Antimicrobial Nanoarchitectonics: From Synthesis to Applications

By Alexandru Mihai Grumezescu

Antimicrobial Nanoarchitectonics: From Synthesis to Applications brings together recent research in antimicrobial nanoparticles, specifically in the sustained and controlled delivery of antimicrobials. Particular attention is given to i) reducing the side effects of antibiotics, ii) increasing the pharmacological effect, and iii) improving aqueous solubility and chemical stability of different antimicrobials. In addition, antimicrobial nanoparticles in drug delivery are discussed extensively. The book also evaluates the pros and cons of using nanostructured biomaterials in the prevention and eradication of infections. It is an important reference resource for materials scientists and bioengineers who want to learn how nanomaterials are used in antimicrobial therapy.

• Provides readers with the information necessary to select the appropriate bionanomaterial to solve particular infection problems
• Includes case studies, showing how particular bionanomaterials have been used to cure infections
• Explains the central role that nanotechnology plays in modern antimicrobial therapy
• Evaluates the pros and cons of using nanostructured biomaterials in the prevention and eradication of infections

• Language: English
• Publisher: Elsevier Science
• Release date: Jun 22, 2017
• ISBN: 9780323527347

Book preview

Antimicrobial Nanoarchitectonics

From Synthesis to Applications

Edited by

Alexandru Mihai Grumezescu

University Politehnica of Bucharest,

Department of Science and Engineering of Oxide Materials and Nanomaterials,

Faculty of Applied Chemistry and Materials Science, Bucharest, Romania

Table of Contents

Cover

Title page

Copyright

List of Contributors

Foreword

Preface

Chapter 1: New Trends in the Antimicrobial Agents Delivery Using Nanoparticles

Abstract

1. Introduction

2. Nanoparticles for Drug-delivery Systems

3. Polymeric Carriers Used to Prepare Nanoparticles as Drug Carriers

4. Recent Trends in Nanoparticulate Drug-Delivery Systems

5. Application of Nanoparticles/Diverse and Emerging Trends in Nanoparticles Applications

6. Concluding Remarks and Future Prospects

Chapter 2: Nanostructures as Antimicrobial Therapeutics

Abstract

1. Introduction

2. Nanoparticles as Antimicrobial Agents

3. Mode of Action of Nanoparticles

4. Nanoparticles Use in Antimicrobial Therapy

5. Types of Nanoparticles

6. Commerically Available Antimicrobial Nanoparticles

7. Biosafety Issues

8. Conclusions

Chapter 3: Nanoformulation and Application of Phytochemicals as Antimicrobial Agents

Abstract

1. Phytochemicals

2. Types of Phytochemicals

3. Extraction and Purification Methods

4. Antimicrobial Activity of Phytochemicals

5. Nanoformulations of Phytochemicals

6. Applications of Nanoformulated Phytochemicals

7. Conclusions

Chapter 4: Antimicrobial Activities of Metallic and Metal Oxide Nanoparticles From Plant Extracts

Abstract

1. Introduction

2. Biosynthesis of Metallic Nanoparticles

3. Antimicrobial Activities of Nanoparticles from Plant Extracts

4. Mechanism of Action

5. Future Prospectives

Chapter 5: Nanogels: A New Dawn in Antimicrobial Chemotherapy

Abstract

1. Introduction

2. Properties of Nanogels

3. Classification of Nanogels

4. Synthesis of Nanogels

5. Characterization

6. Routes of Administration of Nanogel

7. Application of Nanogels

8. Toxicity of Nanogel

9. Disadvantages of Nanogel

10. Conclusions

Chapter 6: Silver Nanoparticles: A Novel Antimicrobial Agent

Abstract

1. Introduction

2. Antimicrobial Activity

3. Antifungal Mechanism

4. Antibacterial Mechanism

5. Application

6. Conclusions and Future Prospects

Chapter 7: Recent Advances of Nanostructures in Antimicrobial Therapy

Abstract

1. Introduction

2. Nanoliposomes for Antimicrobial Therapy

3. Nanoparticles for Antimicrobial Therapy

4. Nanomicelles for Antimicrobial Therapy

5. Nanodendrimers for Antimicrobial Therapy

6. Quantum Dot for Antimicrobial Therapy

7. Nanopolymersomes and Nanoconjugates for Antimicrobial Therapy

8. Nanogels for Antimicrobial Therapy

9. Carbon Nanotubes for Antimicrobial Therapy

10. Nanographene Oxide for Antimicrobial Therapy

11. Nanobubbles for Antimicrobial Therapy

12. Nanodevices and Nanostructures for Sepsis Therapy

13. Conclusions and Perspective

Chapter 8: Metals and Metal Oxides: Important Nanomaterials With Antimicrobial Activity

Abstract

1. Introduction

2. Brief Account of Antibiotic Resistance in Pathogenic Bacteria

3. Costs of Fighting Infectious Diseases and Antibiotic Resistance

4. Alternative Antimicrobial Agents

5. Nanoantibiotics: An Alternative Approach to Combat Antibiotic Resistance

6. Selective Activity of Nanoparticles

7. Metal and Metal Oxide NPs Based Commercial Products

8. Advantages and Disadvantages of Nanoantibiotics

9. Nanotoxicology Perspective

10. Dose Optimization

11. Conclusions

Chapter 9: Antimicrobial Properties and Therapeutic Applications of Silver Nanoparticles and Nanocomposites

Abstract

1. Introduction

2. Synthesis of Silver Nanoparticles: Methods Overview

3. Biological Properties of Silver Nanoparticles

4. Toxicity of Silver Nanoparticles

5. Polymer-Based Nanosilver Composites: Preparation, Biological Activity, and Toxicity

6. Conclusions

Acknowledgments

Chapter 10: Drug Resistance in Tuberculosis: Nanomedicines at Rescue

Abstract

1. Introduction

2. Drug Resistance in Tuberculosis

3. Mechanism of Drug Resistance

4. Currently Available Methods and Their Disadvantages in Treating Drug Resistance

5. Nanotechnology: An Answer to Treatment of Multidrug-Resistant TB

6. Future Prospects

Chapter 11: Nanomaterials as Enhanced Antimicrobial Agent/Activity-Enhancer for Transdermal Applications: A Review

Abstract

1. Antimicrobials in General

2. Conventional Antimicrobial Agents

3. Antimicrobials for Transdermal Applications

4. New Materials as Antimicrobials for Transdermal Applications

5. New Approaches Toward Rapid Transfers Through a TDDS

6. Future Prospects

Acknowledgments

Chapter 12: Nanosize Dendrimers: Potential Use as Carriers and Antimicrobials

Abstract

1. Introduction

2. Role of Nanoparticles Against Microbes

3. Dendrimers as Antimicrobial Agents

4. Dendrimers as Antiviral Compounds

5. Dendrimers as Diagnostic AIDS for Microbial Infection

6. Expert Opinion and Outlook

7. Conclusions

Acknowledgments

Chapter 13: Silver Nanostructures in Medicine: Synthesis and Biological Activity

Abstract

1. Introduction

2. Basic Structures of Silver at the Nanoscale

3. Synthesis of Nanosilver

4. Potential Toxicity of Silver Nanomaterials

5. Antimicrobial Properties of Silver Nanomaterials

6. Antiinflammatory Properties of Silver Nanomaterials

7. Summary and Future Research

Chapter 14: Nanoparticles in Antiviral Therapy

Abstract

1. Introduction

2. Virus Replication Cycle

3. Selected Antiviral Agents

4. Antiviral Resistance

5. Overview of Particulate Carriers for Drug Delivery

6. Targeted Delivery of Antiviral Agents

7. Treatment of Several Enveloped Viruses With Nanocarriers

8. Concluding Comments

Chapter 15: Applications of Metallic Nanoparticles in Antimicrobial Therapy

Abstract

1. Introduction

2. Advantages and Disadvantages of Metallic Nanoparticles

3. Metallic Nanoparticles Classification and Characteristics

4. Specific Applications in Antimicrobial Therapy

5. Future Perspectives

6. Conclusions

Chapter 16: Nanostructures for Antimicrobial Therapy—The Modern Trends in the Treatment of Bacterial Infections

