Nanostructures for Oral Medicine

Nanostructures for Oral Medicine

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: Bacterial polyester nanoparticles for drug delivery

Abstract

1. Introduction

2. Amphiphlic Block Copolymers

3. Polymeric Nanoparticles in Drug-Delivery Applications

4. Biodegradable Bacterial Polyesters Poly(R)-Hydroxyalkanoic Acids

5. Targeting Drug Delivery using Ligand-Conjugated PHA Nanoparticles (Active Targeting)

6. Chemical Modification of PHA Polymers for Drug Delivery (Passive Targeting)

7. Synthesis of Surface Modified PHB-mPEG Diblock Copolymer

8. Self-Assembly of Diblock Copolymer Into Nanoparticles

9. Characterization of PHA–mPEG Nanoparticles

10. Drawbacks and Challenges

11. Conclusions and Future Perspectives

Chapter 2: A novel approach to the oral delivery of bionanostructures for systemic disease

Abstract

1. Introduction

2. NanoStructures for Oral Drug Delivery

3. The Gastrointestinal Mucus Barriers

4. Strategies for Effective Oral Delivery of Drugs

5. Challenges in the Oral Delivery Route

6. Characteristics of the Transporter Used in Oral Delivery Nanostructures

7. Therapeutic Applications of Oral Delivery Nanostructures

8. Synthesis of Nanoparticles

9. Characterization of Nanoparticles

10. Conclusions

Chapter 3: Biodegradable polymeric nanostructures: design and advances in oral drug delivery for neurodegenerative disorders

Abstract

1. Introduction

2. Biodegradable Polymeric Materials

3. Nanocarriers Technology and Recent Modifications to Improve Their Specificity

4. Advances in Polymeric Nanocarriers as Vehicles for Oral-Delivery Systems

5. New Approaches and Clinical Applications in Neurodegenerative Disorders

6. Future Perspectives

Chapter 4: Nanostructured systems for transbuccal drug delivery

Abstract

1. Introduction

2. Oral Mucosa

3. Buccal Mucosa Chemical Permeation Enhancers: Chemical Structure, Mechanisms, and Biopharmaceutical Applications

4. Nanoparticles and Nanostructures for Transbuccal Drug Delivery

5. Limitations

6. Conclusions

Acknowledgments

Chapter 5: Trends in orally viral vector gene delivery and therapy

Abstract

1. Introduction

2. Nanoparticles and Microparticles Applications in Oral Delivery of Drug Molecules and Therapeutic Genes

3. The Crucial Intake Site of the Absorption of Nanoparticles and Microparticles in the Gastrointestinal Tract

4. The Characteristics of Particles and the Effect of Intake In Vivo

5. Protein Transduction and the Absorption of Nanoparticles

6. Ways to Promote the Absorption of Particles

7. The Feasibility of Oral Gene Delivery

8. The Oral Gene Delivery Vector System

9. The Uptake of Oral Viral Vector

10. The Selection of Viral Vectors Suitable for Oral Delivery

11. The Digestion Circumstance of Oral Gene Delivery

12. The Transmission, Distribution, and Transgenic Product Pharmacokinetics of Oral Viral Vectors

13. Potential, Problems, and Prospects

14. Conclusions

Chapter 6: Nanostructures for oral delivery of therapeutic nucleic acids

Abstract

1. Introduction

2. Oral Delivery of Therapeutic Nucleic Acids

3. Oral Delivery Systems for Nucleic Acid Administration (Table 6.2)

4. Conclusions

Chapter 7: Challenges in oral drug delivery: a nano-based strategy to overcome

Abstract

1. Introduction

2. Biopharmaceutical Classification of Drugs

3. Measurement of Parameters Determining Bioavailability

4. Transport Mechanism in GIT

5. Gastrointestinal Luminal Milieu and Drug Absorption

6. Improving Drug Bioavailability

7. Pharmaceutics Approach Enabling Physical Modification of Drugs

8. Improving Stability of Oral Drugs

9. Nanostructures in Oral Drug Delivery

10. Conclusions

Acknowledgment

Conflict of Interest

Chapter 8: Oral pellets loaded with nanoemulsions

Abstract

1. Pellets

2. Nanoemulsions

3. Biopharmaceutical Classification System (BSC) and Applications of Pellet to Improve Dissolution Rate of Drugs in BCS Class II

4. Case Study

5. Conclusions

Chapter 9: Oral drug delivery potential of dendrimers

Abstract

1. Introduction

2. Oral Route and its Implication

3. Nanocarriers in Oral Delivery

4. Dendrimers in Oral Drug Delivery

5. Synthetic Approaches of Dendrimer

6. Unique Properties of Dendrimers

7. Host Guest Interactions of Dendrimers and Bioactives

8. Drugs Delivered Through Oral Route Using Dendrimers as a Nanocarrier

9. Conclusions and Future Prospects

10. Abbreviations

Chapter 10: Nanovaccines for oral delivery-formulation strategies and challenges

Abstract

1. Introduction

2. Oral Vaccine Delivery

3. Intestinal Immune Response

4. Challenges in Oral Vaccine Delivery

5. Nanocarrier Based Oral Vaccine Delivery

6. Nanocarrier Formulation Strategies

7. Regulatory Aspects of Oral Nanovaccines

8. Future Prospects

Chapter 11: Nanosystems for oral delivery of immunomodulators

Abstract

1. Introduction

2. Oral Route for Immunomodulators

3. Need of Nanosystems for Immunomodulators

4. Oral Nanosystems for Immunomodulators

5. Methods for Characterization of Nanosystems

6. Fate of Immunomodulators After Oral Delivery

7. Future Prospects

8. Conclusions

Abbreviations

Chapter 12: Tannic acid modification of metal nanoparticles: possibility for new antiviral applications

Abstract

1. Introduction

2. Syntheses and Characterization of Metallic Nanoparticles Colloids (AuNPs, AgNPs, Ag/CuNPs) with Tannic Acid

3. Toxicity and Antiviral Properties of Tannic Acid Modifies Metallic Nanoparticles Colloids (AuNPs, AgNPs, Ag/CuNPs)

4. Conclusions

Acknowledgments

Chapter 13: Polyelectrolyte-drug ionic complexes as nanostructured drug carriers to design solid and liquid oral delivery systems

Abstract

1. Introduction

2. Pharmaceutical Polyelectrolytes

3. Polyelectrolyte-Drug Complexes in Aqueous Dispersion

4. Polyelectrolyte-Drug Complexes in the Solid State

5. Conclusions

Abbreviations

Chapter 14: Polysaccharide based nano/microformulation: an effective and versatile oral drug delivery system

Abstract

1. Introduction

2. Chitosan

3. Hyaluronic Acid

4. Chondroitin Sulfate

5. Heparin

6. Cyclodextrins

7. Other Polysaccharides

8. Polysaccharide Blends (PSB) in Oral Drug Delivery

9. Conclusion and Future Prospects

Chapter 15: Recent advancements in oral delivery of insulin: from challenges to solutions

Abstract

1. Introduction

2. Diabetes Mellitus

3. Diagnosis Test for Diabetes

4. Insulin Therapy

5. Plants Used in the Treatment of Diabetes

6. Diabetes in World Scenario

7. Insulin

8. Action of Insulin

9. Oral Delivery of Insulin

10. Problems in Oral Delivery

11. Strategies to Improve Oral Delivery of Insulin

12. Recent Breakthroughs in Oral Insulin Delivery

13. Commercialization

14. Recent Challenges and Future Prospects

Chapter 16: Nanotechnology for oral delivery of anticancer drugs: an insight potential

Abstract

1. Introduction

2. Remarkable Addressing Issues Concerns for Challenging of Oral Chemotherapy

3. Specific Consideration of Anticancer Drugs Appropriate for Oral Delivery

4. Nanocarrier System for Oral Delivery of Cancer Therapeutics

5. Concluding Remarks

Chapter 17: Nanomaterials: promising structures for the management of oral cancer

