior of Niosomes

10. Pharmaceutical Applications and Administration of Niosomes

11. Final Consideration and Outlook

Chapter 7: Nanofibrous and nanoparticle materials as drug-delivery systems

Abstract

1. Introduction

2. Nanoparticle Materials in Drug-Delivery Systems

3. Nanofibrous Materials as Drug-Delivery Systems

4. Future Directions

Chapter 8: Brush polymer-based nanostructures for drug delivery

Abstract

1. Introduction

2. Structural Design of BP-Based Drug-Delivery Systems

3. BP-Based Encapsulated Drug-Delivery Systems

4. BP-Based Conjugated Drug-Delivery Systems

5. Multifunctional BP-Based Drug-Delivery Systems

6. Summary

Acknowledgments

Chapter 9: Drug delivery systems based on titania nanostructures

Abstract

1. Introduction

2. Nanostructured TiO2 Used for Drug Delivery Systems

3. Drug Loading

4. Drug Release

5. Functionalization of TiO2 Nanostructures

6. Other Types of Nanostructured TiO2 Used as Drug Delivery Systems

7. Conclusions

Chapter 10: Redox activated polymeric nanoparticles in tumor therapy

Abstract

1. Introduction

2. Reactive Chemical Species in Human Physiology

3. Origins of Enhanced Free Radical Production in Tumors

4. Active and Passive Drug-Delivery Systems

5. Redox Responsive Drug-Delivery Systems

6. Miscellaneous Systems

7. Conclusions

Chapter 11: Polymeric micro- and nanoparticles for controlled and targeted drug delivery

Abstract

1. Introduction

2. Polymeric Micro- and Nanoparticles for a Controlled Delivery of Active Substances

3. Formulation of Micro- and Nanopolymer Particles

4. The Most Widely Used Incorporation Techniques

5. Characteristics of Polymeric Micro- and Nanoparticles With an Encapsulated Vitamin as an Active Substance and Their Comparison

6. Conclusions

Acknowledgments

Chapter 12: Novel gels: implications for drug delivery

Abstract

1. Introduction

2. Hydrogels

3. In situ Gel

4. Emulsion Gels

5. Microgel

6. Nanogels

7. Vesicular Gel

8. Future Prospects

Chapter 13: Nanosuspension drug delivery system: preparation, characterization, postproduction processing, dosage form, and application

Abstract

1. Introduction

2. Preparation of Liquid Nanosuspension DDS

3. Characterization of Nanosuspension DDS

4. Postproduction Processing

5. Dosage Form of Nanosuspension DDS

6. Application of Nanosuspension DDS

7. Summary and Outlook

Acknowledgments

Chapter 14: Polymer-based nanocarriers for therapeutic nucleic acids delivery

Abstract

1. Introduction

2. Current Challenges and Barriers for Therapeutic Nucleic Acids Delivery

3. Advantages and Uniqueness of Polymer-Based Nanocarriers for Addressing Existing Challenges and Barriers

4. Recent Examples of Polymer-Based Nanocarriers for Therapeutic Nucleic-Acids Delivery

5. Other Considerations for Polymer-Based Nanocarriers for Therapeutic Nucleic Acids Delivery

6. Conclusions

Acknowledgments

Chapter 15: Multifunctional therapeutic hybrid nanocarriers for targeted and triggered drug delivery: recent trends and future prospects

Abstract

Abbreviations

1. Introduction

2. Metal Nanoparticles

3. Silica Nanoparticles

4. Polymeric Nanoparticles

5. Core/Shell Nanoparticles

6. Conclusion and Future Prospects

Chapter 16: Lipid-based nanocarriers for ocular drug delivery

Abstract

1. Introduction

2. Routes of Delivery (Thakur and Kashiv, 2011)

3. Major Physiological Barriers of the Eye to Topical Ocular Drug Delivery

4. Requisites of Controlled Ocular Delivery (Wilson, 2004)

5. Lipid-Based Nanocarriers as Topical Ocular Delivery Systems (Gan et al., 2013)

6. Conclusions

Chapter 17: Nanoparticulate carrier(s): an emerging paradigm in new generation vaccine development

Abstract

1. Introduction

2. Advantages of Nanoparticulate-based Vaccine Delivery

3. Generation of Immune Response

4. Design Aspects in the New Generation of Vaccine Development

5. Nanocarrier(s) Properties that Make Suitable Cargo for Vaccine Delivery

6. Nanoparticulate Carriers as a Versatile Platform for Vaccine Delivery

7. New Generation Vaccines

8. Conclusions

Chapter 18: Pathogen-specific nucleic acid aptamers as targeting components of antibiotic and gene delivery systems

Abstract

1. SELEX for Selection of Specific and High-Affinity Aptamers

2. Aptamers for Pathogenic Cells

3. Nanoparticle-Based Antimicrobial Gene Delivery

4. Functionalization of Nanocarriers

5. Conclusions and Future Perspectives

Chapter 19: Multifunctional nanosized emulsions for theragnosis of life threatening diseases

Abstract

Abbreviations

1. Introduction

2. O/W-Type Nanosized Emulsions (NE) Generations

3. Future Perspectives

4. Conclusions

Chapter 20: Therapeutic nanostructures for pulmonary drug delivery

Abstract

1. Introduction

2. Nanoparticles

3. Pulmonary Drug Delivery

4. Drugs Suitable for Pulmonary Drug Delivery

5. Nanostructures for Drug Delivery to the Lungs

6. Pulmonary Delivery Devices

7. Deposition of Inhaled Particles in Respiratory Tract

8. Fate of Inhaled Particles

9. Evaluation of the Fate of Inhaled Particles

10. Conclusions

Chapter 21: Nanostructures in transdermal drug delivery systems

Abstract

1. Introduction

2. Skin Anatomy

3. Permeation Pathways Across Skin

4. Advantages of Transdermal Drug Delivery Compared to Other Routes of Administration

5. Advantages of Nanostructures in TDDS

6. Physicochemical Properties of Nanostructures Required for Good Permeation

7. Types of Nanostructures Used in TDDS

8. Limitations of Nanostructures in TDDS

9. Applications of Nanostructures in TDDS

10. Conclusions and Future Perspectives

Chapter 22: Advancement in pulmonary drug delivery systems for treatment of tuberculosis

Abstract

1. Introduction

2. Burden of Disease and Progress Toward Global Targets

3. Pathogenesis of Tuberculosis

4. Current Antitubercular Chemotherapy

5. Pulmonary Drug Delivery

6. Advanced Dry Powder Inhalers (DPI)

7. Carriers Used for Pulmonary Delivery of ATDs

8. Conclusions and Future Prospectives

Acknowledgment

Chapter 23: Nanosized devices as antibiotics and antifungals delivery: past, news, and outlook

Abstract

1. Introduction

2. Liposomes

3. Solid Lipid Nanoparticles (SLN)

4. Mucoadhesive Drug Delivery Systems

5. Chemical Drug Delivery Systems

6. Conclusions and Future Outlooks

Chapter 24: Drug delivery mediated by confined nanosystems: structure-activity relations and factors responsible for the efficacy of formulations

Abstract

1. Introduction

2. Surfactant-Based Formulations; Structure-Activity Relations as Criteria for the Choice of Building Blocks

3. Cationic Surfactants as Agents for DNA Transfection

4. Binding/Release Properties of Self-Assembled Systems

5. Biomaterials for Hydrophilic Peptides

6. Penetration Through BBB

7. Conclusions

Acknowledgment

Chapter 25: Therapeutic use of monoclonal antibodies: general aspects and challenges for drug delivery