Abstract

1. Introduction

2. Epidemiological Aspects of Antimicrobial Resistance

3. The Mechanism of Antimicrobial Resistance and Its Ability to Spread Among Bacterial Strains

4. Characterization of Existing Antibiotics on Their Properties to Affect the Bacteria

5. Nanotechnological Approaches in Terms of Solving Antimicrobial Resistance

6. Nanoparticles Revealing Antimicrobial Action

7. Magnetite-Containing Nanocapsules

8. Liposomal Nanoparticles (LNPs)

9. Conclusions

Acknowledgment

Chapter 17: Nanomedicine: Emerging Trends in Treatment of Malaria

Abstract

1. Introduction

2. Emergence of Drug Resistant Parasite

3. Role of Nanomedicines to Overcome Problems Associated with Conventional Antimalarial Therapy

4. Case Studies

5. Future Aspects

6. Conclusions

Acknowledgments

Chapter 18: Toxicity of Nanoparticles: Etiology and Mechanisms

Abstract

1. Introduction

2. Sources of Toxic NPs and Health Effects

3. NPs Physico-chemical Properties Classification and Health Effects

4. Mechanism of Toxicity

5. Molecular Mechanism of Toxicity

6. Diagnostic and Therapies for NP Toxicity

7. Conclusions

Index

Copyright

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List of Contributors

Yii S. Aing,     Curtin University, Sarawak, Malaysia

Abdulaziz A. Al-Khedhairy,     King Saud University, Riyadh, Saudi Arabia

Aleksandar Arsenijevic,     University of Kragujevac, Kragujevac, Serbia

Nebojsa Arsenijevic,     University of Kragujevac, Kragujevac, Serbia

José M. Bermúdez,     Research Institute for the Chemical Industry (INIQUI, National University of Salta-CONICET), Salta, Argentina

Kripal Bhalala,     National Institute of Pharmaceutical Education and Research (NIPER), Raebareli, Uttar Pradesh, India

Prakash S. Bisen

Jaipur National University, Jaipur, Rajasthan

Jiwaji University; Davars Campus, Gwalior, Madhya Pradesh, India

Robert E. Burrell,     University of Alberta, Edmonton, AB, Canada

Joana Carrola,     University of Aveiro, Aveiro, Portugal

Yen S. Chan,     Curtin University, Sarawak, Malaysia

Balu A. Chopade,     University of Pune, Pune, Maharashtra, India

Alicia G. Cid,     Research Institute for the Chemical Industry (INIQUI, National University of Salta-CONICET), Salta, Argentina

Clara I. Colino,     University of Salamanca; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain

Guido Crisponi,     University of Cagliari, Cittadella Universitaria, Monserrato-Cagliari, Italy

Michael K. Danquah,     Curtin University, Sarawak, Malaysia

Bhaskar Das,     Indian Institute of Technology Guwahati, Guwahati, Assam, India

Debashree Das,     Dr Hari Singh Gour University, Sagar, Madhya Pradesh, India

Meenal Dixit,     Jaipur National University, Jaipur, Rajasthan, India

Iola F. Duarte,     University of Aveiro, Aveiro, Portugal

Carmen S.R. Freire,     University of Aveiro, Aveiro, Portugal

Sally Fung,     University of Alberta, Edmonton, AB, Canada

Anuj Garg,     National Institute of Pharmaceutical Education and Research (NIPER), Raebareli, Uttar Pradesh, India

Sougata Ghosh,     University of Pune, Pune, Maharashtra, India

Ulviyya A. Hasanova,     Baku State University, Baku, Azerbaijan

Zhi-Yao He,     Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China

Arun K. Iyer,     Wayne State University, Detroit, MI, United States

Indrani Jadhav,     Jaipur National University, Jaipur, Rajasthan, India

Jaison Jeevanandam,     Curtin University, Sarawak, Malaysia

Sangeeta N. Kale,     Defence Institute of Advanced Technology, Pune, Maharashtra, India

Tatjana Kanjevac,     University of Kragujevac, Kragujevac, Serbia

Sushil K. Kashaw,     Dr Hari Singh Gour University, Sagar, Madhya Pradesh, India

Varsha Kashaw,     SVN Institute of Pharmaceutical Sciences, SVN University, Sagar, Madhya Pradesh, India

Shams T. Khan,     Aligarh Muslim University, Aligarh, Uttar Pradesh, India

Rohini Kitture,     Defence Institute of Advanced Technology, Pune, Maharashtra, India

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

Nitendra Kumar,     Indian Institute of Technology Guwahati, Guwahati, Assam, India

Joanna I. Lachowicz,     University of Cagliari, Cittadella Universitaria, Monserrato-Cagliari, Italy

José M. Lanao,     University of Salamanca; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain

Dong Gun Lee,     Kyungpook National University, Bukgu, Daegu, Republic of Korea

Abel M. Maharramov,     Baku State University, Baku, Azerbaijan

Serenella Medici,     University of Sassari, Sassari, Italy

Carmen G. Millán,     University of Salamanca; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain

Jelena Milovanovic,     University of Kragujevac, Kragujevac, Serbia

Marija Milovanovic,     University of Kragujevac, Kragujevac, Serbia

Remya Mohanraj,     Houston Community College, Houston, TX, United States

Patricia L. Nadworny,     Innovotech Inc., Edmonton, AB, Canada

Maryam Nasirpour,     University of Aveiro, Aveiro, Portugal

Valeria M. Nurchi,     University of Cagliari, Cittadella Universitaria, Monserrato-Cagliari, Italy

Helena Oliveira,     University of Aveiro, Aveiro, Portugal

Santiago D. Palma,     National University of Córdoba, University City, Córdoba, Argentina

Sharadwata Pan,     Indian Institute of Technology, New Delhi, Delhi, India

Sanjukta Patra,     Indian Institute of Technology Guwahati, Guwahati, Assam, India

Massimiliano Peana,     University of Sassari, Sassari, Italy

Ricardo J.B. Pinto,     University of Aveiro, Aveiro, Portugal

Mahammadali A. Ramazanov,     Baku State University, Baku, Azerbaijan

Analía I. Romero,     Research Institute for the Chemical Industry (INIQUI, National University of Salta-CONICET), Salta, Argentina

Prashant Sahu,     Dr Hari Singh Gour University, Sagar, Madhya Pradesh, India

Divya Shrivastava,     Jaipur National University, Jaipur, Rajasthan, India

Nehi Sinha,     Jaipur National University, Jaipur, Rajasthan, India

Ugir H. Sk,     CSIR-Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh, India

Hillary M. Sweet,     University of Alberta, Edmonton, AB, Canada

Devendra Singh Tomar,     National Institute of Pharmaceutical Education and Research (NIPER), Raebareli, Uttar Pradesh, India

Mercedes Villegas,     Research Institute for the Chemical Industry (INIQUI, National University of Salta-CONICET), Salta, Argentina

Natalia Angel Villegas,     National University of Córdoba, University City, Córdoba, Argentina

Muhammad Wahajuddin,     CSIR-Central Drug Research Institute (CDRI), Lucknow, Uttar Pradesh, India

Xia-Wei Wei,     Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China

Yu-Quan Wei,     Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China

J. Barry Wright,     University of Saskatchewan, Saskatoon, SK, Canada

Jatinder V. Yakhmi,     Homi Bhabha National Institute, Mumbai, Maharashtra, India

JiEun Yun,     Kyungpook National University, Bukgu, Daegu, Republic of Korea

Hinojal Zazo,     University of Salamanca; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain

Maria Antomietta Zoroddu,     University of Sassari, Sassari, Italy

Foreword

It is a pleasure and a privilege to write the foreword for Antimicrobial Nanoarchitectonics: From Synthesis to Applications. This timely volume describes the use of nanoparticles and nanostructured materials as promising new strategies to overcome microbial drug resistance.