Abstract

1. Oral Cancer

2. Nanoparticles in Cancer Treatment and Diagnosis

3. Nanomaterials in Early Diagnosis of Oral Cancer

4. Nanotherapeutics in Oral Cancer

5. Nanomaterials in Tumor Imaging of Oral Cancer

6. Conclusions

Chapter 18: Therapeutic potential of solubilized nanolignin against oral diseases

Abstract

1. Studies of Nanostructure of Lignin

2. Biological Activity

3. Efficient Utilization of Plant Resources by Alkaline Extraction

4. Utilization of Lignin and Its Components

5. Clinical Application

6. Future Direction

Acknowledgments

Chapter 19: Novel lipid nanostructures for delivery of natural agents with antioxidant, antiinflammatory and antistroke potential: perspectives and outcomes

Abstract

1. Introduction

2. Stroke

3. Oxidative Stress Inflammation, Antioxidants, and Their Mechanism of Action

4. Bioactives with Potential Antioxidant, Antiinflammatory, and Antistroke Effects

5. Limitations of Bioactives to Elicit the Desired Therapeutic Response

6. Novel Lipid Nanostructures

7. Conclusions: Way Ahead with LNs

Acknowledgement

Chapter 20: Chitosan-based nanoparticulate systems for oral drug delivery

Abstract

1. Introduction

2. Novel Technologies for Chitosan-Based Nanoparticles

3. Oral Chitosan Nanosystems: Key Findings

4. Conclusions

Chapter 21: Phytonanoconjugates in oral medicine

Abstract

1. Introduction

2. Mechanism of Polyphenol Protection

3. Nanostructures in Oral Delivery

4. Mechanism of Absorption of Phytonanoconjugates in Epithelial Cells Via Endocytotic Cellular Uptake

5. Biofate and Pharmacokinetics of the Nanocarriers in the GI Tract After Oral Administration

6. Phytonanoparticles in Oral Medicine

7. Other Phytonanoconjugates

8. Remarks and Future Perceptions

Chapter 22: Design and development of pharmaceutical microprocesses in the production of nanomedicine

Abstract

1. Microfluidics: Origins, Present, and Future

2. Lyotropic Liquid Crystals as Drug Delivery Systems

3. Lipid-Carrying Systems

4. Microspheres

5. Polymerosomes

6. Conclusions

Chapter 23: Mesoporous materials and technologies for development of oral medicine

Abstract

1. Introduction

2. Development of Mesoporous Materials as Potential Drug Carriers

3. Drug-Loading Techniques

4. Characterization and Stabilities Studies of Poorly Soluble Oral Drug Formulation

5. Application of Functional Mesoporous Materials in Smart Oral Dosage Form

6. Summary and Outlook

Chapter 24: Nanodentistry: novel approaches

Abstract

1. Introduction

2. Types and Properties of Nanostructures Used in Dentistry

3. Nanotechnology in Dentistry

4. Preventive Nanodentistry

5. Challenges Faced by Nanodentistry

6. Conclusions

Chapter 25: The role of nanomedicine, nanotechnology, and nanostructures on oral bone healing, modeling, and remodeling

Abstract

1. Introduction

2. Nanomedicine

3. TERM and Nanomedicine

4. Fabrication Methods for Nanomaterials and Nanostructures

5. Application of Nanotechnology in Dentistry

6. Application of Nanomedicine in Oral Bone Regeneration

7. Nanotechnology and Cell Therapy in Oral Bone Regeneration

8. Current Challenges and Future Directions

Chapter 26: Therapeutic applications of nanotechnology in dentistry

Abstract

1. Introduction

2. Origin of Nanotechnology Concept and History

3. Nature and Timeline of Nanomaterials

4. Synthesis, Characteristics, and Classifications of Nanomaterials

5. Nanobiomaterials in Dentistry

6. Conclusive Remarks

Chapter 27: Oral nanomedicine and the emergent process of clinical translation

Abstract

1. Introduction

2. Understanding Clinical Trials

3. Overview of Oral Nanomedicine and Clinical Trials

4. Analyzing Selected Trials

5. Final Considerations

6. Appendix

Chapter 28: Carbon-based nanostructures for electrochemical analysis of oral medicines

Abstract

1. Introduction

2. Oral Drugs

3. Voltammetric Methods for Electrochemical Analysis of Oral Medicines Using Carbon-Based Nanostructures

4. Carbon-Based Nanostructures in Electrochemical Analysis of Oral Medicines

5. Conclusions

Abbreviations

Chapter 29: Scientometric overview regarding oral cancer nanomedicine

Abstract

1. Overview

2. The Citation Classics in Oral Cancer Nanomedicine

3. Conclusions

Index

Copyright

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List of Contributors

Satish Agrawal,     CSIR-Central Drug Research Institute, Lucknow, India

Hafsa Ahmad,     CSIR-Central Drug Research Institute, Lucknow, India

Fabiana Alovero,     National University of Cordoba (UNC), Córdoba, Argentina

Nicolas Anton,     University of Strasbourg, Strasbourg, France

Abhishek Arya,     CSIR-Central Drug Research Institute, Lucknow, India

Mohamadreza Baghaban-Eslaminejad,     Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran

Anil Kumar Bajpai,     Government Autonomous Science College, Jabalpur, India

R. Baskaran,     National Health Research Institutes, Zhunan, Taiwan

Marcelo P. Bernuci,     University Center of Maringa, Maringá, Brazil

Karolina Bien,     Military Institute of Hygiene and Epidemiology, Warsaw, Poland

Prakash S. Bisen

Jaipur National University, Jaipur

Jiwaji University

Tropilite Foods Pvt Ltd., Gwalior, India

Mariza Bortolanza,     University of Sao Paulo, São Paulo, Brazil

Virginie Busignies,     University of Bordeaux; CNRS, Bordeaux INP, ENSAM, I2M, Talence, France

Grzegorz Celichowski,     University of Lodz, Lodz, Poland

Christine Charrueau,     UTCBS, CNRS; INSERM; University of Paris Descartes, Sorbonne Paris City; Chimie ParisTech, PSL Research University, Paris, France

Nagendra S. Chauhan,     Government Ayurvedic College Campus, Raipur, India

Raje Chouhan,     Government Autonomous Science College, Jabalpur, India

Máximo P. Díaz,     Instituto Tecnológico de Querétaro, Santiago de Querétaro, Mexico

Daniele Ribeiro de Araújo,     Federal University of ABC, Santo André, Brazil

Nathalie Ferreira Silva de Melo,     São Leopoldo Mandic Institute and Research Center, Campinas, Brazil

Lígia Nunes de Morais Ribeiro,     University of Campinas—UNICAMP, Campinas, Brazil

Eneida de Paula,     University of Campinas—UNICAMP, Campinas, Brazil

Elaine Del-Bel,     University of Sao Paulo, São Paulo, Brazil

Meenal Dixit,     Jaipur National University, Jaipur, India

Yuan-Cai Dong,     Institute of Chemical and Engineering Sciences, A*STAR, Jurong Island, Singapore

Anil K. Dwivedi,     CSIR-Central Drug Research Institute, Lucknow, India

Aylin T. Ermertcan,     Manisa Celal Bayar University, Manisa, Turkey

Virginie Escriou,     UTCBS, CNRS; INSERM, University of Paris Descartes, Sorbonne Paris City; Chimie ParisTech, PSL Research University, Paris, France

Görkem Eskiizmir,     Manisa Celal Bayar University, Manisa, Turkey

Ana Figueiras

REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Coimbra

Health Sciences Centre, Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal

Michelle Franz-Montan,     University of Campinas—UNICAMP, Piracicaba, Brazil

Kunihiko Fukuchi,     Showa University, Tokyo, Japan

Toshiyuki Fukuda,     Satoen Co., Ltd., Shizuoka, Japan

Shilpi Goswami,     Government Autonomous Science College, Jabalpur, India

Avinash Gothwal,     Central University of Rajasthan, Ajmer, India

Jaroslaw Grobelny,     University of Lodz, Lodz, Poland

Lokesh Gupta,     Central University of Rajasthan, Ajmer, India

Madhu Gupta,     Shri Rawatpura Sarkar Institute of Pharmacy, Datia, India

Umesh Gupta,     Central University of Rajasthan, Ajmer, India

Rosa Martha Perez Gutierrez,     National Polytechnic Institute, Mexico City, Mexico