Abstract

1. General Introduction

2. Mabs Production

3. Antibody–Drug Conjugates

4. Nanotechnology’s Potential Impact on Mabs

5. Therapeutic Applications of Monoclonal Antibodies

6. Future Trends of Monoclonal Antibodies

Chapter 26: Targeted drug delivery via chitosan-coated magnetic nanoparticles

Abstract

1. Nanotechnology-Based Targeted Drug-Delivery Systems

2. Targeting Strategies in Drug Delivery

3. Magnetic Nanoparticles

4. Chitosan as a Surface Coating Material for Magnetic Nanoparticles

5. Synthesis Methods for Chitosan-Coated Magnetic Nanoparticles

6. Magnetically Targeted Drug Delivery via Chitosan-Coated Magnetic Nanoparticles

7. Cellular Internalization of Chitosan-Coated Magnetic Nanoparticles

8. Drug Release From Chitosan-Coated Magnetic Nanoparticles

9. Toxicity of Chitosan-Coated Magnetic Nanoparticles

10. Administration Routes of Chitosan-Coated Magnetic Nanoparticles

11. Concluding Remarks

Chapter 27: Drug delivery: advancements and challenges

Abstract

1. Introduction

2. Drug Delivery into the Brain

3. Oral Drug Delivery Systems

4. Targeted Drug Delivery

5. Nanomaterials for Drug Delivery

6. Modern Drug Delivery: Challenges

7. Conclusions

Chapter 28: Stimuli-responsive liposome and control release drug

Abstract

1. Introduction

2. Liposomes

3. Stimuli-Responsive Liposome

4. Conclusions

Acknowledgments

Chapter 29: Nanotechnology to enhance transdermal delivery of hydrophilic humectants for improved skin care: a model for therapeutic applications

Abstract

1. Basic Concepts

2. Transdermal Agents Delivery and Nanotechnology

3. Humectants for Improved Skin Care: A Model for Therapeutic Applications

4. Conclusions and Lessons From Humectants for Skin Care Modeling Therapeutic Applications of Nanotechnologies

Chapter 30: Nanostructures for drug delivery: pharmacokinetic and toxicological aspects

Abstract

1. Introduction

2. Nanoparticles and Drug Delivery

3. Main Applications

4. Pharmacokinetic Characteristics of Nanoparticles in Drug Delivery Systems

5. Toxicological Effects of Nanoparticles

6. Determination of Toxicity

7. Toxicity

8. Conclusions

Acknowledgments

Index

Copyright

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List of Contributors

Naveed Ahmed,     Quaid-i-Azam University, Islamabad, Pakistan

Houman Alimoradi,     University of Otago, Dunedin, New Zealand

Daniel A. Allemandi,     National University of Salta-CONICET, Salta, Argentina

Mohammad Amani-Tehran,     Amirkabir University of Technology, Tehran, Iran

Sepideh Amjad-Iranagh,     Amirkabir University of Technology, Tehran, Iran

Xueqin An,     East China University of Science and Technology, Shanghai, China

Ashleigh Anderson,     University of Ulster, Jordanstown, Northern Ireland

Ecaterina Andronescu,     University Politehnica of Bucharest, Bucharest, Romania

Roohollah Bagherzadeh,     Amirkabir University of Technology, Tehran, Iran

Xavier Banquy,     University of Montreal, Montreal, QC, Canada

José M. Bermúdez,     National University of Córdoba, Córdoba, Argentina

Sourav Bhandari,     ISF Educational Society, Moga, India

Najma Bibi,     Quaid-i-Azam University, Islamabad, Pakistan

Alexandra Bolocan

Emergency University Hospital

Carol Davila University of Medicine and Pharmacy, Bucharest, Romania

Burhan Bora,     Ege University, Bornova-Izmir, Turkey

Chong Cheng,     University at Buffalo, State University of New York, Buffalo, NY, United States

Alicia Cid,     National University of Córdoba, Córdoba, Argentina

Adrian G. Ciucă,     University Politehnica of Bucharest, Bucharest, Romania

Sarha Cupri,     University of Catania, Catania, Italy

Nily Dan,     Drexel University, Philadelphia, PA, United States

James Davis,     University of Ulster, Jordanstown, Northern Ireland

Gokcen B. Demirel,     Gazi University, Ankara, Turkey

Marek K. Dobke,     University of California San Diego, San Diego, CA, United States

Steven Dominguez,     University of California San Diego, San Diego, CA, United States

Surabhi Dubey,     Dr. H.S. Gour Vishwavidyalaya, Sagar, India

Safaa S. El-Gamal,     Alexandria University, Alexandria, Egypt

Amal H. El-Kamel,     Alexandria University, Alexandria, Egypt

Noha S. El-Salamouni,     Pharos University in Alexandria, Alexandria, Egypt

Serap Evran,     Ege University, Bornova-Izmir, Turkey

Ragwa M. Farid,     Pharos University in Alexandria, Alexandria, Egypt

Virginia Fuochi,     University of Catania, Catania, Italy

Pio Maria Furneri,     University of Catania, Catania, Italy

Dinar Gabdrakhmanov,     A.E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, Kazan, Russian Federation

Allan B. Gamble,     University of Otago, Dunedin, New Zealand

Chityal Ganesh Kumar,     CSIR-Indian Institute of Chemical Technology, Hyderabad, India

Tarun Garg,     ISF Educational Society, Moga, India

Farzaneh Ghasemkhah,     Amirkabir University of Technology, Tehran, Iran

Irina Gheorghe,     Research Institute of the University of Bucharest (ICUB), Bucharest, Romania

Gregory I. Giles,     University of Otago, Dunedin, New Zealand

Amit K. Goyal,     ISF Educational Society, Moga, India

Cristina I. Grecu,     University Politehnica of Bucharest, Bucharest, Romania

Khaled Griesh

University of Otago, Dunedin, New Zealand

Arabian Gulf University, Manama, Kingdom of Bahrain

Alexandru Mihai Grumezescu,     University Politehnica of Bucharest, Bucharest, Romania

Rijun Gui

East China University of Science and Technology, Shanghai

Qingdao University, Qingdao, China

Ufuk Gunduz,     Middle East Technical University, Ankara, Turkey

Mehrdad Hamidi,     Zanjan University of Medical Sciences, Zanjan, Iran

Patrice Hildgen,     University of Montreal, Montreal, QC, Canada

Alina M. Holban

University Politehnica of Bucharest

Research Institute of the University of Bucharest (ICUB), Bucharest, Romania

Fatemeh Jahanmard,     Amirkabir University of Technology, Tehran, Iran

Magdalena Jarosz,     Jagiellonian University in Krakow, Krakow, Poland

Yousef Javadzadeh,     Tabriz University of Medical Science, Tabriz, Iran

Gunjan Jeswani,     Shri Shankaracharya Group of Institutions, SSTC, Bhilai, India

Arvind K. Jha,     Shri Shankaracharya Group of Institutions, SSTC, Bhilai, India

Anjali Joshi,     Panjab University, Chandigarh, India

Joanna Kapusta-Kołodziej,     Jagiellonian University in Krakow, Krakow, Poland

Ruslan Kashapov,     A.E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, Kazan, Russian Federation

Gul Majid Khan,     Quaid-i-Azam University, Islamabad, Pakistan

Sepideh Khoee,     University of Tehran, Tehran, Iran

Filiz Kuralay,     Ordu University, Ordu, Turkey

Gulbin Kurtay,     Ankara University, Ankara, Turkey

Augustine Lalloz,     University of Montreal, Montreal, QC, Canada

Masoud Latifi,     Amirkabir University of Technology, Tehran, Iran

Pierre L. Latreille,     University of Montreal, Montreal, QC, Canada

Hui Li,     Shanghai Jiao Tong University, Shanghai, China

Gina A. Mackert,     University of California San Diego, San Diego, CA, United States

Siddharth S. Matikonda,     University of Otago, Dunedin, New Zealand

Nishi Mody,     Dr. H.S. Gour Vishwavidyalaya, Sagar, India

Somayeh Mohamadi,     University of Environment, Karaj, Iran

Canan Ozyurt,     Ege University, Bornova-Izmir, Turkey

Santiago D. Palma,     National University of Salta-CONICET, Salta, Argentina

Tatiana Pashirova,     A.E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, Kazan, Russian Federation

Swarnali D. Paul,     Shri Shankaracharya Group of Institutions, SSTC, Bhilai, India

Anna Pawlik,     Jagiellonian University in Krakow, Krakow, Poland

Giulio P. Petronio,     IRCCS San Raffaele Pisana, BioBIM—Multidisciplinary Interinstitutional BioBank, Rome, Italy

Rosario Pignatello,     University of Catania, Catania, Italy

Sujitha Pombala,     CSIR-Indian Institute of Chemical Technology, Hyderabad, India