The treatment of serious bacterial infections in clinical practice is often complicated by the development of antimicrobial resistance (AR) to conventional drugs, which has been highlighted as one of the major four public health concerns in Europe. AR is of particular concern in nosocomial and hospital-acquired infections. The inappropriate use of antibiotics has contributed to increased AR, both by selecting far more resistant members of a microbial population, and by eliminating the patient’s indigenous microbiota, which might otherwise compete with the pathogen.

Conventional treatment for infections typically consists of long-term therapy with a combination of antibiotic drugs, which may lead to side effects and contribute to poor patient compliance. Significantly, the increasing emergence of resistance to commonly used antibiotic and antifungal drugs has emphasized the need for the development of novel therapeutics and approaches, which will not only destroy resistant organisms, but also not lead to new induction of resistance.

Over the last few decades, the applications of nanotechnology in medicine have been extensively explored in many medical areas, especially in drug delivery and in the design of functionalized surfaces with improved biological properties, such as increased biocompatibility and resistance to microbial colonization. A 2006 European Technological Observatory survey showed that more than 150 pharmaceutical companies were developing nanoscale-based therapeutics.

Since the development of new antimicrobial agents is an elaborate and difficult process, nanotechnology-based strategies aiming to improve the efficacy of natural and synthetic antimicrobial compounds or to replace existing antibiotics hold great promise for improving the future fight against resistant infections. Nanomedicines have the potential to improve anti-microbial treatment, by incorporating, encapsulating, or conjugating a variety of drugs in order to target specific cell populations, and to offer tunable and site-specific drug release. Intelligent or smart drug delivery approaches are based on the use of nanocarrier systems to control the local release of antibiotic drugs and to maximize their target activity. Nanocarriers have the potential to modify modern drugs by increasing their efficacy, stability, solubility, and biocompatibility and by decreasing their toxicity, while maintaining their therapeutic effects. Nanovehicles can offer sustained drug release and can concurrently deliver multiple different therapeutic agents for combined therapy. Due to the high surface-volume ratio of nanocarriers, they offer reduced dosage and frequency of administration of potentially toxic substances. This potential toxicity applies to some antibiotics and most anticancer agents, and the use of nanocarriers can provide an adequate supply of these active substances over an extended period of time.

Several different classes of antimicrobial nanoparticles and nanosized carriers can be used for antibiotic delivery, and have proven their effectiveness for treating infectious diseases. Moreover, many types of nanomaterials are currently being investigated for various applications that may improve medical devices, by increasing their resistance to microbial colonization and biofilm development. These nanotechnology-enabled devices will reduce health care risks by increasing the durability and quality of prostheses, improving patient comfort and quality of life, and reducing the costs of their maintenance. The advantages offered by nanotechnology can be successfully combined with natural products with inherent antibiofilm/microbiostatic/microbicidal activities, resulting in an efficient strategy to combat AR.

The contents of this book are expected to offer valuable information for future research in the hot field of AR, by highlighting the numerous advantages provided by antimicrobial nanomaterials and their applications in the development of new antimicrobial therapies. Approaches such as these may play a significant role in the international effort to save the world from the potential disaster threatened by the out-of-control development of AR.

Michael R. Hamblin

Massachusetts General Hospital, Boston, MA, United States

Harvard Medical School, Boston, MA, United States

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

Mariana C. Chifiriuc

University of Bucharest, Bucharest, Romania

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

Preface

Nanotechnology offers a great variety of solutions for antimicrobial therapy. In the actual context of permanently increasing microbial resistance rates to antibiotics, novel antimicrobial approaches for targeted therapy are urgently needed. The field of nanoarchitectonics introduces the concept of specifically engineering materials in nanoscale to achieve a particular goal. The architecture of nanosized drug-delivery systems is currently under intensive research, since it seems to control numerous key aspects of the therapy, such as drug properties, delivery, stability, and controlled release.

Current approaches aim to utilize more natural products not only in antimicrobial therapy, but also in prophylaxis, thus developing nanosystems functionalized with natural antimicrobials. This approach is preferentially embraced since natural products do not select as much antimicrobial resistance as synthetic antibiotics. Moreover, nanosystems may overcome disadvantages of natural antimicrobials by stabilizing their structure, controlling their release, and reducing volatility-related issues and side effects associated with the use of high amounts of active compounds.

The aim of this book is to reveal the most recent findings in the field of antimicrobial nanoarchitectures, elaborating on the progress made in research and therapy, as well as discussing future perspectives in personalized treatment of infections.

This book, entitled Antimicrobial Nanoarchitectonics: From Synthesis to Applications, contains 18 clearly illustrated chapters, prepared by outstanding international researchers from Argentina, India, USA, Korea, China, Saudi Arabia, Portugal, Canada, Serbia, Spain, Italy, and Azerbaidjan.

Chapter 1, New Trends in the Antimicrobial Agents Delivery Using Nanoparticles, prepared by José M. Bermudez et al., reviews the latest trends and emerging technologies related to drug-delivery platforms based on nanoparticle systems. The preparation and study of these novel drug-delivery systems open unpredictable opportunities and result in biological and pharmacological applications for combating infectious diseases.

Chapter 2, prepared by Niha M. Kulshreshtha, entitled Nanostructures as Antimicrobial Therapeutics, highlights the recent advances in the field of antimicrobial nanoparticles, exposing their unique properties and mode of action, along with their biocompatibility issues.

Jaison Jeevanandam et al., in Chapter 3, Nanoformulation and Application of Phytochemicals as Antimicrobial Agents, discuss biochemical process advancements in the extraction and purification of phytochemicals with antimicrobial properties. Various nanoformulation technologies essential to enhancing the antimicrobial efficacy of phytochemicals and possible applications are also revealed.

Chapter 4, Antimicrobial Activities of Metallic and Metal Oxide Nanoparticles from Plant Extracts, prepared by Remya Mohanraj et al., provides a review of the antimicrobial activities exhibited by metallic nanoparticles synthesized using various plant extracts. Additionally, background information regarding their mechanism of action, green synthesis, and future prospects is highlighted.

Prashant Sahu et al., in Chapter 5, Nanogels: A New Dawn in Antimicrobial Chemotherapy, describe the recent development of nanogel drug delivery systems in terms of their efficacy in antimicrobial chemotherapy.

Chapter 6, Silver Nanoparticles: A Novel Antimicrobial Agent, prepared by Ji Eun Yun et al., discusses silver nanoparticles that increase the antibacterial capacity of conventional drugs, which confront the problem of resistance and inhibit the formation of biofilms. The authors also reveal the main antimicrobial mechanisms: membrane disruption, apoptosis, and synergy.

Chapter 7, prepared by Zhi-Yao He et al., entitled Recent Advances of Nanostructures in Antimicrobial Therapy, focuses on the potential of nanostructures (nanoliposomes, nanoparticles, nanomicelles, nanogels, nanodendrimers, nanodevices, nanopolymersomes, nanoconjugates, nanobubbles, carbon nanotubes, nanographene oxide, and quantum dots) to reverse resistance to antimicrobial agents.

Shams Tabrez Khan et al., in Chapter 8, Metals and Metal Oxides: Important Nanomaterials With Antimicrobial Activity, present an up-to-date overview of different types of nanoparticles that exhibit prominent antimicrobial activity against pathogenic microorganisms. Suitability of these nanoparticles for use as supplementary antimicrobials, antimicrobial agents, food packaging, textile, deodorants, in skin care products, oral hygiene, and in fortifying the surfaces of medical devices prone to microbial infections, are also discussed.

Chapter 9, Antimicrobial Properties and Therapeutic Applications of Silver Nanoparticles and Nanocomposites, prepared by Ricardo J.B. Pinto et al., gives an up-to-date perspective on the preparation, biological properties, and toxicity of AgNPs intended for therapeutic applications. Moreover, the preparation and testing of AgNPs polymer-based composites are addressed in the last section, as this area configures an important strategy toward the development of novel nanosilver products with improved stability, therapeutic properties, and toxicity profiles.

Nitendra Kumar et al., in Chapter 10, Drug Resistance in Tuberculosis: Nanomedicines at Rescue, summarize emerging efforts in combating tuberculosis, particularly using antimicrobial NPs and antibiotic delivery systems as new tools to tackle the current challenges in therapy.