Gabriel H. Hawthorne,     University Center of Maringa, Maringá, Brazil

Kang Moo Huh,     Chungnam National University, Daejeon, Republic of Korea

Ana C. Issy,     University of Sao Paulo, São Paulo, Brazil

Indrani Jadhav,     Jaipur National University, Jaipur, India

Sougata Jana,     Gupta College of Technological Sciences, Asansol, India

Alvaro F. Jimenez-Kairuz,     National University of Cordoba (UNC), Córdoba, Argentina

Namrata A. Kadwadkar,     Institute of Chemical Technology, Mumbai, India

Amir Kamali,     Shiraz University, Shiraz, Iran

Taisei Kanamoto,     St. Marianna University School of Medicine, Kanagawa, Japan

Sayali Karandikar,     Bharati Vidyapeeth’s College of Pharmacy, Navi-Mumbai, India

Iliyas Khan,     Central University of Rajasthan, Ajmer, India

Prachi B. Kharkar,     Institute of Chemical Technology, Mumbai, India

Zohaib Khurshid,     King Faisal University, Al-Hofuf, Saudi Arabia

Ozcan Konur,     Yildirim Beyazit University, Ankara, Turkey

Kayoko Kotohda,     Cascade Resources Laboratory Co., Ltd., Nagano, Japan

Malgorzata Krzyzowska,     Military Institute of Hygiene and Epidemiology, Warsaw, Poland

Niha M. Kulshreshtha,     Jaipur National University, Jaipur, India

Sevinc Kurbanoglu,     Ankara University, Ankara, Turkey

Yong-Kyu Lee,     Korea National University of Transportation, Chungju, Republic of Korea

Kumaran Letchmanan,     Institute of Chemical and Engineering Sciences, A*STAR, Jurong Island, Singapore

Sabyasachi Maiti,     Gupta College of Technological Sciences, Asansol, India

Ruben H. Manzo,     National University of Cordoba (UNC), Córdoba, Argentina

Alejandro R. Martínez,     Instituto Tecnológico de Querétaro, Santiago de Querétaro, Mexico

Juan Vicente Mendez Mendez,     National Polytechnic Institute, Mexico City, Mexico

Jorge E. Miranda Calderon,     Laboratory of Molecular Pharmacy and Controlled Release, México D.F., Mexico

Amit Mirani,     Institute of Chemical Technology, Mumbai, India

Ali Moshiri,     Iran University of Medical Sciences, Tehran, Iran

Yuvashree Muralidaran,     VIT University, Vellore, India

Shariq Najeeb,     Al-Farabi Colleges, Riyadh, Saudi Arabia

Hideki Nakashima,     St. Marianna University School of Medicine, Kanagawa, Japan

Wai Kiong Ng,     Institute of Chemical and Engineering Sciences, A*STAR, Jurong Island, Singapore

Thi Trinh Lan Nguyen,     University of Strasbourg, Strasbourg, France

Norma A. Noguez Méndez,     Laboratory of Molecular Pharmacy and Controlled Release, México D.F., Mexico

Md Nurunnabi

Chungnam National University, Daejeon

Korea National University of Transportation, Chungju, Republic of Korea

Hirokazu Ohno,     Maruzen Pharmaceuticals Co. Ltd., Tokyo, Japan

Takaaki Oizumi,     Daiwa Biological Research Institute Co., Ltd., Kanagawa, Japan

María E. Olivera,     National University of Cordoba (UNC), Córdoba, Argentina

Piotr Orlowski,     Military Institute of Hygiene and Epidemiology, Warsaw, Poland

Ahmad Oryan,     Shiraz University, Shiraz, Iran

Sibel A. Ozkan,     Ankara University, Ankara, Turkey

V. Vijaya Padma

Bharathiar University, Coimbatore, India

China Medical University

Asia University, Taichung, Taiwan

Xochitl C. Palomec,     Laboratory of Molecular Pharmacy and Controlled Release, México D.F., Mexico

Sandeep Patankar,     Bharati Vidyapeeth’s College of Pharmacy, Navi-Mumbai, India

Vandana B. Patravale,     Institute of Chemical Technology, Mumbai, India

L. Bharathi Priya,     Bharathiar University, Coimbatore, India

Carlos T. Quirino Barreda,     Laboratory of Molecular Pharmacy and Controlled Release, México D.F., Mexico

Gokulakannan Ragavan,     VIT University, Vellore, India

María V. Ramírez-Rigo,     National University of the South, Bahía Blanca, Argentina

Katarzyna Ranoszek-Soliwoda,     University of Lodz, Lodz, Poland

Ihtesham Ur Rehman,     The University of Sheffield, Sheffield, United Kingdom

Vishnu Revuri,     Korea National University of Transportation, Chungju, Republic of Korea

Andreza Maria Ribeiro

Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal

Department of Engineering and Material Sciences, University of Federal of Paraná (UFPR), Curitiba, Brazil

Hiroshi Sakagami,     Meikai University School of Dentistry, Saitama, Japan

Mohsin Shah,     Khyber Medical University, Peshawar, Pakistan

Ashok K. Sharma,     Central University of Rajasthan, Ajmer, India

Vikas Sharma,     Shri Rawatpura Sarkar Institute of Pharmacy, Datia, India

Shou-Cang Shen,     Institute of Chemical and Engineering Sciences, A*STAR, Jurong Island, Singapore

Hong Sheng,     Meikai University School of Dentistry, Saitama, Japan

Divya Shrivastava,     Jaipur National University, Jaipur, India

Anurag K. Singh,     Central University of Rajasthan, Ajmer, India

Nehi Sinha,     Jaipur National University, Jaipur, India

Swapnil S. Talkar,     Institute of Chemical Technology, Mumbai, India

Pierre Tchoreloff,     University of Bordeaux; CNRS, Bordeaux INP, ENSAM, I2M, Talence, France

Shigemi Terakubo,     St. Marianna University School of Medicine, Kanagawa, Japan

Emilia Tomaszewska,     University of Lodz, Lodz, Poland

César G. Urioste,     Laboratory of Molecular Pharmacy and Controlled Release, México D.F., Mexico

Bengi Uslu,     Ankara University, Ankara, Turkey

Thierry F. Vandamme,     University of Strasbourg, Strasbourg, France

Israel Arzate Vazquez,     National Polytechnic Institute, Mexico City, Mexico

Abraham F. Vega,     Laboratory of Molecular Pharmacy and Controlled Release, México D.F., Mexico

Francisco Veiga,     REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal

Pragasam Viswanathan,     VIT University, Vellore, India

Vishal Waybhase,     Bharati Vidyapeeth’s College of Pharmacy, Navi-Mumbai, India

Jingqi Xie

Huaqiao University, Quanzhou

Engineering Research Center of Molecular Medicine, Ministry of Education

Key Laboratory of Molecular Medicine in Fujian Province, Xiamen, China

Ruian Xu

Huaqiao University, Quanzhou

Engineering Research Center of Molecular Medicine, Ministry of Education

Key Laboratory of Molecular Medicine in Fujian Province, Xiamen, China

Masaji Yamamoto,     Maruzen Pharmaceuticals Co. Ltd., Tokyo, Japan

Kerim Yapici,     Cumhuriyet University, Sivas, Turkey

Toshikazu Yasui,     Meikai University School of Dentistry, Saitama, Japan

Sung C. Yoon

Gyeongsang National University, Jinju

ReSEAT Program, KISTI, Daejeon, Republic of Korea

Hidenobu Yoshida,     Cascade Resources Laboratory Co., Ltd., Nagano, Japan

Muhammad S. Zafar

Taibah University, Al Madinah, Saudi Arabia

Riphah International University, Islamabad, Pakistan

Sana Zohaib,     King Faisal University, Al-Hofuf, Saudi Arabia

Foreword of the Series

Material science and engineering at the nanoscale have brought revolutionary advances to the biomedical sciences, overturning many of the known traditional approaches. Nanotechnology has driven many of the most successful innovative technologies, and their impressive record of accomplishment has made nanostructures promising candidates for future therapy. 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 highly 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 together in one place all the most recent and innovative aspects regarding the impact of nanomaterials in both current and future therapy. The book is organized in 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 in this volume was paid 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. The design of nanoscale agents in order to specifically and safely carry therapeutic agents to their final destination is an intriguing approach to future targeted therapeutics. 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 book 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.