Yedla Poornachandra,     CSIR-Indian Institute of Chemical Technology, Hyderabad, India

Daniela A. Quinteros,     National University of Salta-CONICET, Salta, Argentina

Jean M. Rabanel,     University of Montreal, Montreal, QC, Canada

Goutam Rath,     ISF Educational Society, Moga, India

Soledad Ravetti,     National University of Villa Maria, Córdoba, Argentina

Petre Rotărescu,     University Politehnica of Bucharest, Bucharest, Romania

Harish Sharma,     Shri Shankaracharya Group of Institutions, SSTC, Bhilai, India

Rajeev Sharma,     Dr. H.S. Gour Vishwavidyalaya, Sagar, India

Ruchi Sharma,     Lovely Professional University, Jalandhar, India

Tamilvanan Shunmugaperumal,     Lovely Professional University, Jalandhar, India

Narinder Singh,     Panjab University, Chandigarh, India

Oleg Sinyashin,     A.E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, Kazan, Russian Federation

Magdalena Stevanović,     Institute of Technical Sciences of the Serbian Academy of Sciences and Arts, Belgrade, Serbia

Grzegorz D. Sulka,     Jagiellonian University in Krakow, Krakow, Poland

Haotian Sun,     University at Buffalo, State University of New York, Buffalo, NY, United States

Karolina Syrek,     Jagiellonian University in Krakow, Krakow, Poland

Raja Sekharan Thenrajan,     Sankaralingam Bhuvaneswari College of Pharmacy, Sivakasi, India

Amrit Pal Toor,     Panjab University, Chandigarh, India

Ozge Ugurlu,     Ege University, Bornova-Izmir, Turkey

Gozde Unsoy,     Middle East Technical University, Ankara, Turkey

Gaurav Verma

Panjab University, Chandigarh, India

Massachusetts Institute of Technology, Cambridge, MA, United States

Suresh P. Vyas,     Dr. H.S. Gour Vishwavidyalaya, Sagar, India

Zhiqiang Xie,     Louisiana State University, Baton Rouge, LA, United States

Mehmet Yılmaz,     Sinop University, Sinop, Turkey

Morteza Yaghoobian,     Shahid Beheshti Medical University, Tehran, Iran

Shadi Yaqoubi,     Tabriz University of Medical Science, Tabriz, Iran

Yun Yu,     University at Buffalo, State University of New York, Buffalo, NY, United States

Weien Yuan,     Shanghai Jiao Tong University, Shanghai, China

Lucia Zakharova,     A.E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, Kazan, Russian Federation

Fatemeh Zamani

Amirkabir University of Technology, Tehran

Hazrat-e Masoumeh University, Qom, Iran

Jiuhong Zhang,     Kent State University, Kent, OH, United States

Nan Zhang,     Shanghai Ocean University, Shanghai, People’s Republic of China

Jian Zhong,     Shanghai Ocean University, Shanghai, People’s Republic of China

Foreword of the Series

Material science and engineering at the nanoscale has brought revolutionary advances to the biomedical sciences, overturning many of the traditionally known approaches. Nanotechnology has driven many of the most successful innovative technologies, and the impressive record of accomplishments in the field make nanostructures promising candidates for medical therapy applications. The advantages that nanomaterials have already provided to therapeutics, such as targeted and controlled delivery, wide accessibility, high specificity, low side effects, improved efficiency, and impressive versatility are currently considered key elements in designing personalized medicine approaches for prophylaxis, diagnosis, and therapy.

Therapeutic nanostructures can be greatly diverse, and their unique properties have led to the development of highly specialized biosensors, more efficient drug delivery vehicles, and controlled release targeting systems to fight severe or incurable diseases, such as cancer, infections, and cardiovascular disease.

In view of the astounding progress made in the field of therapeutic nanotechnology and its rapidly progressing expansion, this book aims to collect in one place all the recent and most innovative aspects of nanomaterials in both current and future therapy. The series is organized into five volumes, covering the main areas that are relevant for the design and implementation of nanostructures in medical therapies.

The first volume, Nanostructures for Novel Therapy: Synthesis, Characterization, and Applications, describes methods to obtain and characterize nanosystems, emphasizing their biomedical applications. Special attention is paid in this volume to modern synthesis methods to reduce side effects and limit the toxicity of nanomaterials in biomedical applications. Numerous examples of nanostructures designed for therapy, as well as the most efficient synthesis and characterization routes for these materials, are clearly described and critically analyzed.

The second volume, entitled Nanostructures for Drug Delivery, covers one of the most widely utilized and investigated applications of nanomaterials in the biomedical field, namely, drug delivery. Designing nanostructures to specifically and safely carry therapeutic agents to their final destination is an intriguing approach to future targeted therapies. This approach could provide a treatment for previously incurable diseases, as well as reducing the side effects of current drugs. Many highly active drugs are severely limited by side effects related to their unspecific sites of action. This volume introduces the readers to the amazing field of nanomedicine by discussing the versatility and variety of nanovehicles for drug delivery and targeting. Moreover, readers will find numerous examples and will learn about the currently used or investigational drug delivery agents for therapy, prophylaxis, and diagnosis.

Volume 3, Nanostructures for Antimicrobial Therapy, highlights the impressive progress made by nanotechnology in the design of novel antimicrobial approaches. Since microbial resistance to antibiotics is a real and increasingly worrying issue across all countries, the development of more efficient antimicrobial agents to provide control of future infections is at a high priority. Antimicrobial nanosystems have proved to be remarkably efficient against drug-resistant microorganisms, plus they are able to fight biofilm-associated infections and can control the social behavior of microbial communities. Nanostructures can also reduce microbial virulence factors and reduce pathogenesis mechanisms, offering a promising alternative for future therapy.

Volume 4, entitled Nanostructures for Cancer Therapy, covers the applications of nanomedicine in cancer diagnosis and treatment. The use of nanoparticles for cancer therapy is not in itself a new approach, but numerous recent advances have been made in this area. The aim of this volume is to cover the most interesting new approaches in the management of this deadly disease. Nanosized drugs are currently believed to represent the most efficient approach in cancer chemotherapy, and this volume provides coverage of the latest and most novel findings, while also discussing possible improvements in more established types of nanosystems that can increase the efficiency of cancer therapy.

The final volume of this series, entitled Nanostructures for Oral Medicine, covers the progress made in applications of nanotechnology in treating various diseases of the oral cavity as well as progress in nanotechnology applications in dentistry. Readers can learn about the most efficient modern materials used to treat or to prevent widely encountered oral diseases such as gingivitis, periodontitis, caries, and dental plaque. Moreover, restorative dentistry also now makes wide use of nanomaterials.

Overall, this book series provides a state-of-the-art compendium of knowledge, and a crystal ball for seeing into the future of biomedical nanotechology and nanomedicine. It has appeal for researchers, clinicians, engineers, pharmacologists, pharmacists, oncologists, infectious disease experts, and dentists. In addition, interested general readers will discover the impact, current progress, and future applications of nanotechnology in therapeutics and diagnosis. Taken together, nanoscale approaches will improve the efficiency of personalized medicine for better management of diseases in the 21st century.