Chapter 11, Nanomaterials as Enhanced Antimicrobial Agent/Activity-Enhancer for Transdermal Applications: A Review, prepared by S.N. Kale, focuses on the applicability of nanomaterials for dermal applications (such as wound healing, inflammation control, or postburn sepsis treatments). Stimuli-sensitive properties of nanomaterials are being envisaged for smarter medicinal patches. The effects of the size of nanoparticles, their surface/volume ratio, and their chemical and physical properties are correlated to their crucial role in affecting the cellular membrane integrity, metabolic processes, and morphology.

Chapter 12, Nanosize Dendrimers: Potential Use as Carriers and Antimicrobials, prepared by Ugir Hossain Sk, discusses how various dendrimers can serve as unique platforms to transport antimicrobial agents and how nanoformulations can improve therapies for various infectious diseases. Also, the authors summarize several preclinical studies of the dendrimer’s role in antimicrobial therapy.

Hillary M. Sweet et al., in Chapter 13, Silver Nanostructures in Medicine: Synthesis and Biological Activity, reviews the advances in nanostructured silver materials, focusing on their toxicity, antimicrobial, and antiinflammatory properties. The pros (antimicrobial and antiinflammatory activity) and cons (toxicity and proinflammatory activity) of these technologies are presented via a detailed examination of the literature. In addition to providing the most recent data on silver nanomaterial activity, this chapter also suggests areas of potential interest for future development and innovation.

Chapter 14, prepared by Marija Milovanovic et al., entitled Nanoparticles in Antiviral Therapy, summarizes the antiviral activity of different nanoparticle-based approaches, currently available for the treatment of viral infections, and discusses metal nanoparticles as possible future antiviral drugs.

Chapter 15, Applications of Metallic Nanoparticles in Antimicrobial Therapy, prepared by H. Zazo et al., provides an extensive overview about different kinds of metallic nanoparticles and about current research and clinical trials addressing the use of nanoparticles within the field of infectious diseases.

Abel Mammadali Maharramov et al., in Chapter 16, Nanostructures for Antimicrobial Therapy—the Modern Trends in the Treatment of Bacterial Infections, offer up-to-date information about antimicrobial resistance and modern nanotechnological approaches in terms of solving of antimicrobial resistance problems.

Chapter 17, Nanomedicine: Emerging Trends in Treatment of Malaria, prepared by Anuj Garg et al., presents an overview about the way of better use of existing antimalarial drugs using a new-age drug delivery platform: nanomedicine.

Joanna Izabela Lachowicz et al., in Chapter 18, Toxicity of Nanoparticles: Etiology and Mechanisms, describe the sources of nanoparticles and their toxic effects. The authors dedicate particular attention to nanoparticles used in the health care industry that draw abundantly upon nanotechnology. Also, the chapter approaches and discusses the mechanisms of toxicity, which is important not only in preventing intoxication with nanoparticles, but also in preparing tailored treatments.

Alexandru M. Grumezescu

University Politehnica of Bucharest, Bucharest, Romania

http://grumezescu.com/

Chapter 1

New Trends in the Antimicrobial Agents Delivery Using Nanoparticles

José M. Bermúdez*

Alicia G. Cid*

Analía I. Romero*

Mercedes Villegas*

Natalia Angel Villegas**

Santiago D. Palma**

*    Research Institute for the Chemical Industry (INIQUI, National University of Salta-CONICET), Salta, Argentina

**    National University of Córdoba, University City, Córdoba, Argentina

Abstract

In recent years, there has been an unprecedented explosion of research and applications in the field of nanotechnology. Advances in nanotechnology have paved the way to the discovery of innumerable methods for prevention or treatment of various diseases.

Nowadays, novel infectious diseases have emerged, many of which are responsible for life-threatening disorders. A lack of new antibiotics for treatment of illnesses, combined with the appearance of multidrug-resistant strains, has generated the imperative requirement for innovative strategies in the development of newer antimicrobial therapies. In this context, one of the most active research areas of nanotechnology has been the development of nanoparticles, which has become the subject of interest of many research groups in a variety of fields. Nanoparticles with appropriate physicochemical properties can be taken up by cells of the body more easily than much larger molecules. Drugs may be encapsulated, adsorbed, or conjugated to the nanoparticles. These strategies impart uniqueness, which can lead to improved performance in many of the dosage forms. Nanoparticles used for medical applications have to be biocompatible, biodegradable, and nontoxic. The preparation and study of these novel drug-delivery systems open unpredictable opportunities and result in biological and pharmacological applications to combating infectious diseases.

Keywords

nanoparticles

antimicrobial

drug-delivery systems

Outline

1 Introduction

2 Nanoparticles for Drug-Delivery Systems

3 Polymeric Carriers Used to Prepare Nanoparticles as Drug Carriers

3.1 Natural Polymers

3.2 Semisynthetic Polymers

3.3 Synthetic Biodegradable Polymers

4 Recent Trends in Nanoparticulate Drug-Delivery Systems

4.1 Biological Transport of Nanoparticles

4.2 Ideal Properties of Nanoparticle Delivery Systems

4.3 Types of Nanoparticulate Drug Delivery System

5 Application of Nanoparticles/Diverse and Emerging Trends in Nanoparticles Applications

6 Concluding Remarks and Future Prospects

References 

1. Introduction

In recent years, there has been an unprecedented explosion of research and applications in the field of nanotechnology. Nanotechnology has the potential to significantly improve the prevention, detection, and treatment of diseases. There is a tremendous amount of excitement that this field of nanotechnology will build momentum and produce new avenues for the treatment of diseases. Inherent to this optimism are the related challenges in the areas of medical applications.

The word nanotechnology began as a technical term, but recently it became a popular term representing the current state-of-the-art technology. Until a few decades ago, it was uncommon to find words with the prefix nano (e.g., nanotechnology, nanomaterials, nanoparticles, nanoemulsions, and nanotubes). It is highly noticeable how the word nano has been dynamically incorporated into our scientific language and even into our day-to-day lives. This can be explained by the evident advantages of working at the nanoscale level compared with the traditional micro/macroscale level. The term nanotechnology was used for the first time in 1974 by Norio Taniguchi to describe the intimate engineering (atoms or molecules) of the matter. The most common consensus, however, is that nanotechnology investigates and manipulates materials and phenomena where at least one length scale is below 100 nm. Some early studies reported the potential of nanoscale drug-delivery systems, and since then a myriad of these delivery systems have been documented (Khanna and Speiser, 1969; Krause et al., 1985). The biomedical and pharmaceutical fields have been utilizing nanomaterials for various applications, such as tissue engineering, gene therapy, chemotherapy, peptide/protein delivery, molecular imaging, and high-throughput screening/assay, so the exact definition of nanotechnology is difficult to make solely based on size.

The dream of delivering a pharmaceutically active molecule to a specific site in the body has been a long-held aspiration with beginnings that may be traced back to Paul Ehrlich, who in the early 20th century coined the phrase magic bullet to describe such an entity (Sykes, 2000). Today, extensive pharmaceutical research has led to the development of drug-delivery systems (DDSs) and strategies that go some way to fulfilling this idea, but few that could be described as magic bullets.

Nanotechnology, a multidisciplinary scientific undertaking, involves the creation and utilization of materials, devices, or systems on the nanometer scale, and is currently undergoing explosive development on many fronts. It is expected to spark innovation and to play a critical role in various biomedical applications, especially in drug delivery, as is shown by the wealth of information presented in this chapter; in particular, advances in nanotechnology that enable drugs to preserve their efficacy while being delivered to precise therapeutic targets are creating a host of opportunities for drug developers. In addition, by combining nanotechnology-based target-specific drug therapy with methods for early diagnosis of pathologies, we are getting closer to creating the ultimate functional drug carrier.