The third volume, 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 very real and worrying issue growing throughout the world, the development of more efficient antimicrobial agents has a high priority to allow control of infections in the future. Antimicrobial nanosystems have proved to be highly efficient against drug-resistant microorganisms, are able to fight biofilm-associated infections and control the social behavior of microbial communities. Nanostructures can also reduce microbial virulence factors and reduce pathogenesis mechanisms thus offering a promising alternative for future therapy.

The fourth volume, 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 advances have been recently made in this area, and the aim of this book 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 novel findings, while also discussing possible improvements in more established types of nanosystems to increase the efficiency of cancer therapy.

Last but not least, the fifth 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 and in dentistry. Readers will have the chance to 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 will provide a state-of-the-art compendium of knowledge, and a crystal ball to see into the future of biomedical nanotechology and nanomedicine. It will appeal to researchers, clinicians, engineers, pharmacologists, pharmacists, oncologists, infectious disease experts, and dentists. More many interested general readers may 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

Harvard Medical School, Boston, MA, United States

Harvard-MIT Division of Health Sciences and Technology, Cambridge, 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 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, since nanostructured therapeutics proved their efficiency and amazing impact in improving therapy, prophylaxis, and diagnosis. The emerging field of nanosized materials have 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 in order 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 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 are dissected. The field of oral diseases represents a wide-interest and priority field since 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 contain very recent but accessible information regarding the progress of nanostructures in therapeutics and give a novel perspective about future therapy of severe diseases.

Alexandru Mihai Grumezescu

University Politehnica of Bucharest, Bucharest, Romania

About Volume V

The fifth volume of the series Therapeutic Nanostructures is entitled Nanostructures for Oral Medicine. This volume reveals numerous applications of nanostructures in oral medicine. Various key approaches, such as drug design and delivery, oral vaccines, and therapeutic systems for oral applications, are discussed and exemplified in this volume. Oral medicine represents a widely investigated field, where nanotechnology has found numerous applications. From improved implantable materials to specialized drug-delivery systems, nanomaterials have offered solutions to serious clinical conditions from diagnosis to therapy. The book describes not only the preparation of oral nanomedicines but also their main properties, applications and principal advantages and drawbacks. Applications and impact on human life quality of recently developed nanomaterials aimed at oral therapy are also presented here. Similar to general medicine, the trend in oral medicine seems to follow technological progress, the specificity and sensibility of nanostructured drugs playing an important role in the design of tailored approaches for oral therapy. Aspects related to oral cancers, oral drug delivery, personalized therapy, regenerative local medicine, and disease-preventing oral nanoagents are widely dissected in this book.

Volume V contains 29 chapters, prepared by outstanding international researchers from Turkey, India, Pakistan, South Korea, Brazil, Portugal, Iran, China, Poland, France, Argentina, Japan, Taiwan, Mexico, Singapore, Iran, Saudi Arabia, and the United Kingdom.

In Chapter 1, entitled Bacterial Polyester Nanoparticles for Drug Delivery, Mohsin Shah and Sung Chul Yoon describe the methods of preparation and characterization of drug-encapsulated polymeric nanoparticles formulated with various copolymers, drug release kinetics, and evaluation of their localization in cancer cells in vitro and in vivo.

Rosa Martha Perez Gutierrez et al., in Chapter 2, entitled A Novel Approach to the Oral Delivery: Nanostructures and Biomaterials for Systemic Disease, shed light on oral delivery nanostructures researched in medicine, including synthesis techniques and materials that can be effectively used for controlled oral drug delivery application used in disease treatments.

Chapter 3, prepared by Andreza Maria Ribeiro et al., entitled Biodegradable Polymeric Nanostructures: Design and Advances in Oral Drug Delivery for Neurodegenerative Disorders, highlights the main advances in polymeric nanocarriers as vehicles for oral delivery systems used in the therapy of neurodegenerative disorders. First, a brief introduction into the field of biodegradable polymeric materials used in nanostructures formulation is presented. Considering their structure and characteristics, the next section offers a detailed description of the technologies and recent modifications to improve their specificity. Finally, new approaches are presented with clinical applications in neurodegenerative disorders.

Chapter 4, entitled Nanostructured Systems for Transbuccal Drug Delivery, prepared by Michelle Franz-Montan et al., outlines the use of nanostructures as tools for the development of new formulations for topical use at the oral mucosa in dental clinical practice. Topics covered in this chapter include the structure, organization, and permeability of oral mucosa; permeation pathways at oral mucosa; chemical permeation enhancers for oral mucosa topical formulations; mechanisms of permeation enhancers; and the use of the following nanostructures to improve transbuccal drug delivery for the treatment of oral mucosa infections, inflammation, and pain conditions: liposomes, polymeric nanoparticles/micelles, nanostructured lipid carriers, and cyclodextrins.

Chapter 5, entitled Trends in Orally Viral Vector Gene Delivery and Therapy, prepared by Jingqi Xie and Ruian Xu, highlights the merits and disadvantages of novel applications and their relationship between sizes and structures of nanoparticles and the efficacy of oral gene delivery and therapy. In addition, this chapter reveals orally viral vector gene delivery timing, and systematically discusses the effect of age, delivery route, cell preference, organ distribution, and so on on orally viral vector delivery and trends in oral viral vector gene delivery and therapy.

Virginie Busignies et al., in Chapter 6, entitled Nanostructures for Oral Delivery of Therapeutic Nucleic Acids, discuss the barriers to oral delivery of nucleic acids and review the various technologies already tested in preclinical study and the experimental models available to assay oral delivery systems.

Pragasam Viswanathan et al., in Chapter 7, entitled Challenges in Oral Drug Delivery: A Nano-Based Strategy to Overcome, offer an overview about the strategy to override such drawbacks by ushering in various nanotechnology platforms, such as polymer-based nanocarriers, lipid-based nanocarriers, and metal- and inorganic-based nanoparticles.

Thi Trinh Lan Nguyen et al., in Chapter 8, Oral Pellets Loaded With Nanoemulsions, present an up-to-date review about nanoemulsion and its subsequent transformation into pellet systems that offer several advantages for improving solubility and dissolution rates of poorly water-soluble drugs for oral delivery in order to overcome the poor absorption of some active pharmaceutical ingredients.

Anurag Kumar Singh et al., in Chapter 9, entitled Oral Drug Delivery Potential of Dendrimers, focus on the oral potential applicability of dendrimers for delivering various categories of drugs, such as antimicrobial agents, antifungal drugs, and certain catheter-related substances.

Chapter 10, prepared by Sayali Karandikar et al., entitled Nanovaccines for Oral Delivery-Formulation Strategies and Challenges, summarizes nanoformulation strategies for oral delivery of vaccines, which can potentially help to overcome existing problems. Also, this chapter briefly presents their challenges and regulatory aspects.

Chapter 11, prepared by Prachi B. Kharkar et al., entitled Nanosystems for Oral Delivery of Immunomodulators, gives an insight into nanostructurated immunomodulators, their routes of administration, and newer sophisticated methods of their formulation for better therapeutic effect.

Chapter 12, entitled Tannic Acid Modification of Metal Nanoparticles: Possibility for New Antiviral Applications, prepared by Malgorzata Krzyzowska et al., presents an up-to-date overview about tannic-acid-modified silver nanoparticles consisting of a novel potential microbicide for herpes virus infection in the mucosal tissues.