Michael R. Hamblin

Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, United States

Department of Dermatology, Harvard Medical School, Boston, MA, United States

Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, United States

Preface

About the Series (Volumes I–V)

In our permanently changing world, novel therapeutics are constantly required to manage health and well-being of population. Although numerous diseases are currently considered incurable, massive progress made in biomedicine but also in associated fields, such as chemistry, physics, engineering, pharmacology and materials science, offers a new light to the therapeutics domain. In this context, most physicists and researchers believe that a personalized and adequate treatment may significantly improve the outcome of severe diseases and ensure a faster healing. Nanotechnology offers great perspectives for personalized medicine because nanostructured therapeutics proved their efficiency and amazing impact in improving therapy, prophylaxis, and diagnosis. The emerging field of nanosized materials has numerous applications in the biomedical field, especially in therapy. This series of five volumes came out by the need of learning about recent progress of the science of nanostructured materials to improve current therapy and lead to the next level. The books offer an interesting and updated perspective regarding applications of nanomaterials in therapy of most investigated and difficult-to-treat diseases, such as cancer and severe infections. The presentation approach of each chapter contained in those five volumes is clear and easy to understand by most readers and of a great interest for biomedical specialists, researchers, and engineers. The series is organized in an attractive manner for students and academics on the field, starting with a volume dealing with synthesis, characterization, and main applications of nanostructures, emphasizing on their impact in therapy. Next volume reveals the most recent progress made on a very investigated field, considered a key element in personalized medicine and future therapy, namely nanostructured drug delivery systems. Their impact in antimicrobial therapy is also widely discussed, and suggestive examples are given and explained. Moreover, a whole volume is dedicated to the management of the disease of the century—cancer—revealing the huge value added by the utilization of nanosystems in the therapy of this deadly disease. Important aspects related to improved diagnosis and prophylaxis are highlighted. In the last volume, the progress and novel applications of nanotechnology in oral medicine is dissected. The field of oral diseases represents an interesting and a priority field because both physicists and researchers believe that they can be prevented and treated more easily with targeting systems and nanofunctional prosthetics. All chapters are clearly illustrated to highlight most important or difficult-to-understand aspects, and suggestive examples are often enumerated in organized tables, which are explained and discussed. Overall, the series contains very recent but accessible and very interesting information regarding the progress of nanostructures in therapeutics and gives a novel perspective about future therapy of severe diseases.

Alexandru Mihai Grumezescu

University Politehnica of Bucharest, Bucharest, Romania

About Volume II

The second volume of the series Therapeutic Nanostructures is entitled Nanostructures for Drug Delivery. This volume reveals the main types of nanosized drug delivery systems, dissecting their main advantages and drawbacks in the therapy of severe and difficult-to-treat diseases. Nanosized carriers are commented in all stages of their preparation and use, starting with suitable synthesis methods, appropriate characterization, and functionalization, and ending with their application in drug delivery and therapy. A special attention is given to green nanotechnology which enables the production of natural, biocompatible and less toxic nanosystems which may be efficiently used in delivering pharmacological agents. Numerous properties of such drug delivery systems are highly appreciated for future therapy, namely longtime circulation in the bloodstream, target specificity, stimuli responsively, possibility of intracellular delivery, contrast functionality, and increased stability. Different ways for the control of the load capacity and release profile are also analyzed in many of the chapters.

Volume II contains 30 chapters, prepared by outstanding researchers affiliated in the USA, Canada, Argentina, Ireland, Italy, New Zealand, Poland, Serbia, Romania, Russia, Turkey, Egypt, Iran, Pakistan, India, and China.

In Chapter 1, entitled Therapeutic Nanomaterials: From a Drug Delivery Perspective, C. Ganesh Kumar et al. focus on the synthetic routes and applications of nanomaterials as potential drug delivery agents. Different nanomaterial types including polymeric nanomaterials, dendrimers, nanoparticles, carbon nanotubes, quantum dots, and their applications have been discussed and a number of case studies have been presented in this chapter.

Nily Dan, in Chapter 2, entitled Core–Shell Drug Carriers: Liposomes, Polymerosomes, and Niosomes, reveals the three types of main formulations used as drug nanocarriers and summarizes studies of their performance in biomedical applications such as cancer therapy (tumor targeting) or transport through the blood–brain barrier.

Chapter 3, entitled The New Nanocarriers Based on Graphene and Graphene Oxide for Drug Delivery Applications, prepared by Somayeh Mohamadi and Mehrdad Hamidi, gives an overview about a new carbon-based carrier for drug delivery applications. The unique properties of graphene nanosheets such as two-dimensional planar structure with sp² hybridation, large surface area, chemical and mechanical stability, super conductivity, and good biocompatibility provide the opportunity to design drug carriers with dual-targeting function.

In Chapter 4, entitled Nanostructured Nanoparticles for Improved Drug Delivery, Jean Michel Rabanel et al. provide a comprehensive view of the different types of structures found in nanoparticles intended for medical use reported so far in the literature, together with some insight regarding their fabrication processes and their physicochemical properties and how this nanoparticles deliver active compounds in a controlled fashion to the human body or developed imaging strategies.

Chapter 5, entitled Design of Functionalized Materials for Use in Micro and Nanoscale Drug Delivery Devices and Smart Patches, prepared by Ashleigh Anderson and James Davis, provides a critical overview of the latest developments in functional materials and nanoscale device architectures that can facilitate controlled drug delivery.

Chapter 6, entitled Niosomes: A Novel Approach in Modern Drug Delivery Systems, prepared by Sepideh Khoee and Morteza Yaghoobian, discusses about new drug delivery vehicles and gives a brief description on the preparation, applications, advantages and disadvantages of particular delivery system—niosomes.

Fatemeh Zamani et al., in Chapter 7, entitled Nanofibrous and Nanoparticle Materials as Drug-Delivery Systems, emphasize on the emerging area of nanoparticles synthesis through electrospinning technique to generate biomimetic nanofibers and nanoparticles as drug delivery devices that are responsive to different stimuli, such as temperature, pH, light, and the electric/magnetic field for controlled release of therapeutic substances.

Yun Yu et al., in Chapter 8, entitled Brush Polymer-Based Nanostructures for Drug Delivery, give an overview on the advantages of brush polymer (BP)-based drug delivery systems. Also, future research directions of BP-based drug delivery systems are highlighted.

Magdalena Jarosz et al., in Chapter 9, entitled Drug Delivery Systems Based on Titania Nanostructures, focus on different titanium (TiO2) nanostructures used as drug delivery systems, such as nanotubular and nanoporous TiO2, TiO2 nanoparticles, and nanowhiskers.

Houman Alimoradi et al., in Chapter 10, entitled Redox Activated Polymeric Nanoparticles in Tumor Therapy, focus on the biochemical basis for oxidative stress in tumors, its role in cell-signaling, the pathophysiology of tumor vasculature, and the differences in the redox-metabolism between cancer cells and nonmalignant tissues. The recent developments toward designing redox responsive drug delivery systems which have been classified as polysulfide, polyselenide, quinones, metal complexes, arylboronic esters, aryl oxalate, and other miscellaneous examples are also discussed.

Chapter 11, entitled Polymeric Micro- and Nanoparticles for Controlled and Targeted Drug Delivery, prepared by Magdalena Stevanović, reports the production and applications of polymeric micro- and nanoparticles with a special emphasis on obtaining polyester particles, the incorporation of different active substances within polymer matrix, the degradation and release process of active substances from the polymeric particles, the physiochemical and biological properties of such obtained systems, as well as their application as drug delivery systems.

Chapter 12, entitled Novel Gels: Implications for Drug Delivery, prepared by Swarnali D. Paul et al., describes all the emerging prospects of novel gels along with their formulation aspects, manufacturing technologies, and current applications, focusing on therapeutic potential.

Chapter 13, entitled Nanosuspension Drug Delivery System: Preparation, Characterization, Postproduction Processing, Dosage Form, and Application, prepared by Jiuhong Zhang et al., gives an overview about nanosuspension drug-delivery system (DDS) discussing preparation methods, characterization methods, postproduction process including the solidification techniques and surface modification process, common dosage forms, and clinical applications of nanosuspension DDS.

Chapter 14, entitled Polymer-Based Nanocarriers for Therapeutic Nucleic Acids Delivery, prepared by Weien W. Yuan and Hui H. Li, describes the challenges, advantages, and recent progress of polymer-based nanocarriers for therapeutic nucleic acids delivery. Considerations for manufacturing, safety issues, and regulatory requirements for these novel nanocarriers are also discussed.

Chapter 15, entitled Multifunctional Therapeutic Hybrid Nanocarriers for Targeted and Triggered Drug Delivery: Recent Trends and Future Prospects, prepared by Gulbin Kurtay et al., presents new generation and promising hybrid nanocarriers based on noble metal, porous silica, polymer, and core/shell therapeutics which exhibit active targeting, triggered release of cargo, and imaging capability for in vivo studies.