The two fabrication methods in nanotechnology are bottom–up and top–down. The former builds nanomaterials from the atomic and molecular levels, whereas the latter generates nanostructures out of macrosized materials. Several authors use the expression top–down to describe the preparation of nanosystems by the rupture (e.g., milling) of a material block. Even though top–down methods are reliable and provide device complexity, they involve greater use of energy and more waste products than bottom–up methods. The expression bottom–up, however, relates to the fabrication of nanosystems by the assembly of basic components, such as atoms or molecules (Kumar et al., 2011; Sharma et al., 2010).

Fabricated nanosized devices or drug carriers, often called nanocarriers or nanovehicles, provide various advantages for effective drug delivery. Nanocarriers can carry poorly soluble, unstable, or systemically toxic drugs with extended blood half-lives and reduced side effects. A material at the nanoscale is expected to have different properties and behavior than larger particles due to the fact that nanosystems have a much greater surface area. Less material can be used for specific important technological, economic, and environmental applications. The large surface area causes nanosystems to be more reactive than larger particles, and some of the fundamental chemical and physical properties change.

An increased surface area and quantum effects are the two main factors by which nanomaterials differ substantially from other materials, since they may modify material properties, such as, for example, reactivity, strength, or in vivo behavior. The change on the properties can be explained because the number of atoms in the surface increases when the particle size decreases.

On moving forward into the 21st century, it is apparent that modern medicine still faces many challenges. Nanotechnology is indeed one area that may offer scientific advances in the coming years, which could lead to significant progress in the improvement of therapeutic outcomes. In particular, the development of nanoparticulate drug delivery systems (NPDDSs) may enhance the probability of getting a drug to its target site (Lockman et al., 2002).

Products of nanotechnology are expected to revolutionize modern medicine, as evidenced by recent scientific advances and global initiatives to support nanotechnology and nanomedicine research. The field of drug delivery is a direct beneficiary of these advancements. Due to their versatility in targeting tissues, accessing deep molecular targets, and controlling drug release, nanoparticles are helping address challenges to face the delivery of modern, as well as conventional drugs. Since the majority of drug products employ solids, nanoparticles are expected to have a broad impact on drug product development.

For many decades, pharmaceutical research has been interested in modifying DDSs. In recent years, due to the enormous expansion in various fields and sets of scientific skills, the scope has been expanded to incorporate many abilities in investigating drug delivery covering genetics, physics, bioelectronics, electrical engineering, biotechnology, polymers science, and molecular pharmaceutics.

As shown in this text, a variety of nanostructures are being investigated as functional drug carriers for treating a wide range of therapies, most notably cardiovascular defects, autoimmune diseases, and cancer. While the concept of nanoparticles in drug delivery is not new, the number of research programs and active drug development projects in this field has escalated as funding for nanotechnology has increased. The result is the emergence of a host of novel nanotechnologies tailored to meet the physicochemical and therapeutic requirements of drug developers. With all this potential for advanced drug delivery and targeted therapy with reduced side effects, nanotechnology-based DDSs hold the promise of significantly improving quality of life through nanomedicine. Nanoparticles are building the bridge of scientific knowledge connecting bulk materials to atomic or molecular structures.

In pharmaceutics, approximately 90% of all medicines, the active ingredient is in the form of solid particles. Researchers have demonstrated that unparalleled opportunities for targeting can be achieved by drugs formulated in the nano range. With the arrival of technical and analytical capabilities for measuring particle size in nanometer range, research and development of DDSs has been moving from micro- to nanoscale particles. The interest of many investigations is aimed at the use of technology to reduce particle size to nanometer ranges, allowing for decreased dose and reactive nature of molecules, and for the delivery of drugs at target sites. Therefore, considerable research is being conducted to develop nanocarriers as DDSs.

One of the most active research areas of nanotechnology has been the development of nanoparticles, which has become the subject of interest of many research groups in a variety of fields. Nanoparticles were first developed by Speiser and coworkers (Kreuter and Speiser, 1976) around 1970 and are defined as solid colloidal particles, less than 1 m in size, that consist of macromolecular compounds. Since then, a considerable amount of work on nanoparticles has been and is being carried out around the world in the field of drug/gene delivery.

Nanoparticles range in size from 10 to 1000 nm, and they can be made from natural or artificial polymers and other macromolecules. Nanoparticles with appropriate physicochemical properties can be taken up by cells of the body more easily than much larger molecules. Drugs may be encapsulated, adsorbed, or conjugated to the nanoparticles. These strategies impart uniqueness, which can lead to improved performance in many of the dosage forms. With the development in nanotechnology, it is now possible to produce drug nanoparticles that can be utilized in a variety of innovative ways. New drug delivery pathways can now be used that can increase drug efficacy and reduce side effects.

Drugs or other biologically active molecules are dissolved, entrapped, or encapsulated in the nanoparticles or are chemically attached to the polymers or adsorbed to their surface. The selection of the appropriate method for preparing drug-loaded nanoparticles depends on the physicochemical properties of the polymer and the drug. On the other hand, the procedure and the formulation conditions will determine the inner structure of these polymeric colloidal systems. Two types of systems with different inner structures are possible: (1) a matrix-type system composed of an entanglement of oligomer or polymer units, defined here as a nanoparticle or nanosphere, and (2) a reservoir-type system, consisting of an oily core surrounded by a polymer wall, defined here as a nanocapsule. Various colloidal nanoparticulate systems in use for drug/gene delivery are as shown in Fig. 1.1. The term nanoparticle will be used to refer to both systems, including nanoparticles, as well as nanocapsules.

Figure 1.1   Different types of nanoparticles structures.

A drug’s delivery vehicle can have a significant impact on its efficacy. Nanoscale manipulation of drug delivery vehicles can substantially improve pharmacokinetics, pharmacodynamics, nonspecific toxicity, immunogenicity, and biorecognition properties (Couvreur and Vauthier, 2006; Kopecek, 2003). As a result, applying these technologies to pharmaceutical development has the potential to revolutionize the delivery of biologically active compounds. The ideal DDS needs to protect drugs from degradation via enzymatic, mechanical, or chemical pathways. It should also have enhanced diffusion through the epithelium, targeted tissue distribution, or increased penetration into its target cell depending on the application (Couvreur and Vauthier, 2006). Therefore, drug delivery vehicles need to be rationally designed to overcome many of these physical barriers.

Over the past few decades, there has been considerable interest in developing biodegradable nanoparticles as potential candidates for controlled drug delivery. Various polymers (Chandra and Rustgi, 1998) have been used in drug delivery research, as they are expected to be capable of delivering drugs to the target site and thus increase the therapeutic benefit while minimizing side effects (Kreuter, 1994).

The topic of this chapter is the NPDDSs with antimicrobial applications. In order just to show a barometer of the interest in these systems, Fig. 1.2 shows the collected outcome data obtained by invoking the keywords nanoparticles and antimicrobial from four well-known scientific publication databases in the past 10 years. The number of records displayed by the year of publishing evidences increasing interest and research activity in the past decade. For better development of the nanoparticulate systems, it is essential to understand the pharmaceutically relevant properties of nanoparticles. DDSs based on nanoparticles present major challenges, and there are changes that occur almost daily. That is why the aim of this chapter is to review the latest trends and emerging technologies related to drug delivery platforms based on nanoparticle systems.

Figure 1.2   Number of articles on nanotechnology in drug delivery using keywords nanoparticles and antimicrobial as a function of the year.

2. Nanoparticles for Drug-delivery Systems

Nanoparticles have been studied extensively as carriers for drugs employed in a wide variety of routes of administration, including parenteral (Verrecchia et al., 1995), ocular (Bourlais et al., 1998), and peroral (Kreuter, 1991) pathways. The ability to formulate nanoparticles for sustained release of drugs that are going off patent presents a strategy to manage product life cycle by the development of formulations with decreased dosing frequency. The term nanoparticle is a collective name for any colloidal carrier of submicrometer dimension and includes nanospheres, nanocapsules, and liposomes. Nanospheres represent the simplest carrier and are solid, monolithic systems in which the drug is dissolved or entrapped throughout the particle matrix. Alternatively, it may be adsorbed onto the surface. No continuous membrane surrounds the particle, as illustrated in Fig. 1.3A. Nanocapsules are reservoir-type systems comprising an oily liquid core surrounded by a polymeric shell (Rollot et al., 1986). The drug is usually dissolved in this liquid core but may be more closely associated with the shell polymer and the exposed surface (Fig. 1.3B). Liposomes are closely related to nanocapsules in structural layout but consist of an aqueous core surrounded by a bilayer membrane composed of lipid molecules, such as phospholipids (New, 1990), as illustrated in Fig. 1.3B. The drug can be located in the aqueous core or in the bilayer membrane. Solid nanoparticles offer distinct advantages in developing drugs that can be attributed to their physical stability and the ability to modify the materials used in formulations looking for controlled release characteristics.