Chapter 13, Polyelectrolyte-Drug Ionic Complexes as Nanostructured Drug Carriers to Design Solid and Liquid Oral Delivery Systems, prepared by Maria E. Olivera et al., deals with the description of main pharmaceutical applications of drug-delivery systems based on the unique properties of complexes of polyelectrolytes with ionizable drugs.

Chapter 14, prepared by Md Nurunnabi et al., entitled Polysaccharide Based Nano/Micro Formulation: An Effective and Versatile Oral Drug Delivery System, focuses on potential applications of polysaccharides for oral drug delivery, their biocompatibility, as well as their advantages and disadvantages over conventional strategies. The authors also highlight recent advances in oral drug delivery based on specific polysaccharides, including chitosan, heparin, hyaluronic acid, beta glucan, and chondroitin sulfate.

Raje Chouhan et al., in Chapter 15, entitled Recent Advancements in Oral Delivery of Insulin: From Challenges to Solutions, present an overview of diabetes highlighting various aspects of insulin therapy, including insulin analogs, oral delivery of insulin, mechanistic action of insulin, challenges of oral administration of insulin, and breakthroughs in insulin delivery at the global level. The chapter also discusses economical aspects related to the commercialization level of insulin.

Madhu Gupta et al., in Chapter 16, Nanotechnology for Oral Delivery of Anticancer Drugs: An Insight Potential, review the challenges encountered in oral delivery with various nanoconstructs employed for oral anticancer drug delivery comprehensively as well as their applications.

Chapter 17, entitled Nanomaterials: Promising Structures for the Management of Oral Cancer, prepared by Görkem Eskiizmir et al., presents the role and potential effectiveness of using nanomaterials in different aspects of oral cancer. Recently, nanotechnology has offered new strategies in cancer management: (1) early detection of cancers via specialized probes and biosensors, (2) better diagnosis and staging via improving the imaging systems, (3) nanoscale drug-delivery systems that may provide a significant decrease in adverse effects and toxicities of chemotherapeutics, and (4) nanotheranostics that integrate both diagnosis and therapy simultaneously.

Hiroshi Sakagami et al., in Chapter 18, entitled Therapeutic Potential of Solubilized Nanolignin Against Oral Diseases, offer relevant information about the lignin-carbohydrate complex and its excellent anti-HIV activity and anti-UV activity, in contrast to its weak tumor-selective cytotoxicity.

Chapter 19, prepared by Hafsa Ahmad et al., Novel Lipid Nanostructures for Delivery of Natural Agents With Antioxidant, Antiinflammatory, and Antistroke Potential: Perspectives and Outcomes, presents many bioactive nanocombinations with antioxidant, anti-inflammatory, and neuroprotective effects that might promote alleviation of neuronal and tissue damage following stroke and reverse pathophysiological changes in ischemia-reperfusion injury that fail clinically due to degradation, poor aqueous solubility, and subsequent bioavailability.

Sougata Jana and Sabyashachi Maiti, in Chapter 20, entitled Chitosan-Based Nanoparticulate Systems for Oral Drug Delivery, discuss various methods of preparation of chitosan-based nanoparticles, structural modifications of chitosan, and the latest developments in the field of oral drug delivery.

Chapter 21, prepared by Lohanathan Bharathi Priya and Viswanadha Vijaya Padma, entitled Phytonanoconjugates in Oral Medicine, focuses on the role of nanostructures conjugated to phytochemicals (phytonanoconjugates) in oral medicine by extensively reviewing of the latest research findings.

Chapter 22, entitled Design and Development of Pharmaceutical Microprocesses in the Production of Nanomedicine, prepared by Norma Angélica Noguez Méndez et al., presents an up-to-date overview about the microfluidics and examples of nano- and microparticles involved in this field: liquid crystals (LCs) and solid lipid nanoparticles (SLNs). Also, the authors present details about synthetic polymersomes that imitate biological membrane functions.

Chapter 23, prepared by Shou-Cang Shen et al., entitled Mesoporous Materials and Technologies for Development of Oral Medicine, presents recent progress in the development of mesoporous materials as drug carriers for applications in oral medicine formulation according to the types of mesoporous excipients, drug loading techniques, characterization and stability studies, and applications in oral medicine.

Nehi Sinha et al., in Chapter 24, entitled Nanodentistry: Novel Approaches, focus on the role of nanostructures to keep teeth and oral tissues healthy and functioning. The challenges faced by this technology for the betterment of human health are also discussed.

Chapter 25, entitled The Role of Nanomedicine, Nanotechnology, and Nanostructures on Oral Bone Healing, Modeling, and Remodeling, prepared by Mohamadreza Baghaban-Eslaminejad et al., covers the most important information regarding manufacturing methods, available and future options, and the role of nanostructures on bone health, healing, and repair based on their basic to clinical evidence.

Muhammad Sohail Zafar et al., in Chapter 26, entitled Therapeutic Applications of Nanotechnology in Dentistry, highlight recent developments regarding therapeutic applications of nanomaterials in dentistry. In addition, chemistry, synthesis, properties, and benefits of therapeutic nanomaterials over conventional materials in relation to dentistry are discussed.

Chapter 27, prepared by Gabriel Henrique Hawthorne et al., Oral Nanomedicine and the Emergent Process of Clinical Translation, discusses the translational research from laboratory approaches to clinical applications inside oral nanomedicine. Analyzing the clinical trials conducted in a field is the only way of predicting the potential for clinical impact of the new approaches, and oral nanomedicine stands in a promising position.

Chapter 28, prepared by Sevinc Kurbanoglu et al., entitled Carbon-Based Nanostructures for Electrochemical Analysis of Oral Medicines, gives an up-to-date overview about electrochemical assay of oral drugs using carbon-based nanostructures such as fullerene polymers, carbon nanotubes, carbon nanohorns, carbon nanodiamonds, and grapheme. Also, advantages and disadvantages of producing techniques are detailed.

Chapter 29, entitled Scientometric Overview Regarding Oral Cancer Nanomedicine, by Ozcan Konur, highlights important papers influencing the development of the research field as well as in determining the key research fronts in the field of cancer nanomedicine. This book chapter presents the first bibliometric study focusing on the 25 citation classics in oral cancer nanomedicine following a brief bibliometric overview of the research in these underlying research areas.

Ecaterina Andronescu

University Politehnica of Bucharest, Bucharest, Romania

Alexandru Mihai Grumezescu

University Politehnica of Bucharest, Bucharest, Romania

Chapter 1

Bacterial polyester nanoparticles for drug delivery

Mohsin Shah*

Sung C. Yoon**,†

*    Khyber Medical University, Peshawar, Pakistan

**    Gyeongsang National University, Jinju, Republic of Korea

†    ReSEAT Program, KISTI, Daejeon, Republic of Korea

Abstract

Bacterial polyesters, polyhydroxyalkanoic acids (PHAs), are accumulated in the form of nanogranular inclusions in the cells of many bacteria and may serve as carbon and energy reserves. The use of PHA nanoparticles for controlled drug delivery has been shown to be potentially useful. Another type of polyester, synthetic PLGA, has been the focus of many DDS studies because of its biodegradable and biocompatible nature. In this chapter, we describe the methods of preparation and characterization of drug-encapsulated polymeric nanoparticles formulated with PHA-b-PEG) copolymers, drug release kinetics, and the evaluation of their localization in cancer cells in vitro and in vivo. Comparative analysis of drug loading and bioavailability of many hydrophobic drugs and nanostructures of drug-loaded nanoparticles between the two types of polyesters will be made.