Ragwa M. Farid et al., in Chapter 16, entitled Lipid-Based Nanocarriers for Ocular Drug Delivery, give an up-to-date overview about lipid-based nanocarriers that can enhance the corneal absorption of both hydrophilic and lipophilic drugs and improve their ocular bioavailability. Nanostructured lipid carriers (NLCs) and lipid drug conjugates (LDCs) have emerged as a new generation of solid lipid nanoparticles (SLNs) to overcome problems of low entrapment efficiency and drug expulsion during storage.

Rajeev Sharma et al., in Chapter 17, entitled Nanoparticulate Carrier(s): An Emerging Paradigm in New Generation Vaccine Development, summarize the cutting edge technologies of nanoparticulate-carrier-based new generation and vaccine development, including design, trials, and clinical outcomes.

Chapter 18, entitled Pathogen-Specific Nucleic Acid Aptamers as Targeting Components of Antibiotic and Gene Delivery Systems, prepared by Canan Ozyurt et al., presents an overview of current cell-specific aptamer-conjugated nanoparticles. Also, the authors address two issues: nanoparticle-based antimicrobial gene delivery and modification of nanocarriers with aptamers.

Tamilvanan Shunmugaperumal et al., in Chapter 19, entitled Multifunctional Nanosized Emulsions for Theragnosis of Life Threatening Diseases, envision the use of the multifunctional oil-in-water (o/w) nanosized emulsions (NE) that carries imaging agents, anticancer or lipid lowering or antiatherosclerotic drug molecules and homing devices together for simultaneous imaging/diagnosing and treatment of cancer and atherosclerosis. A complete outline is given on the formulation of drug-loaded NE together with active and passive targeting moieties for accessing the unreachable organs present inside the human body.

Chapter 20, entitled Therapeutic Nanostructures for Pulmonary Drug Delivery, prepared by Yousef Javadzadeh and Shadi Yaqoubi, discusses about pulmonary drug delivery, inhalers, nanoparticles, and the advantages and fate of inhaled nanoparticles.

Najma Bibi et al., in Chapter 21, entitled Nanostructures in Transdermal Drug Delivery Systems, dissect the benefits of transdermal drug delivery over other delivery systems, arguing about the barriers in the skin to be faced by nanomaterials and their permeation pathways. Physicochemical characteristics required for the good penetration of nanostructures are also discussed.

Chapter 22, entitled Advancement in Pulmonary Drug Delivery Systems for Treatment of Tuberculosis, prepared by Tarun Garg et al., presents an overview about the importance of pulmonary drug delivery systems such as liposomes, niosomes, nanoparticles, microparticles, dendrimers, solid lipid nanoparticles, micelles, nanosuspensions, nanoemulsions, and microemulsions for an effective treatment of tuberculosis. The advances in delivery devices from conventional metered dose inhalers to dry powder inhalers are also discussed along with their applications.

Chapter 23, entitled Nanosized Devices as Antibiotics and Antifungals Delivery: Past, News and Outlook, prepared by Pio M. Furneri et al., discusses about developments in the field of (nanosized) delivery systems encapsulating antibacterial and antifungal drugs. A specific attention has been given to the pharmaceutical, microbiological, and clinical outcomes of systems for which authors have provided in vitro microbiological data and, more hopefully, in vivo results.

Chapter 24, entitled Drug Delivery Mediated by Confined Nanosystems: Structure-Activity Relations and Factors Responsible for the Efficacy of Formulations, prepared by Lucia Zakharova et al., presents different ways for the control of the load capacity and release profile. The chapter also discusses about the ability of formulated drug to integrate with cell membrane and penetrate through the blood-brain barrier.

Daniela Alejandra Quinteros et al., in Chapter 25, entitled Therapeutic Use of Monoclonal Antibodies: General Aspects and Challenges for Drug Delivery, identified and described the major issues associated with therapeutics approaches, formulating drawbacks, and delivering antibody drugs, particularly focused on the challenges and opportunities that these present for the future.

Chapter 26, entitled Targeted Drug Delivery Via Chitosan-Coated Magnetic Nanoparticles, prepared by Gozde Unsoy and Ufuk Gundu, presents an up-to-date review about polymer-coated magnetic nanoparticles, characterized by high surface-to-volume ratios, which are excellent scaffolds for loading targeting moieties, permeation enhancers, imaging tags, and drugs, simultaneously providing diagnostic and therapeutic capabilities.

Narinder Singh et al., in Chapter 27, entitled Drug Delivery: Advancements and Challenges, elaborate an updated idea regarding the effect of various drug delivery systems in contrast to their toxicity with a focus on nanocarriers and nanosystems.

Chapter 28, entitled Stimuli-Responsive Liposome and Control Release Drug, prepared by Xueqin An and Rijun Gui, presents an up-to-date review about the relative thermal, light, magnetism, and pH stimuli responsive properties of liposomes. Also, the mechanism of controlled drug release is discussed.

Chapter 29, entitled Nanotechnology to Enhance Transdermal Delivery of Hydrophilic Humectants for Improved Skin Care: A Model for Therapeutic Applications, prepared by Steven Dominguez et al., presents current status on research and development of some of the most promising agents, including nanotropocollagen and hyaluronic acid, which can serve as models for nanotechnology employed for transcutaneous active pharmaceutical ingredients (APIs) delivery.

Chapter 30, entitled Nanostructures for Drug Delivery: Pharmacokinetic and Toxicological Aspects, prepared by Adrian G. Ciucă et al., offers an extensive and updated report of the recent progresses and degree of toxicity that could be generated by a number of new medical therapies, with a great impact on medicine, namely therapeutic devices based on nanoparticles.

Ecaterina Andronescu

University Politehnica of Bucharest, Bucharest, Romania

Alexandru Mihai Grumezescu

University Politehnica of Bucharest, Bucharest, Romania

Chapter 1

Therapeutic nanomaterials: from a drug delivery perspective

Chityal Ganesh Kumar

Yedla Poornachandra

Sujitha Pombala    CSIR-Indian Institute of Chemical Technology, Hyderabad, India

Abstract

Limitations in conventional chemotherapy have resulted in efforts to develop a good drug delivery system for the treatment of several diseases. Many promising drugs that were identified failed to reach the market due to associated drug delivery problems. The ultimate aim of drug delivery systems is to tailor-make the drug formulation to meet the individual requirements under the control of pathophysiological or in vivo conditions, rather than the in vitro characteristics. However, a challenge remains to develop cost-effective, better, and safer nanomaterials for efficient drug loading and controlled drug release. In the recent past, several nanomaterials have been identified with appreciable biocompatibility and therapeutic properties. This chapter focuses on the subject of nanomaterials with regard to their synthetic routes and application as potential drug delivery agents. Different nanomaterial types, including polymeric nanomaterials, dendrimers, nanoparticles, carbon nanotubes, and quantum dots, have been discussed and a number of case studies have been presented.

Keywords

nanotechnology

nanoscience

nanomaterials

drug delivery

nanoparticles

dendrimers

polymers

quantum dots

antimicrobial

therapeutics

Chapter Outline

1 Introduction

2 General Methods of Synthesis of Nanomaterials

2.1 Physical Methods

2.2 Chemical Methods

2.3 Biological Methods

3 Characterization of Nanomaterials

4 Applications of Nanomaterials for Drug Delivery

4.1 Polymeric Nanomaterials

4.2 Polymeric Micelles

4.3 Dendrimers

4.4 Polysaccharide-Based Nanomaterials

4.5 Nanoparticles

4.6 Carbon Nanotubes

4.7 Quantum Dots

5 Conclusions

References

1. Introduction

Nanotechnology is an emerging interdisciplinary field having confluence of various disciplines, such as physics, chemistry, material science and engineering devoted to the construction of structures in the nanometer regime (often 100 nm or smaller) with diverse physical and chemical properties. Although nanoscience and nanotechnology are new research areas, the use of nanomaterials by mankind was known since antiquity. Red colloidal gold tinctures as drugs for longevity, the so-called Makaradhwaja and Jin Tu were used in India and China, respectively, since ancient times (Hayat, 1989; Mahdihasan, 1985). The use of noble nanomaterials by glassmakers dates back to the Roman Empire, which is evidenced by the exotic Lycurgus Cup of 4th century AD that exhibited dichroic effect due to the presence of colloidal silver and gold particles (Barber and Freestone, 1990). Similar examples exist on the use of noble metallic nanomaterials in stained-glass windows of old European cathedrals and for coloring ceramic vases and ornaments by the Chinese (Burda et al., 2005). In the early 19th century, antibacterial preparations based on colloidal silver, such as Collargol (Argentum Crede) and Protargol (Argenti proteinatum) were marketed in Europe (Kolthoff, 1925). Paul Ehrlich first presented the concept of drug targeting or site-specific drug delivery in 1909. The magic bullet concept was put forth by him and his colleagues when they synthesized the first man-made antibiotic, arsphenamine, for the treatment of syphilis. This molecule after some chemical modifications inhibited the pathogens without affecting the host cells and acted as a magic bullet. Furthermore, he also introduced the concepts, such as chemoreceptor and chemotherapy, and linked the chemical structure of the compound to their pharmacological activity (Bosch and Rosich, 2008).