Figure 1.3   (A) The morphology of nanospheres, where drug can be either dispersed throughout the polymeric matrix of the particle or adsorbed onto the surface. (B) The morphology of nanocapsules, where drug is dispersed mostly in a liquid core. Drug can also be associated with the polymeric shell, either by dispersal through the polymer or by adsorption to it.

Basically, they can all be defined as solid carriers, approximately spherical and ranging in size from 10 to 1000 nm. They are generally polymeric in nature (synthetic or natural) and can be biodegradable or nonbiodegradable in character. Biodegradable polymers used include poly(alkylcyanoacrylates) (Couvreur and Vauthier, 1991), polylactic-co-glycolic acid (PLGA) (Govender et al., 1999), chitosan (Janes et al., 2001), and gelatin (Leo et al., 1997), while nonbiodegradable polymers include poly(styrene) (Fritz et al., 1997), poly(acrylamide) (Hsiue et al., 2002), and poly(methylmethacrylate) (Papatheofanis and Barmada, 1991).

Nanoparticles show several advantages in relation to other materials, such as (1) better stability in biological fluids and during storage, (2) easy preparation and diversity in preparation techniques, (3) easy large-scale manufacturing, (4) batch-to-batch reproducibility, and (5) controlled release. Nanoparticles also satisfy the purpose of encapsulating and delivering active substances known as carriers or vectors to a target site. Unequivocally, nanotechnology is quickly becoming a vanguard with respect to DDSs. This results from the fact that products of this technology, such as nanoparticles can be used to treat a wide variety of challenging diseases, including diabetes, infection diseases, heart diseases, neurodegenerative disorders, and cancer, for which therapeutic alternatives are limited.

One of the primary objectives in the development of DDSs is the controlled delivery of a drug to its site of action at an optimal rate (Donbrow, 1991) and in the most efficient way possible. Targeting a drug to its site of action would not only improve the therapeutic efficacy but also enable a reduction in total dose of the drug that must be administered to achieve a therapeutic response, thus minimizing unwanted toxic effects. One possibility to reach this goal may be drug delivery by nanoparticles. Chiefly due to their small particle size below 1 μm, these DDSs offer various advantages for many medical and veterinary applications (Kreuter, 1983; Marty and Oppenheim, 1977). However, as with any new technology, the risks of nanoparticulate systems must be heavily researched to ensure that the advantages of therapeutic treatment far outweigh any possible side effects. The pharmaceutical manufacturers are primarily responsible for ensuring the safety and efficacy of nanoparticles for clinical use. The effectiveness of nanoparticles in drug delivery can be attributed to many factors, such as physical and biological stability, good tolerability of the components, simplicity of the manufacturing process, possibility of facile scale-up of the manufacturing process, and amenability to freeze-drying and sterilization.

3. Polymeric Carriers Used to Prepare Nanoparticles as Drug Carriers

Polymeric nanoparticles have been investigated as drug delivery devices for several decades due to their ability to carry a wide variety of drugs or genes and to sustain delivery for an extended period of time. Nanoparticles are submicron-sized polymeric colloidal spheres that can entrap an active agent within the polymer matrix, or the active agent can be adsorbed or conjugated to the outside of the particle. Different polymers serve various functions in delivery systems as a result of their unique properties. An ideal system involves a polymer with well-known physical and chemical properties to encapsulate the biologically active agent, thus protecting, targeting, and releasing the drug in a predictable manner after local or systemic administration. The aim of the use of this technology is to improve therapeutic effects while adverse effects are minimized.

Polymers used for nanoparticles are generally categorized into three classes: natural, semisynthetic, and synthetic. Polymers used in DDSs, whether natural or synthetic, need to have minimal effects on biological systems after administration in the body and should be biodegradable, nontoxic, and readily excreted from the body. Polymeric nanoparticles are typically prepared from biodegradable polymers to avoid accumulation of the polymer matrix on repeat dosing.

Cellulose, chitosan, alginate, gelatin, pullulan, and gliadin can be mentioned as examples among biodegradable and biocompatible natural polymers used for nanoparticles. Since these polymers may vary in chemical composition, and hence physical properties, their performance and behavior may be less predictable when used for nanoparticles. Furthermore, these polymers are sometimes immunogenic.

On the other hand, polymers with accurate chemical composition, and then physical properties, can be synthetized. In this regard, synthetic polymers can be designed looking for specific characteristics, such as permeability, controlled rates of dissolution, erosion and degradation, or, even more, targeting. Polyanhydrides, polylactide (PLA), PLGA, poly-ɛ-caprolactone, and polyphosphazene are examples of biodegradable synthetic polymers commonly used for nanoparticles. Whether natural or synthetic, biocompatibility and biodegradability are desired properties of polymers when injected or implanted into the body.

There are two methods for the preparation of nanoparticles; one involves the polymerization of monomers, and the other includes chemical modification of preformed polymers. According to the technologies used, nanospheres or nanocapsules can be obtained. Nanospheres consist of a dense polymeric matrix in which the drug can be dispersed, whereas nanocapsules present a liquid core surrounded by a polymeric shell.

Nanoparticle preparation methods based on the polymerization of monomers generally involve introducing the monomer to an aqueous phase or dissolving the monomer in a nonsolvent of the polymer (Lockman et al., 2002). In these systems the polymerization usually takes place in a two-step reaction: a nucleation phase occurs first, after which a growth phase begins. The polymerization can be carried out in two ways, either in emulsion or interfacially. In emulsion polymerization, triggers for polymer growth are used, such as high-energy radiation, UV light, or hydroxyl ions. Emulsion polymerization offers many advantages: it is a fast process when compared to other processes, the process does not require stabilizers and surfactants, and the process can easily be scaled up.

Compared to microparticles, nanoparticles offer several advantages, such as the ability to penetrate extracellular and intracellular areas that may be inaccessible to other delivery systems due to their small size.

Biodegradable nanoparticles have received much attention because they do not require further intervention, that is, removal, after being placed into the body. Depending on the formulation type, the drug is released by one or a combination of several mechanisms: desorption of adsorbed drug, diffusion through the polymer matrix, diffusion through the polymeric membrane shell in the case of nanocapsules, and polymer degradation and erosion (Jain, 2000; Mainardes and Silva, 2004; Uhrich et al., 1999). These mechanisms are influenced by the rate of degradation of the material, and the choice of polymer largely dictates the controlled release properties of the system. Many factors outside of the kinetics of degradation must be considered for a polymer used in a drug delivery device, including the difficulty of preparation, biocompatibility, favorable interactions with the active agent, and mechanical properties (Jain, 2000; Uhrich et al., 1999).

Nanocapsules and nanospheres differ in their release profiles due to the nature of the containment of the active agent. Nanospheres encapsulate the drug molecules within the matrix of polymer in a uniform distribution. The release of the drug from the matrix occurs through diffusion, as well as erosion of the matrix itself. If diffusion occurs more quickly than degradation, then the process is diffusion dependent; otherwise the process of degradation is highly influential (Niwa et al., 1993). An initial burst release is observed due to the presence of drug near or adsorbed to the large surface area of the nanoparticle. After the burst effect, diffusion largely controls the release, leading to an exponential delayed release rate. Matrix-type nanoparticles usually exhibit first-order kinetics (Fresta et al., 1995; Radwan, 1995).