Keywords

PHA

PLGA

polymer nanoparticles

drug-delivery system

nanomedicine

Chapter Outline

1 Introduction

2 Amphiphlic Block Copolymers

3 Polymeric Nanoparticles in Drug-Delivery Applications

4 Biodegradable Bacterial Polyesters Poly(R)-Hydroxyalkanoic Acids

4.1 Properties of PHA

4.2 Biodegradation of PHA

4.3 General Applications of PHA

4.4 PHA as Drug Carrier

5 Targeting Drug Delivery using Ligand-Conjugated PHA Nanoparticles (Active Targeting)

6 Chemical Modification of PHA Polymers for Drug Delivery (Passive Targeting)

7 Synthesis of Surface Modified PHB-mPEG Diblock Copolymer

8 Self-Assembly of Diblock Copolymer Into Nanoparticles

9 Characterization of PHA–mPEG Nanoparticles

9.1 Core–Shell Topology in Aqueous Solution

9.2 Morphological Characteristics of PHA–mPEG Nanoparticles

9.3 Drug Loading in PHA–mPEG Nanoparticles

9.4 Drug Release from PHA–mPEG Nanoparticles

9.5 Cellular Uptake of PHA–mPEG Nanoparticles

10 Drawbacks and Challenges

11 Conclusions and Future Perspectives

References

1. Introduction

Over the past few decades, there has been considerable progress in developing biodegradable nanoparticles as effective drug delivery devices (Jendrossek and Handrick, 2002). Different types of biodegradable polymers both synthetic and natural have been utilized in the preparation of nanoparticles (Anderson and Dawes, 1990; Doi, 1990). Nanoparticles are submicron-sized polymeric colloidal particles with a size range 1–1000 nm and drugs may be encapsulated, adsorbed, or dispersed in them (Jendrossek et al., 1996; Jendrossek and Handrick, 2002; Verlinden et al., 2007). In the preparation of particles for drug-delivery systems, biodegradable materials are preferably used in order to prevent the side effects associated with nonbiodegradable polymers. The products result after the degradation of the biopolyesters that must be biocompatible and nontoxic. In general, nanoparticles prepared from polymers can be divided into three different categories, depending on their structure. Capsules are the first category. Nanocapsules are submicroscopic colloidal drug carrier systems composed of an oily or an aqueous core surrounded by a thin polymer membrane (Madison and Huisman, 1999). Another example of a vesicular system is the liposomes. In an aqueous environment, phospholipid molecules form a lipid bilayer, resulting in the formation of liposomes. Several types of liposomes can be prepared, including unilaminar, multilaminar, and multivesicular (Sun et al., 2007). The disadvantages of liposomes are the unreliable reproducibility of liposomes and exchange of phospholipids with certain blood components (Sudesh and Doi, 2000). The second category is polymeric micelles. Polymeric nanoparticles are nanosized, supramolecular core/shell structures formed by self-aggregation of individual amphiphilic macromolecules comprised of inner concealed hydrophobic and outer exposed hydrophilic domains (Jendrossek and Handrick, 2002; Jendrossek et al., 1996; Verlinden et al., 2007). This core–shell structure enables the solubilization of hydrophobic drugs in the core hydrophobic domain (Kumagai and Doi, 1993). The micelles are formed spontaneously above a certain copolymer concentration: the critical micelle concentration (CMC) (Kim et al., 1999; Kumagai and Doi, 1993). The third category of nanoparticles is particles that consist of a more or less homogeneous polymeric matrix. Analogous to microspheres, these particles are generally referred to as nanospheres. These particles are larger than micelles and may be more polydispersed in terms of size (Pötter and Steinbüchel, 2005).

2. Amphiphlic Block Copolymers

Amphiphilic copolymers can be synthesized by introducing hydrophilic groups, such as hydroxyl, carboxyl, amine, glycol, and hydrophilic polymers, such as polyethylene glycol (PEG), poly(vinyl alcohol), poly(acryl amide), poly(acrylic acid), poly(hydroxyethyl methacrylate), poly(vinyl pyridine), and poly(vinyl pyrrolidone) to a hydrophobic central moiety (Mergaert et al., 1994). In the amphiphilic block copolymers, the hydrophilic part is covalently linked with strongly hydrophobic polymers. On exposing to the aqueous environments, the hydrophobic core of the polymer is buried inside with exposed hydrophilic domains (Klingbeil et al., 1996). In such amphiphilic structure of polymeric micelles, hydrophobic drug molecules are solubilized within the hydrophobic core, which acts as a cargo for loading high amounts of drugs, whereas the shell maintains a hydration barrier that protects the integrity of each micelle (Kumagai and Doi, 1993). Moreover, the hydrophilic moiety used as surface coating also protect the nanoparticles from the induction of immune response. The use of biodegradable amphiphilic nanoparticles as drug carriers is advantageous because it releases the drug via two steps; first, diffusion release of the mPEG segment, and second, degradation release of the biodegradable polymer segment (Jendrossek et al., 1995). Several studies have been performed over the past few years with micelle-forming block copolymers. Most of these have been conducted on loading of hydrophobic drugs in the amphiphilic copolymers with core–shell morphology (Bhatt et al., 2008; Cui et al., 2002; Kim et al., 1999). Various hydrophobic drugs, including griseofulvin (Cui et al., 2002), doxorubicin (DOX) (Preusting et al., 1993; Wong et al., 2002), and amphotericin B (Martin and Williams, 2003) have been successfully loaded into the micelle compartments of these copolymers. Some of these have been used in clinical trials and the in vitro and in vivo efficacies of these micelles have been evaluated.

3. Polymeric Nanoparticles in Drug-Delivery Applications

With the development of new materials and a combination of nanotechnology and biotechnology it could be possible to make artificial organs and implants through cell growth, which could repair damaged nerve cells, replace damaged skin, tissue, or bone (Williams et al., 1999). Another application of bionanotechnology in medicine is drug delivery where research is especially intensive on the possibility of manipulating nanoparticles to deliver drugs because nanoparticles can have a better solubility and absorption potential than bigger particles (Verlinden et al., 2007). The nanoparticles can carry the drug and perhaps release it in fine-tuned doses over an extended time period to a targeted area, reducing the side effects of the traditional drugs.

Polymeric nanoparticles in pharmaceutical applications have gained plenty of research attention during recent decades (Zhang et al., 1997). Although, the research concerning formulation of polymer based nanoparticles into drug delivery devices has been extensive, only a few polymeric nanoparticulate products have reached the market. One known product, Abraxane, consist of intravenously administered 130-nm nanoparticles prepared from the protein albumin bound with paclitaxel, a drug used in cancer therapy (Zhang et al., 1995). Another cancer drug, DOX transdrug, consisting of DOX-loaded poly(isohexylcyanoacrylate) nanoparticles is currently at the Phase II/III clinical trials (Xiong et al., 2010). In particular among the drugs used in nanoparticle formulations, cancer therapeutics are widely studied because their formulation might reduce toxicity of the drug while improving efficacy of the treatment (Mei et al., 2006). In addition to drug molecules, other candidates to be encapsulated in or coupled with nanoparticles include macromolecules like proteins, peptides, and genes (nucleic acids) (Zhao et al., 2003). These kinds of molecules tend to be inactivated in the body by enzymatic degradation. In terms of controlled release, nanoparticles provide protection against the body conditions resulting in sustained release and maintenance of bioactivity before the drug reaches the target. The most effective strategy adopted by these nanoparticulated drug carriers to selectively target the solid tumors is the exploitation of anatomical and pathophysiological abnormalities of the tumor vasculature, utilizing the principle of enhanced permeability and retention (EPR) effect (Williams et al., 1999). The difference between normal inflammatory tissues and tumor tissues is reflected in their clearance velocities. Usually the macromolecules like nanoparticles, nanocapsules; lipid nanoparticles delivered into the interstitial space of normal inflammatory tissue is cleared more rapidly. On the other hand tumor tissues have leaky vessels and poor aligned lymphatic vessels as results the macromolecules leak out more easily into the tumor tissues and retain longer due to their defective lymphatic system. This phenomenon is called as EPR effect as explained by Maeda et al. (2001). The size and surface of the nanoparticulate carrier plays a very crucial role with respect to uptake by the tumor. Particles <200 nm in size with hydrophilic surfaces tend to exhibit improved EPR effect, which has been attributed to the increased residence time of the carrier in blood (Williams et al., 1999). Moreover, this increased plasma half-life of particulate drug carrier, as well as accumulation in tumor is strictly correlated to the molecular weight of the macromolecule or polymer used for making the nanoparticles long circulating.