In 2004, the concept of nanomedicine was put forth by the European Science Foundation, which represents a new area in the field of drug delivery research (Reis et al., 2007). A significant attention has been focused on the potentials of nanoscience and nanotechnology in drug delivery because they offer site-specific, time-controlled delivery of different molecular weight drugs and other bioactive molecules. The concept of drug delivery as a noninvasive system has recently emerged as a highly competitive and fast developing technology for treating medical infections and diseases. In this context, the nanomediated drug delivery systems, such as nanoparticles, dendrimers, carbon nanotubes, quantum dots, and so on are believed to have great potential to develop various drug carrier systems to address the growing burden of new diseases. One of the main challenges in drug delivery is to deliver the drug at the target site in the body to avoid potential side effects to the normal tissue. These nanomaterials can be modified for better efficiency to facilitate a large amount of drugs through nanocarriers, which can eventually reach the inaccessible areas, such as brain tissues, cancer cells, and other infected tissues. According to BCC Research Report (www.bccresearch.com/market-research/pharmaceuticals/advanced-drug-delivery-markets-phm006j.html), the global market for advanced drug delivery systems was valued at $151.3 billion in 2013. It was forecasted that this market value will rise to reach nearly $173.8 billion in 2018 at a 5-year compound annual growth rate of 2.8%. To meet this remarkable global demand, the synthesis of nanomaterials for diverse drug delivery applications has been a burgeoning area of research in the field of nanotechnology. This chapter focuses on the synthetic routes and characterization of various nanobiomaterials, and their drug delivery applications have been reviewed.

2. General Methods of Synthesis of Nanomaterials

Two types of approaches are generally applied for the fabrication of different types of nanomaterials (Fig. 1.1), namely the top–down approach, a process of stable division of bulk material into nanoparticles and the bottom–up approach, in which the nanoparticles are built up from the atomic level to nanolevel through clusters (Fig. 1.2). In top–down approach, the dissolution of metal from its respective bulk material is the basic principle. Several methods adopted in the top–down approach include laser ablation, solvated metal atom dispersion (Lin et al., 1986), high vacuum evaporation (Aiyer et al., 1994), electric arc reduction (Bradley, 1994), and electrochemical reduction (Reetz and Helbig, 1994). The combination of atoms or clusters to form nanoparticles is called bottom–up approach, which has gained popularity in recent years because there is a precise control over size and monodispersity of the nanoparticles (Toshima and Yonezawab, 1998). In this method, different reducing agents, such as sodium borohydride, trisodium citrate, tannic acid, hydrazine, ascorbic acid, and tartaric acid were used to reduce the metal ions to form nanoparticles (Cushing et al., 2004). Metal nanoparticles, such as Au, Ag, Pt, Pd, and Rh can be prepared using mild reducing agents under ordinary conditions. The synthetic strategies of nanomaterials integrate both synthesis and assembly into a single method with better control over size, shape, and structure. The size, morphology, stability, and other properties of the nanomaterials are strongly influenced by the experimental conditions, interaction of reducing agents, and stabilizing agents. Therefore, the selection and design of a synthetic route plays a key role for determining the properties, stability, and applications of nanomaterials (Sharma et al., 2009). Currently, the techniques available for the production of nanomaterials essentially fall into three categories, such as physical, chemical, and biological methods.

Figure 1.1   Different Types of Nanomaterials

Figure 1.2   Top–Down and Bottom–Up Approach for Nanomaterial Synthesis

2.1. Physical Methods

A wide range of nanoparticles can be produced using different metals by employing physical methods with minor modifications. Several physical methods, such as sputter deposition, laser ablation or cluster beam deposition, microwave, evaporation–condensation, mechanical milling and pulsed wire discharge (PWD) are employed for the nanomaterial fabrication. Laser ablation and ball milling are the most commonly used methods for the preparation of nanoparticles using different kinds of solvents (Marine et al., 2000). However, the major limitation is that it is very difficult to produce ultrafine particles using these methods. Further, the physical synthetic methods involve costly equipments or vacuum systems for the preparation of nanomaterials. In case of mechanical milling, the main advantages are the simple operation, low cost of production and the possibility to scale up the process to produce large quantities (McCormick and Froes, 1998). Further, the important factors that affect the quality of the nanoparticles include the mill type, milling speed, temperature, time, atmosphere, shape, and size distribution of the grinding medium, weight ratio of ball to powder and the amount required for filling the vial (Suryanarayana, 2001). Sonolysis is also an efficient method for the synthesis of nanomaterials. For example, the iron oxide nanoparticles can be synthesized by decomposition (thermolysis or sonolysis) of organometallic precursors. Very high temperature hot spots generated by the rapid disintegration of sonically generated cavities allows the conversion of ferrous salts into magnetic nanoparticles. In this case, the different polymers, organic stabilizing agents, or structural hosts are used to limit growth of the nanomaterial (Dinega and Bawendi, 1999; Osuna et al., 1996; Puntes et al., 1999;  2002; Verelst et al., 1999). Some of the major advantages of physical methods include the use of no toxic chemicals, it is comparatively fast, lack of solvent contamination and the uniformity of nanomaterial distribution; however, the major disadvantage of these methods is the lesser quantity and poor quality of the nanomaterials produced as compared to chemical methods. These methods are also time-consuming and still under developmental stage.

2.2. Chemical Methods

Various chemical approaches have been employed for the fabrication of large amounts of nanomaterials within a shorter time period with fairly good control on the size distribution. Using chemical synthetic routes, different shapes of nanomaterials could be achieved by adjusting the concentration of the reacting chemicals and controlling the reaction environment (Murray et al., 2000). For metal nanoparticle synthesis, the most common approach employed is the chemical reduction method, which involves the reduction of an ionic metal salt in an appropriate medium in the presence of reducing agents. Different organic and inorganic reducing agents, such as sodium citrate, ascorbic acid, sodium borohydride, dimethylformamide, have been used for the reduction of metal ions in aqueous or nonaqueous solutions. For example, in citrate reduction method, the reducing agent (citrate) reduces Au+ ions resulting in the formation of colloidal gold (Au⁰), followed by aggregation into oligomeric clusters, which eventually leads to size distribution and the formation of Au⁰ nanoparticles (Turkevich et al., 1951). During synthesis, the capping agents play a key role in the stabilization of nanomaterials to prevent their aggregation (Oliveira et al., 2005).

Different polymers, such as polyethylene glycol (PEG) and poly(lactic-co-glycolic acid) copolymer (PLGA) and its derivatives are employed for the chemical synthesis of polymeric nanomaterials. Nanoprecipitation (solvent deposition) and oil/water emulsion are some of the methods used for the fabrication of functional (polyCOOH, polyCONHOH) polymeric nanoparticles using PLGA–COOH/PLGA–PEG–COOH polymers of different molecular weights (10–45 kDa). Some of the important methods employed for the fabrication of polymeric nanomaterials are depicted in Fig. 1.3. Dendrimers are highly branched three-dimensional nanostructures finding a wide range of therapeutic applications. Their synthesis interfaces between molecular and polymer chemistry methods. The fabrication of dendrimers involves the step-by-step controlled synthesis, and they relate to the polymer chemistry due to their repetitive structure comprising of monomers (Bosman et al., 1999; Frechet and Tomalia, 2001; Majoral and Caminade, 1999; Newkome et al., 2001). During the synthesis process, the dendrimer grows outward from a multifunctional core molecule. The core molecule reacts with monomers containing one reactive and two dormant molecules, resulting in the first-generation dendrimer. Later, the new fringe of the molecule is activated for reactions with further monomers. However, for the fabrication of dendrimers, two major synthetic strategies are employed, including divergent and convergent approaches. Both these strategies have relative advantages and disadvantages and the appropriate synthetic route depends mainly on the kind of monomer used and the target polymer structure (Kawaguchi et al., 1995; Labbe et al., 1996). Some of the major disadvantages observed with the use of chemical methods are the cost, energy intensive process, and toxic chemicals that are used as reducing agents, organic solvents used to generate hazardous waste that are potentially harmful to the environment and to biological systems.