Conversely, nanocapsules have a reservoir-like morphology and exhibit release profiles as such. The drug is contained in the core and must diffuse through the polymer shell in order to be released. This morphology theoretically leads to zero-order kinetics of release. It has been shown experimentally that drug release from nanocapsules can occur by either partitioning of the drug or diffusion across the polymer coating (Lu et al., 1999). Additionally, it has been shown that the method of drug incorporation, conjugation, or adsorption greatly affects the release profile, with adsorption leading to higher burst release and a quicker overall release (Soppimath et al., 2001).

3.1. Natural Polymers

Natural polymers are hydrophilic and mostly water-soluble and thus ideal for encapsulating hydrophilic drugs. The release rate from a natural polymer matrix usually is controlled by the degree of cross-linking using different agents, such as gluteraldehyde or formaldehyde. Thermal cross-linking can also be used. The importance of natural polymers is that chemical variations in the polymeric matrices give rise to synthetic polymers, which in a general sense are modified natural polymers.

3.1.1. Alginates

Alginates are linear copolymers formed by polymeric blocks of glucuronic and mannuronic acids linked together in different sequences (Tonnesen and Karlsen, 2002). When in aqueous media, salts of these polymers exchange sodium ions with divalent cations, forming water-insoluble gels (Rajaonarivony et al., 1993). They can carry different type of molecules, such as proteins (Wee and Gombotz, 1998), peptides (Wee and Gombotz, 1998), oligonucleotides (Gonzalez Ferreiro et al., 2002), water-soluble drugs, or drugs that degrade in organic solvents. Alginates can be obtained with different molecular weights, and present the advantage of not being immunogenic. Nanoparticles from these polymers can be prepared by extrusion of an aqueous sodium alginate solution through a narrow needle into an aqueous solution of a cationic agent. An egg-box structure, which is the core of the gel matrix, is formed by cross-linking of glucuronic and mannuronic acids. Since ion exchange is reversible, it is possible to use these systems to release therapeutic agents in vivo, because the matrix may redissolve when in contact with sodium present in physiological fluid. Alginate nanoparticles have been tested to deliver antibacterials, such as isoniazid, rifampicin, and pyrazinamide, keeping drug levels above the minimum inhibitory concentration in the liver, lungs, and spleen after pulmonary administration (Ahmad et al., 2005). However, this reversible ion exchange may lead to a rapid release of the therapeutic agent, which is a disadvantage of the use of alginates for nanoparticles. Several attempts have been made to overcome this issue, such as coating the alginate particles with cationic polymers, such as poly-l-lysine or chitosan (De and Robinson, 2003).

3.1.2. Chitosan

Chitosan, an aminopolysaccharide, has extensive applications as a new drug or gene delivery carrier because it is nontoxic, bioabsorbable, and biodegradable. Recently it has become of consequence to develop hydrophilic nanoparticle carriers for water-soluble natural macromolecules, such as peptides, proteins, and polynucleotides.

Chitosan is a naturally derived polysaccharide created by the deacetylation of chitin, a component of crab shells (Mainardes and Silva, 2004). It is a cationic polysaccharide composed of linear β(1,4)-linked d-glucosamine. The advantageous properties of chitosan include its biocompatibility, positive charge, the abundance of amine groups available for cross-linking, ease of processing, mucoadhesiveness, and its degradation into amino sugars, all of which are attractive for drug delivery applications (Agnihotri et al., 2004; Prabaharan and Mano, 2005). Chitosan nanoparticles have been formulated by a variety of techniques including emulsion cross-linking, complex coacervation, emulsion droplet coalescence method, ionic gelation, ionotropic gelation, and the reverse micellar method. The molecular weight of the chitosan, its degree of deacetylation, the extent of cross-linking, and its interactions with the encapsulated molecule play a role in controlling the release of the therapeutic agent from the particle. Due to its charge, the pH of the release media also influences release from chitosan particles. Release mechanisms from chitosan particles take place through desorption of the drug adhered to the surface, diffusion through the polymer matrix, and release due to erosion; these are similar to mechanisms observed for other particles. Release of drugs from surface layers of the matrix involves a large burst effect, but increasing the cross-linking density can reduce this effect (Agnihotri et al., 2004). Diffusion out of the matrix occurs through a three-step process: diffusion of water into the matrix causing swelling, transition from glassy to rubbery polymer, and diffusion of drug out of the matrix. The release follows a typical hydrogel release profile (Agnihotri et al., 2004).

3.1.3. Gelatin

Gelatin is a naturally occurring biopolymer that is biocompatible and biodegradable. The polymer is obtained through heat dissolution and partial hydrolysis of collagen obtained from animal connective tissues. It is a heterogeneous mixture of polypeptides, with one or more chains, consisting essentially of glycine, proline, and hydroxyproline residues, which are degraded in vivo into amino acids. It has been used for many years in pharmaceutical applications, such as capsules and ointments, as well as early nanoformulations (Zwiorek et al., 2005). A desolvation process performed in two steps is necessary to prepare gelatin nanoparticles (Coester et al., 2000). This procedure includes the addition of another polymer more water-soluble than gelatin, or a water-miscible gelatin nonsolvent, to a gelatin/water solution at 40°C (above its gel temperature). Then, the concentrated gelatin particles are separated and cross-linked with glutaraldehyde to harden them. Another technique to prepare these particles is using a oil-in-water (o/w) emulsion or a water-in-oil-in-water (w/o/w) microemulsion as well.

3.2. Semisynthetic Polymers

Semisynthetic polymers may be biodegradable or nonbiodegradable in nature. Examples of widely used semisynthetic polymers are ethyl cellulose, hydroxypropylmethyl cellulose, methacrylic acid derivatives, and cellulose acetate phthalate, to name a few.

The choice of polymer is critical to the fate of the type of nanoparticles that can be created. Once the polymer is chosen, then the formulation process begins.

3.3. Synthetic Biodegradable Polymers

Synthetic polymers have been widely used as drug carriers to encapsulate small or large molecules. Some examples of synthetic polymers are ester derivatives, such as poly(lactic/glycolic acid) (PLA/PLGA) and poly-e-caprolactone (PLA) and others, such as poly(anhydrides), poly(orthoesters), poly(phosphoesters), poly(phosphazenes), and poly(cyanoacrylate) derivatives. Among these, poly(lactic/glycolic acid) polymers have been favored for their biodegradability, nontoxicity, and ease of preparation of micro/nanoparticles. Various synthetic polymers have been used in drug delivery devices, including poly(esters), poly(orthoesters), poly(anhydrides), poly(amides), and phosphorus-containing polymers. Several of the most common polymers used in nanoscale devices are reviewed here.

3.3.1. Poly(esters)

Polylactic acid (PLA), a hydrophobic polymer, could be used alone or copolymerized with poly-glycolic acid. This copolymerization helps to obtain polymers with different physicochemical properties, according to the ratio of each polymer used to obtain the polylactic-co-glycolic acid (PLGA) (FDA-approved polymers). It has been widely used in drug delivery due to its degradation properties, biocompatibility, and the fact that it is very well characterized (Jain, 2000). PLGA degrades in an aqueous environment through the hydrolysis of the backbone ester linkages (Brannon-Peppas, 1995; Jain, 2000). The polymeric device based on PLGA degrades through bulk erosion at a uniform rate throughout the matrix (Jain, 2000). The degradation process is self-catalyzed, as the number of terminal carboxylic acid groups rises with increasing chain scission, and the acids catalyze the hydrolysis. The degradation is highly dependent on the ratio of lactide to glycolide moieties, as lactide is more hydrophobic and reduces the rate of degradation (Jain, 2000; Mainardes and Silva, 2004). Also, important factors in the degradation process are the degree of crystallinity, the molecular weight, and the glass transition temperature of the polymer (Jain, 2000). PLGA has been used to encapsulate a myriad of drugs and genes for controlled delivery applications for many diseases or other applications, and only a few are mentioned here.

Random bulk hydrolysis degradation of PLA and PLGA is catalyzed in acidic media. Both polymers’ nanoparticles have been widely used and comprehensively reviewed, from synthesis, applications, and physical properties to targetability and biological fate (Bala et al., 2004).