The benefits of drugs loaded in the polymeric nanoparticles include protection of the encapsulated pharmaceutical substance, improved efficacy, fewer adverse effects, controlled release and drug targeting to tumor tissues by the EPR effect resulting from defective tumor vascular architecture and impaired lymphatic drainage. Polymeric micelles provide a shielding effect in intracellular drug delivery, wherein drugs remain inside micelles upon endocytosis.

4. Biodegradable Bacterial Polyesters Poly(R)-Hydroxyalkanoic Acids

Poly(R)-hydroxyalkanoic acids (PHA) are a group of storage compounds of carbon and energy that are accumulated during unbalanced growth by many bacteria, that is, in the presence of an excess of a carbon source and if growth is limited by another nutrient, such as nitrogen (Jendrossek and Handrick, 2002; Jendrossek et al., 1996; Verlinden et al., 2007). When the supply of limiting nutrient is restored, the PHA can be depolymerized and subsequently metabolized as carbon and energy sources (Anderson and Dawes, 1990; Doi, 1990). PHA in bacterial cells is deposited intracellularly in the form of inclusion bodies (granules) and it forms up to 90% of the cellular dry weight (Anderson and Dawes, 1990; Doi, 1990; Jendrossek et al., 1996) as shown in Fig. 1.1A. The many different types of PHA isolated to date are primarily linear; head-to-tail polyesters composed of 3-hydroxy fatty acids monomers (Madison and Huisman, 1999). In such types of polyesters, the carboxyl group of one monomer forms an ester bond with the hydroxyl group of the neighboring monomer (Fig. 1.1B). In all PHAs that have characterized so far, the hydroxyl-substituted carbon atom is of R configuration, except in some cases where there is no chirality (Madison and Huisman, 1999). Polyhydroxalkanoates (PHAs) isolated from bacterial cells show material properties that are similar to petrochemically produced polymers. Many microorganisms secrete enzymes, which have the ability to degrade these polyesters enzymatically. Apart from their biodegradable nature, PHA-based polyesters are natural, renewable, and biocompatible. The wide range of physical properties of PHA-based materials and the extended performance, obtainable by chemical modification of the surface or blending provide a broad range of potential end-use applications (Verlinden et al., 2007). The key enzymes utilized by microorganisms for the degradation of PHA-based materials are both extracellular and intracellular PHA depolymerases. Another important property of PHAs is that they can be produced on renewable resources (Braunegg et al., 2004; Madison and Huisman, 1999). Fermentative production of PHAs is based on agricultural products, such as sugars and fatty acids as carbon and energy sources. The origin of this agricultural feedback is CO2 and water, and upon degradation in the environment, it is again converted into CO2 and water.

Figure 1.1   (A) Transmission electron microscopic image of accumulated of PHA granules in Hydrogenophaga pseudoflava. About 70%–90% of bacterial weight consists of accumulated PHA granules in bacterial cytoplasm. Scale bar = 0.5 μm. (B) Chemical structure of polyhydroxyalkanoates (PHAs) Part B: Reprinted with permission from Sun, Z., Ramsay, J.A., Guay, M., Ramsay, B.A., 2007. Fermentation process development for the production of medium-chain-legth poly-3-hydroxyalkanoates. Appl. Microbiol. Biotechnol. 75, 475–485.

4.1. Properties of PHA

The physical properties of PHA are different, and two physical states of PHA granules can be distinguished represented by intracellular native PHA granules and partially crystalline PHA granules (Jendrossek and Handrick, 2002). The native PHA granules are in amorphous state, the surface of which is surrounded with a layer consisting of phospholipids and granule-associated proteins (Hocking and Marchessault, 1994; Pötter and Steinbüchel, 2005). After extraction from the cells using some organic solvents, the phospholipid and protein layer is damaged or lost and the amorphous nature is converted into complete crystalline structure and the PHA after isolation is tough and brittle in nature; such a PHA is called crystalline PHA (Doi, 1995). Many researchers have shown that crystalline PHA is unsuitable for design of different products due to its high crystallinity, thermosensitivity, and brittle in nature (Kim et al., 1999; Kumagai and Doi, 1993). Copolymerization and blending with other degradable polymers were also suggested to enhance the physical properties of the polymer (Doi, 1990; Kim et al., 1999). Copolymers of PHA can be produced by cofeeding of mixed substrates, such as a mixture of glucose and valerate or butyrate, which results in the formation of polymers containing 3-hydroxyvalerate (3HV) or 4-hydroxybutyrate (4HB) monomers (Doi, 1990; Madison and Huisman, 1999). The high number of monomers and the variable monomeric composition of PHA result in an enormous variation of the physical and chemical characteristics of different PHA (Jendrossek and Handrick, 2002). Based on the carbon chain length, PHA is generally divided into two groups, that is, short-chain-length (SCL) and medium-chain-length (MCL) PHA. SCL-PHA consists of (R)-hydroxyalkanoates with carbon number range C3–C5, on the other hand MCL-PHA consist of aliphatic or aromatic (R)-hydroxyalkanoates of C6–C14 (Madison and Huisman, 1999; Sudesh and Doi, 2000). Polyhydorxybutyrate (PHB), poly(3-hydroxyvalerate) (PHV), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), and poly(3-hydroxybutyrate-co-4-hydroxybutyrate) (PHB4HB) form a class of PHAs polyesters typically referred as SCL-PHA.

4.2. Biodegradation of PHA

Besides the typical properties described earlier, an important characteristic of PHA-based materials is their biodegradability in natural environment. In nature, a vast consortium of microorganisms is able to degrade PHAs by secreting PHA hydrolases and PHA depolymerases (Jendrossek et al., 1996; Madison and Huisman, 1999; Verlinden et al., 2007). The activities of these enzymes may vary and depend on the composition of the polymer and also on the environmental conditions (Doi, 1990; Verlinden et al., 2007). Although PHA is water-insoluble, hydrophobic, and partially crystalline polymers, they can be degraded by a large variety of microorganisms (Jaeger et al., 1995). PHA can be degraded either intracellularly by intracellular PHA depolymerases of the accumulating strain, or extracellularly by extracellular PHA depolymerases. Intracellular PHA depolymerases can only degrade native amorphous PHA and cannot degrade crystalline denatured PHA. On the other hand, extracellular PHA depolymerases can degrade only crystalline denatured PHA while it cannot degrade native amorphous PHA (Jendrossek et al., 1996; Jendrossek and Handrick, 2002). Enzymes catalyzing the extracellular degradation of denatured PHA are called extracellular PHA depolymerases. It is well known that microorganisms degrade wide varieties of PHA homopolyesters and copolyesters by excreting extracellular PHB depolymerases into the environment and utilizing the decomposed components as a nutrient source (Abe et al., 1994; Doi, 1990). However, the structural composition of monomer unit in the copolyesters is an important parameter that determines the mobilization of copolyesters by PHB depolymerases (Doi, 1990). PHA-degrading microorganisms are present in diverse habitat, such as soil, activated sludge, laboratory atmosphere, and seawater (Kasuya et al., 1994; Mukai et al., 1993). The enzymatic degradation usually proceeds by the surface erosion of the polymer and the resulting products after enzymatic degradation are water-soluble monomers or oligomers or both.