Figure 1.3   Different Methods Employed for the Synthesis of Polymeric Nanoparticles

2.3. Biological Methods

Currently, with the renewed interest in implementation of green chemistry principles for the fabrication of nanomaterials for obtaining sustainable processes, minimization of waste, and environment-friendly for which simple strategies would be desirable. The synthesis of nanomaterials using biological methods has played a vital importance from a medicinal and technological perspective (Kattumuri et al., 2007; Zhang et al., 2007a). The secrets were originally inspired from nature, which has led to the development of biomimetic methods and advanced nanomaterials. Some of the notable examples are the formation of magnetic nanoparticles by magnetotactic bacteria (Moon et al., 2007) and biosilicification of silica nanospheres by diatoms (Kröger et al., 1999). Since the past few decades, the prokaryotic members were the only candidates being exploited for the capability to reduce insoluble toxic metal ions to soluble nontoxic metal salts due to their valence changes. However, in the recent past, it was observed that highly evolved organisms, such as plants, algae, diatoms, and other components of eukaryotes exhibited the reducing potential to convert the metal ions to metal nanoparticles. The major advantages of nanomaterial synthesis through biological approaches include its rapid synthesis at ambient temperatures, neutral pH, controlled size and morphology, less toxicity, and improved biocompatibility. Biodirected synthesis of metal nanoparticles has gained renewed attention, which uses different biomaterials such as enzymes, phytochemicals or other metabolites with reducing properties derived from various natural sources, such as plants, fungi, yeasts, actinomycetes, and bacteria as both reducing and stabilizing agents (Mohanpuria et al., 2008).

Plants are one of richest sources of natural products, including therapeutically useful compounds. Plants have evolved in the presence of natural nanomaterials. Nevertheless, the probability of plant exposure to nanomaterials has increased to a greater extent with the ongoing increase in the production and use of fabricated nanomaterials. Natural products of plant origin represent one of the most enduring approaches to achieve this target. The presence of diverse secondary metabolites, such as enzymes, proteins, and/or other reducing agents with electron-shuttling compounds, is usually employed in the fabrication of nanoparticles by plant metabolites (Akhtar et al., 2013). The role of plant metabolites for nanomaterial synthesis is directly related to the mechanisms of nanotechnology and green chemistry (Song and Kim, 2008). Several researchers reported that the use of dried leaves, buds, or other plant parts cut into pieces and extracted with different organic solvents resulted in different plant extract fractions. These extracts were incubated with the metal salts under the determined experimental conditions. The plant metabolites present in these extracts served as both reducing and stabilizing agents. The synthesized nanomaterials were reported to have different morphological shapes such as spherical, hexagonal, and triangular, which are mainly dependent on the chemical composition of the extract, concentration, and pH of the medium.

The biological synthesis of nanomaterials from living organisms, such as bacteria, fungi, and plants has huge potential and is encouraged due to the ease in rapid synthesis, controlled toxicity, control over size characteristics, reasonable, and an environment-friendly approach. Microbes can biosynthesize the nanomaterials by grasping target ions from their surrounding environment and then convert the metal ions into the elemental metal through cellular enzymes or metabolites. According to the location of nanoparticle formation they are classified into intracellular and extracellular synthesis (Faivre and Schüler, 2008; Roh et al., 2006). These microbial systems functioning as nanofactories have been investigated for different nanomaterial fabrication using metals, such as gold, silver, platinum, zirconium, zinc, cadmium, and iron (magnetite), which are available as oxides or metallic forms. The nanomaterial synthesis is based on the change of the oxidation state of the element either oxidation or reduction of the metal atoms. The synthesis procedure involves the mixing of metal precursors with the reactants present in crude or partially purified extracts derived from the cell-free supernatants under distinct experimental conditions. In addition, the synthetic conditions, such as pH, temperature, concentration, and reaction time need to be optimized to control the nanomaterial synthesis to obtain the desired size and morphology (Kumar et al., 2010). Biomolecules can also be exploited for the synthesis of metal nanoparticles. The synthesis of hybrid nanomaterials can be achieved using molecular precursors in the presence of biological templates (e.g., DNA, proteins) (Cauerhff and Castro, 2013). Most commonly involved biomolecules are viruses, proteins, peptides, and enzymes. Very few reports are available on the nanoparticle synthesis using this approach. Biomolecules with three-dimensional structures and vast diversity have several advantages and by using these precursors, the nanomaterial synthesis can possess several different characteristics and properties.

3. Characterization of Nanomaterials

The characterization of nanomaterials is important to understand the physicochemical properties that determine their application in diverse research fields. After fabrication of nanomaterials, a series of analytical and imaging techniques are employed for the characterization of the prepared nanomaterials. The solubility, size, morphology, surface charge, surface chemistry, and surface plasmon resonance are the important physicochemical properties of the nanomaterials (Elzey and Grassian, 2010). Usually the nanomaterial properties differ in its size and shape, so the accurate measurement of size and shape is critical for their biomedical applications. The optical properties of nanomaterials are determined based on the measurement of surface plasmon resonance (Kreibig and Vollmer, 1995). In case of metal nanoparticles, the maximum absorbance, which determines the surface plasmon resonance, lies in the ultraviolet region of the electromagnetic spectrum. In the case of gold and silver nanoparticles, the resonance spans within the visible region because of interband transitions (Kumar et al., 2010). This absorption wavelength can be confirmed using UV-visible spectroscopy to identify the type of metal in the sample or to study any changes in the surrounding medium of the nanomaterials (Kreibig and Vollmer, 1995). Scanning electron microscopy (SEM), transmission electron microscopy (TEM), and high resolution transmission electron microscopy (HRTEM) are the different imaging techniques employed to determine the morphological characteristics of the nanomaterials. SEM generates high-resolution images of surface morphology of the different nanomaterials (Joshi and Viswanathan, 2006). TEM has much higher resolution as compared to traditional light microscopy since short wavelength of highly energetic electron beams are used to obtain images of the object under study (Williams and Carter, 1996). HRTEM is a high-magnification imaging mode of the transmission electron microscope that allows the high resolution imaging of the crystallographic structure of the nanomaterials at atomic scale level (O’Keefe et al., 1978). Atomic force microscopy (AFM) is one of the most popular tools to illustrate the material surfaces at nanoscale level. The principles, instrumentation aspects, and the applications of AFM to study the structural and physical properties of nanostructures, nanofibers, and for nondestructive characterization of textile materials are very well described (Dufrêne, 2002; Jalili and Laxminarayana, 2004).