Rapid uptake of polymeric (PLGA, PLA) nanoparticles by the reticuloendothelial system (RES) led to newer-generation products involving the use of copolymers of polyesters (such as PLA and PLGA) and polyethylene glycol (PEG). The optimization of the PEG length at the surface of such nanoparticles has been studied to evade the RES and extend release of the incorporated drug, making it comparable to sterically stabilized liposomes (Lasic et al., 1991). Polymeric nanoparticles are typically prepared using conventional emulsion-based processes. The nanoparticles produced using this process are uniformly spherical in nature.

3.3.2. Poly(anhydrides)

Poly(anhydrides) have a hydrophobic backbone and a hydrolytically labile anhydride linkage. They are biodegradable polymers synthesized by ring-opening polymerization and degrade by surface hydrolysis (Kumar et al., 2002); even the polymer itself is a hydrophobic in nature. These properties lead to surface erosion of the polymeric device and nearly zero-order release. The hydrolytic bond cleavage of poly(anhydrides) produces water-soluble products that in many cases are considered biocompatible. Poly(anhydrides) are most commonly produced through a melt-condensation polymerization. The most common polymers in this class are based on sebacic acid, p-(carboxyphenoxy) propane, and p-(carboxyphenoxy)hexane. Variations in monomer composition, such as hydrophobicity, influence the degradation rate of the polymeric device.

3.3.3. Poly-ɛ-Caprolactones

Sinha et al. (2004) have reviewed different methods to prepare nanoparticles using poly-ɛ-caprolatones. They include solvent displacement, emulsion polymerization, interfacial polymer deposition, and dialysis. Poly-ɛ-caprolatones are chemically stable semicrystalline polymers with low glass transition temperature. Due to their slow degradation, they can be used for long-term drug delivery. A wide range of different drugs have been delivered from poly-ɛ-caprolactone nanoparticles, including retinoic acid, griseofulvin, and tamoxifen.

3.3.4. Poly(orthoesters)

Devices degrading through bulk erosion have an undesirable release profile for many applications, and the need for a device controlling release solely through hydrolysis of chains at the surface of the device effected the design of poly(orthoesters) (Uhrich et al., 1999). The release rates from devices composed of poly(orthoesters) can be controlled by including acidic or basic excipients into the matrix as its hydrolysis is acid catalyzed. This has been used in the release of 5-fluorouracil (Seymour et al., 1994), tetracycline (Roskos et al., 1995), and others. Additionally, the mechanical properties of these polymers can be tailored by choosing from the various diols available (Mainardes and Silva, 2004).

4. Recent Trends in Nanoparticulate Drug-Delivery Systems

The first DDS introduction was a success, and generated an immense interest in relation to the possible applications of these kinds of systems. The major focus was on the entry of drugs in the systemic circulation of the body. The DDS design is focused in two major aspects: spatial placement (targeting a drug to a specific organ or tissue) and temporal delivery of the drug (controlling the delivery rate to the target) (Remington and Gennaro, 2000). If these are achieved, it is possible to provide a therapeutic amount of drug to the proper body site and maintain correct drug concentration circulating in the body, while reducing or preventing side effects.

Progression in polymer technology has made it possible to develop polymeric nanoparticles with modified properties. A DDS is most often associated with fine particulate carriers, such as emulsion, liposomes, and nanoparticles, which are designed to localize drugs in the target site. From the clinical point of view, they might have to be biodegradable and/or highly biocompatible. In addition, high drug content is desirable, because in many cases actual drug loading efficiency is often too low to secure an effective dose at the target site. Biodegradable nanoparticles have received considerable attention as potent vehicles for targeting a site and controlled release of drugs/bioactive components (Davda and Labhasetwar, 2002; Vila et al., 2002). Various nanoparticulate systems composed of different materials are constantly being explored in the areas of drug and gene delivery.

Two mechanisms are described for the delivery of the antimicrobial drug from the nanoparticle-based platform to the microorganism (Fig. 1.4). One includes the fusion of the nanoparticle with the microbial cell wall or membrane, while in the other the nanoparticle binds to the cell and releases the drug into the microorganism through diffusion phenomena.

Figure 1.4   Mechanisms of antimicrobial drug delivery from nanoparticle to microorganisms.

(A) Nanoparticle fuses with the microbial membrane or wall and then releases the drug into the cell. (B) Nanoparticle binds to cell wall and continuously releases the drug, which diffuses into the microbial cell.

The drug-delivery sector has evolved from being simply a part of the pharmaceutical production process to being a driving force for innovation and profits whose industry and commercial interests are steadily growing. The benefits to patients can be seen in improved compliance and medical outcomes. The pharmaceutical industry is able to extend the patent protection through novel DDSs, and to bring new therapies to the market.

The engineering of drug carriers that bear one or more polymeric agents, with each block having a specific role in the solubility and degradative susceptibility of the resulting vehicle, allows for nanoscale design of controlled-release DDSs. Biodegradable polymer-based DDSs feature labile groups, the presence of which can be tuned to control the extent of degradation and therefore drug release over time.

The well-characterized and biocompatible polylactic-co-glycolic acid (PLGA) drug carriers are an example of a system that undergoes bulk erosion by hydrolysis, enabling its utilization in controlled-release applications. The PLGA block copolymer is composed of poly(lactic acid) and poly(glycolic acid), the former of which is slower to degrade due to increased crystallinity and steric hindrance to scission by water. Both of them are safely eliminated by the body. By varying the relative composition of the two blocks on a PLGA nanoparticle surface, drug release rates can be tailored via modulation of the hydrophilic–lipophilic balance. The resulting vehicle allows for nanoscale design of controlled-release DDSs.

NPDDSs are being explored for the purpose of solving the challenges of drug delivery. Most carriers come in many shapes and sizes, and are less than 100 nm in diameter. NPDDSs provide methods for targeting and releasing therapeutic compounds in much-defined regions. These vehicles have the potential to eliminate or at least ameliorate many of the problems associated with drug distribution. As many drugs have a hydrophobic component, they often suffer from problems of precipitation in high concentrations, and there are many examples of toxicity issues with excipients designed to prevent drug aggregation. In order to combat these issues, many NPDDSs provide both hydrophobic and hydrophilic environments, which facilitate drug solubility. Alternatively, many drugs suffer from rapid breakdown and/or clearance in vivo. By encapsulating the drugs in a protective environment, NPDDSs increase their bioavailability, thereby allowing clinicians to prescribe lower doses. With recent advances in polymer and surface conjugation techniques, as well as microfabrication methods, probably the greatest focus in drug-delivery technology is in the design and applications of NPDDSs. Ranging from simple metal–ceramic core structures to complex lipid–polymer matrices, these submicron formulations (Willis, 2004) are being functionalized in numerous ways to act as therapeutic vehicles in a variety of conditions.

NPDDSs can be defined as the DDSs where nanotechnology is used to deliver the drug at nanoscale. Below 100 nm, materials exhibit different, more desirable physical, chemical, and biological properties. Given the enormity and immediacy of the unmet needs of therapeutic areas, such as CNS disorders, this can lead to drugs that can extend lives and prevent untimely deaths (Willis, 2004).

4.1. Biological Transport of Nanoparticles

For drug delivery, most of the sites are accessible through either microcirculation by blood capillaries or pores present at various surfaces and membranes. Most of the apertures, openings, and gates at cellular or subcellular levels are of nanometer size; hence, nanoparticles are the most suited to reach the subcellular level. One of the prime requirements of any delivery system is its ability to move around freely in available avenues and by crossing various barriers that may come in the way. Regarding the human body, the major passages are the blood vessels through which materials are transported in the body. The blood vessels are not left in any organ as an open outlet of the pipe; rather, they become thinner and thinner and are finally converted to capillaries through branching and narrowing. These capillaries go to the close vicinity of the individual cells. After reaching their thinnest sizes, the capillaries start merging with each other to form the veins. These veins then take the contents back to the heart for recirculation. Hence, the supply chain in the body is not in the form of a pipe having an open inlet to the organ and outlet away from the organ. Consequently, for any moiety to remain in the vasculature, it needs to have its one dimension narrower than the cross-sectional diameter of the narrowest capillaries, which is about 2000 nm. Actually, for