4.3. General Applications of PHA

The majority of expected applications of PHAs are as replacement for petrochemical plastics. The plastic materials in current use for packaging and coating applications can be replaced partially or entirely by PHA-based biodegradable materials (Verlinden et al., 2007). The wide range of applications of PHA-based materials and the new and improved products obtained from the copolymerization and blending provide a broad range of potential end-use applications (Bhatt et al., 2008; Cui et al., 2002). PHA has emerged as potential material utilized widely in varieties of medical applications (Martin and Williams, 2003; Williams et al., 1999; Xiong et al., 2010). PHA-based materials are nontoxic and well tolerated by the human body (Mei et al., 2006; Williams et al., 1999; Zhao et al., 2003). PHB and its copolymer PHBV have widely been used for medical applications, such as surgical sutures, wound dressings, lubricating powders, orthopedic uses, and pericardial substrate, as well as in tissue engineering materials (Hocking and Marchessault, 1994; Williams et al., 1999). PHA-based materials are also widely used in the preparation of microparticles and nanospheres for the delivery of varieties of drugs to their site of action without inducing any toxic inflammatory responses for the cells (Chen et al., 2006; Lionzo et al., 2007). Microspheres of PHB loaded with rifampicin were investigated for their use as chemoembolizing agent (Zhang et al., 1997). Thus, functionalized PHA granules seem to be excellent candidates for targeted drug delivery as they combine the biocompatible polymer properties with the properties of formation nano- or microbased carriers.

With technology now in place to allow the properties of PHA polymers to be tailored to specialized application, coupled with a significant increase in the need for new absorbable biomaterials, this class of polymers now appears to have a bright future in medicine and pharmacy. Indeed, a wide range of applications for PHA-based polymers have been described, which include their use as sutures, meniscus repair devices, bone plates and bone plate systems, ligament and tendon grafts, surgical mesh, skin substitutes, bulking and filling agents, formation of cardiac stents, and ocular cell implants (Williams, 2000; Williams et al., 2000).

4.4. PHA as Drug Carrier

Biomaterials have been widely used in medical applications, such as drug delivery, tissue engineering, device-based therapies, and medical imaging (Langer and Tirrell, 2004; Mitragotri and Lahann, 2009). Recently, biodegradable polymeric nanoparticles as drug carriers have attracted great research interest because of their biocompatibility, biodegradability, and sustained release of drugs (Panyam and Labhasetwar, 2003). Synthetic and naturally occurring polymers have played important role in the treatment of diseases and the improvement of health care. Among them, PHAs are promising materials for biomedical applications in tissue engineering and drug-delivery systems because they are natural, renewable, biodegradable, and biocompatible thermoplastics (Hazer, 2010). Different types of PHA homopolymers and copolymers produced by microorganisms have been suggested to be utilizable as tissue engineering materials and controlled release drug vectors (Khang et al., 2001; Köse et al., 2003; Timbart et al., 2004). However, only few PHA-based materials to date have been studied and their pharmacological applications have been evaluated. Microparticles prepared from either PHBV or blends of PHBV and polycaprolactone were used for the sustained release of drugs (Khang et al., 2001; Lionzo et al., 2007). Similarly, wafers produced from PHBV were also utilized for the release of antibiotics (Khang et al., 2000). Nanoparticles prepared from poly(3-hydroxybutyrate) (PHB) are getting much attention because it provides a safe, nontoxic, and biodegradable surface for coating with other materials (Pötter and Steinbüchel, 2005). Apart from that, according to ISO 10993, toxicity experiment on PHB indicated that the substance is safe to be used as nanoparticles in animals (Pötter and Steinbüchel, 2005). However, direct administration of unmodified microbial polyesters as therapeutic agents were found to induce inflammatory responses in animal tissues (Qu et al., 2006; Valappil et al., 2006).

Literature review currently shows two main methods of delivering drugs using PHA as a drug carrier system to a specific site particularly to cancer cells. The first is active targeting of the drug molecule, involving specific surface attached ligands to the polymer surface and then recognition by the specific receptors, which are expressed on the surface of cancer cells. In this method the drug molecules are conjugated with the surface attached ligands by making chemical interactions. The second approach is passive targeting involving no surface-attached ligands. The nanoparticles are simply internalized by simple endocytosis without involving any surface attached ligands. In some cases, the surface is modified with nontoxic and inert substances, which prevent nanoparticles upsonization by the phagocytic cells and also gives dispersibility to the hydrophobic polymer core in aqueous solution. The PHA-based nanoparticles used in drug delivery system is summarized in Table 1.1.

Table 1.1

PHA Nanoparticles in Drug Delivery System

5. Targeting Drug Delivery using Ligand-Conjugated PHA Nanoparticles (Active Targeting)

Different types of surface attached ligands have been exploited using PHA nanocarriers. For example, folate-conjugated P(3HB-co-3HO) nanoparticles encapsulating DOX (DOX/FA-P(3HB-co- 3HO) were synthesized by Zhang et al. (2010) for targeted drug delivery of cancer. The study confirmed that folate conjugated nanoparticles were efficiently internalized by HeLa cells as compared to nonfolate conjugated cells due to competition for the folate receptor, which increased the internalization specificity of folate expressed on cancer cells. Another study done by Kilicay et al. (2011) on delivering etoposide using P(3HB-co-3HHx) nanoparticles conjugated to folate (ETO/FA-P(3HB-co 3HHx)) in mouse fibroblast L929 cell lines. It was observed that ETO/FA-P(3HB-co-3HHx) nanoparticles exhibited much greater cytotoxicity (approximately 58% remaining viable cells) than nonfolate-conjugated particles (approximately 70% remaining viable cells), which were more cytotoxic than free etoposide drug in solution (approximately 88% remaining cell viability).

Apart from folate-based surface-attached ligands, PHA-associated surface granules, such as (PhaP) and PHA synthase (PhaC) have been widely used as surface attachment ligand. Phasin (PhaP) is an amphiphilic protein responsible for the regulation of the size of polyhydroxyalkanoic acid (PHA) granules and their number density in bacterial cells (Pötter and Steinbüchel, 2005; Prieto et al., 1999). It was reported previously that phasins form a layer on the surface of PHA granules, thereby stabilizing them in the aqueous intracellular environment of the bacteria (Nigmatullin et al., 2015). It has been confirmed that PhaP binds with higher affinity to hydrophobic materials (Pötter et al., 2002). Phasin proteins are thermally stable up to 121°C for 20 min (Handrick et al., 2004). They are also stable upon exposure to acid and alkali, as well as organic solvents, such as C1–C8 alkanol, acetone, acetonitrile, and chloroform (Handrick et al., 2004). On the other hand, side PhaC (PHA synthase) required for polymerization is linked to the active site cysteine residue (Pötter et al., 2005; York et al., 2002). It was suggested that the insertion of a desired gene sequence to the PhaP or PhaC genes can produce fusion proteins that could be used for wide range applications (Hooks et al., 2014; Li et al., 2015). Rho et al. (2014) prepared (His)6-tagged or GST-fusion recombinant phasin and utilized for the artificial granule preparation. In addition, they also coloaded P(3HB) depolymerase with the recombinant phasin to prepare self-degradable phasin-coated P(3HB) granules. Yao et al. (2008) fused PhaP with recombinant human epidermal growth factor (rhEGF) and produced rhEGF-Phap fusion proteins. These fusion proteins were then linked to presynthesized P(3HB-co-3HHx) nanoparticles. In order to find intracellular accumulation of the receptor conjugated nanoparticles, Rhodamine-B was loaded into the particles and transplantable murine hepatoma 22 (H22) model cells were implanted into BALB/c mice, which were then treated with Rhodamine-B loaded particles. A variety of tissue types were then sampled to assess particle distribution. Fluorescent microscopy studies demonstrated that Rhodamine-B loaded rhEGF-PhaP-PHBHHX nanoparticles were found selectively accumulated within the tumor in large amounts.

Many studies have also described PhaC as a linker region to conjugate it to PHA nanoparticles. Studies conducted by Kim et al. (2009); Lee et al. (2011) described the use of PhaC to links targeting moieties like RGD4C, a ligand-binding αvβ3 integrin overexpressed in many cancers and preprepared P(3HB) nanoparticles and block copolymers. They found that RGD4C was overexpressed in MDA-MB 231 breast cancer cells showing its higher affinity for targeted particles. Similarly, Kim et al. (2009) produced functionalized P(3HB) granules and linked an A33scFv (targeting moiety) and GFP (imaging moiety)