The infrared spectrum of the nanomaterials is recorded using a Fourier transform spectrometer, employed for the identification of functional groups of the capping/stabilizing agents used in the synthesis of the nanomaterials (Silverstein et al., 2005). Similar to infrared spectroscopy, the Raman scattering can be used for the identification and quantification of the molecule (Eliasson et al., 2001). Surface-enhanced Raman scattering (SERS) is a powerful tool to obtain the signal from fluorescent chromophores (Nabiev et al., 1994). In SERS, an increased intensity at the near-field excitation was observed at the location of the analyte, which is adsorbed to the noble metal. It was recorded that the net surface enhancement increases by 10-order of magnitude (Bjerneld et al., 2000; Xu et al., 1999). Inductively coupled plasma-mass spectrometry (ICP-MS) is a sensitive analytical tool used for the quantification at a lower concentration (in parts per trillion) of both metals (Moldovan et al., 2004) and nonmetals (Wuilloud and Altamirano, 2006) used in the nanomaterial synthesis. ICP-MS is superior over other elemental analytical techniques, such as atomic absorption spectrometry (AAS) and inductively coupled plasma–optical emission spectrometry (ICP–OES), in view of its shorter measurement time, rapid sample processing and superior detection capabilities (Nelms, 2005). X-ray photoelectron spectroscopy (XPS) is used to analyze the atomic composition, chemical state, and electronic state of the elements present on the nanomaterial surfaces. It is also termed as electron spectroscopy for chemical analysis (ESCA) (Azoulay, 1983). Energy dispersive X-ray spectroscopy (EDX) analysis is used to determine the surface elemental composition and provides an overall metal profiling of the sample (Russ, 1984). Dynamic light scattering (DLS), also termed as photon correlation spectroscopy (PCS), is based on light scattering, which is used to determine the average particle size and charge of the nanomaterials (Berne and Pecora, 2000). Zeta potential measurement helps to understand the stability of the nanoparticles in a suspended medium that is dependent on the repulsion forces between the particles. The zeta potential is an indirect measurement of the overall surface charge that the particle acquires in a particular medium (Hunter, 1988). X-ray diffraction (XRD) analysis provides structural information of the crystalline nanomaterials. This technique is used for the identification and characterization of nanomaterials based on their diffraction pattern (Cullity and Stock, 2001).

4. Applications of Nanomaterials for Drug Delivery

Drug delivery is a method or process of administering a pharmaceutical compound or a drug to achieve a therapeutic effect in humans or animals. The ultimate aim of drug delivery systems is to tailor-make the drug formulation to meet the individual requirements under the control of pathophysiological or in vivo conditions rather than the in vitro characteristics (Brannon-Peppas, 1995). Such delivery systems offer several advantages including improved efficacy, reduced toxicity, and improved patient compliance and convenience as compared to conventional dosage forms. Several drug delivery systems have been formulated and investigated for drug delivery through different routes of administration. In contrast to the traditional dosage forms, novel drug delivery systems aim to deliver the drug at a rate directed by the needs of the body during the treatment period, and channel the bioactive entity to the site of action thereby reducing the side effects in other locations (Misra et al., 1997). The application of nanomaterials in drug delivery has gained renewed interest in the recent years due to their unique properties, such as large surface area to volume ratio, which helps to achieve controlled and targeted drug delivery by encapsulation, entrapment, or conjugation of the drug. Using nanomaterials as drug carriers have several benefits, such as their size, which can allow penetrating into cell membranes and lysosomal escape after endocytosis. Apart from the size, surface chemical properties (capping agents) of the nanomaterials are crucial for particle uptake, binding, and stabilization of proteins and distribution. Surface modification of nanomaterials offers several possibilities to improve the drug delivery efficiency in terms of cellular uptake, intracellular transport, and cellular binding. Currently, several types of nanoparticulate systems, including polymeric based drug carriers, dendrimers, nanoparticles, carbon nanotubes, and quantum dots have been used in drug delivery systems.

4.1. Polymeric Nanomaterials

Fabrication of polymeric nanomaterials, for example dendrimers, polymeric micelles, and hyperbranched polymers is a growing area of existing biomaterial science, due to their unique properties and huge potential in drug delivery (Gong et al., 2012; Kim et al., 2012b; Lim and Simanek, 2012; Xu et al., 2012). In polymeric nanomaterials, the polymer used should be biocompatible and often biodegradable. Polymeric nanoparticles are submicron-sized (<1000 nm) polymeric colloidal particles, composed of biodegradable or biostable polymers, in which a therapeutic agent/drug of interest can be entrapped or embedded within their polymeric matrix or conjugated on the surface of nanoparticles. In polymeric nanoparticles, the encapsulated drug molecules are protected from the enzymatic and hydrolytic degradation. In general, polymeric nanoparticles contain a core–shell structure and the core consists of a dense polymer matrix in which a hydrophobic drug can be encapsulated. The core–shell structure can be changed by varying the composition of hydrophilic and hydrophobic groups on the polymers. The halo structure is made up of hydrophilic polymers like different polysaccharides, PEG, and PVP. It serves to give steric stability to the polymeric nanoparticles upon intravenous administration. Poly(ɛ-caprolactone) (PCL), poly(lactic acid) (PLA), PLGA, alginic acid, gelatin, and chitosan are some of the polymers used from a therapeutic perspective. Due to biocompatibility or biodegradability, these polymers are the good candidates for drug delivery applications (Cheng et al., 2007a; Gan and Wang, 2007; Gu et al., 2008; Szlek et al., 2013). When compared to free drugs, the polymeric nanoparticles have several other advantages including improved drug bioavailability, high carrier capacity, ability to release the payload in a controlled manner and adapt to different routes of administration and concentrate in different infectious locations by virtue of their enhanced permeability and protection. Specific molecules conjugated to polymeric nanoparticles have shown enhancement in the targeting of specific cells and tissues (Bharatwaj et al., 2010). Polymeric nanoparticles are structurally stable and can be synthesized with a sharper size distribution. During the polymeric nanoparticle synthesis, different properties, such as size, zeta potential, and drug release profiles can be precisely tuned by selecting different polymers, polymer lengths, surfactants, and solvents (Umamaheshwari and Jain, 2003).

Over the past few decades, drug carriers containing stimulus responsive building blocks as a polymeric structure have drawn tremendous attention in drug delivery applications (Wel et al., 2006). By introducing these stimuli-responsive polymers in magnetite has provided several benefits for the fabrication of novel drug delivery system. Recently, much attention has been directed to the biomedical applications of magnetite nanoparticles, especially in targeted drug delivery devices (Li et al., 2012; Sahu et al., 2012). Kim et al. (2008) reported the synthesis of temperature-responsive magnetomicelles that contains functionalized magnetic core, Fe3O4–undecylenic acid (Fe3O4–UA) and an amphiphilic layer of temperature-responsive polymer. Amphiphilic poly(undecylenic acid-co-N-isopropyl acrylamide) was grafted to the Fe3O4–UA core as a temperature-responsive micellar surface layer to prepare well dispersed Fe3O4–UA-g-P (UA-co-NIPAAm) magnetomicelles. These nanosized magnetomicelles exhibited good potential for temperature-triggered controlled drug release.

4.2. Polymeric Micelles

In general, the polymeric micelles are nanoscopic (>100 nm) and contain amphiphilic block copolymers with a core–shell structure. These polymeric micelles exhibit larger cores than surfactant micelles an important feature for higher solubilization capacity as compared to the regular micelles (He et al., 2011). Polymeric micelles have been investigated extensively for drug delivery applications. They are unique systems where aggregated amphiphilic copolymers are in dynamic equilibrium with free unimers. The use of micelles prepared from amphiphilic copolymers has attracted much attention for poorly soluble drugs due to their solubilization (Li et al., 2011; Xiong et al., 2011). The unique features of polymeric micelles including size, high stability, and low critical micelle concentration (CMC) along with core–shell arrangement qualify them as attractive candidates for use in drug delivery systems for clinical applications, especially for hydrophobic drugs having poor solubility in water (Butun et al., 2011; Chen and Liu, 2012). The polymeric micelles are divided into two groups based on the drug-loading pattern: physical drug entrapment or covalent drug conjugation. In physical drug entrapment micelles, the drug payloads are incorporated in the micelle core through hydrophobic interactions (Gong et al., 2012). The drug physicochemical stability and its release patterns are determined by the equilibrium rates, which are controlled time-dependent. In the case of covalent drug conjugation micelles, the drug binding linkers stably tether the drug molecules in the micelle core until the micelles gather at the site of the action and elicit the drug release because of various stimuli generated by ions, signal peptides, enzymes, and pH (Nishiyama et al., 2005). Several factors that favor the drug loading in polymeric micelles include the physicochemical properties of the drug and core-forming polymer, loading method, and the nature of the solvent used for the same and hydrophobic block length. Other factors that can alter drug loading and release kinetics include chemical composition of the micelle core, polymer–drug compatibility, and physical state of the micelle core (He et al., 2007; Jie et al., 2005).

Stimuli-responsive micelles are potential drug delivery systems, in which the polymeric matrices are synthesized bearing a stimulus-responsive moiety.