Nanostructures for the Engineering of Cells, Tissues and Organs: From Design to Applications

Nanostructures for the Engineering of Cells, Tissues and Organs

From Design to Applications

Edited by

Alexandru Mihai Grumezescu

Faculty of Applied Chemistry and Materials Science, University Politehnica of Bucharest, Romania

Table of Contents

Cover image

Title page

Copyright

List of Contributors

Series Preface: Pharmaceutical Nanotechnology

Preface

Chapter 1. Cell and organ drug targeting: Types of drug delivery systems and advanced targeting strategies

Abstract

1.1 Introduction

1.2 Drug Targeting: What, Why and How?

1.3 Cellular Targeting: Normal Cells and Abnormal Cells

1.4 Organ Targeting

1.5 Conclusion

Glossary

Abbreviations

References

Chapter 2. Cell-penetrating peptides in nanodelivery of nucleic acids and drugs

Abstract

2.1 Introduction

2.2 Applications of Cell-Penetrating Peptides in Delivery of Therapeutic Molecules

2.3 Discovery and Design of Novel Cell-Penetrating Peptides

2.4 Cell-Penetrating Bacterial Effector Proteins as Novel Tools

2.5 Recombinant Production of Cell-Penetrating Peptides for the Delivery Purpose

2.6 Conclusion and Future Respects

Acknowledgments

References

Chapter 3. The current perspectives of nanoparticles in cellular and organ-specific drug targeting in biological system

Abstract

3.1 Introduction

3.2 Role of Nanoparticle Action in the Biological System

3.3 Mechanism of Nanoparticle Action in Cellular and Subcellular System

3.4 Role of Nanoparticle Action in Pathophysiological Condition

3.5 Limitation of Nanoparticles Action in Biological Systems

3.6 Intracellular and Subcellular Targeted Action

3.7 Interaction of Nanoparticle in Biological System

3.8 Pharmacological Action of Nanoparticle

3.9 Therapeutic Application of Nanoparticle

3.10 Future Scopes

Abbreviations

Acknowledgments

References

Further Reading

Chapter 4. Precision medicine and drug targeting: The promise versus reality of target-specific drug delivery

Abstract

4.1 Precision Medicine

4.2 Precision Drugs

4.3 Progress Towards Precision Drugs

4.4 Conclusion

Abbreviations

References

Chapter 5. Brain targeting of payload using mild magnetic field: Site specific delivery

Abstract

5.1 Magnetic Nanoparticles

5.2 Diagnostic Applications Using Magnetic Nanoparticles

References

Chapter 6. Nanoparticles influence in skin penetration of drugs: In vitro and in vivo characterization

Abstract

6.1 Introduction

6.2 Skin Structure

6.3 Mechanisms and Routes of Nanoparticles Skin Penetration

6.4 Characteristics of Nanoparticles for Drug Skin Penetration

6.5 Physical Methods to Enhance Nanoparticle Skin Penetration

6.6 Experimental Techniques for Studying Nanoparticle Skin Penetration

6.7 Conclusion

References

Chapter 7. DNA aptamer-based molecular nanoconstructions and nanodevices for diagnostics and therapy

Abstract

7.1 DNA Aptamers in Diagnostics and Therapy

7.2 Basic Principles of DNA Nanoconstruction Creation

7.3 DNA Nanoconstructions for Aptamer Oligomerization

7.4 DNA Nanoconstructions With Different Aptamers

7.5 Designing Extensive DNA Nanoconstructions

7.6 Examples of Extensive DNA Nanoconstruction Geometry

7.7 Promising Applications of DNA Tiles and DNA Origami

7.8 Conclusions

Acknowledgments

References

Chapter 8. Nanobiodevices for electrochemical biosensing of pharmaceuticals

Abstract

8.1 Nanobiodevices

8.2 Nanobiodevices Based on Bio-Constituents

8.3 Electrochemical Methods in Biosensing

8.4 Conclusion

References

Chapter 9. Imprinted polymeric nanoparticles as nanodevices, biosensors and biolabels

Abstract

9.1 Introduction

9.2 Principles of Imprinting Process

9.3 Overview of Formats of Imprinted Nanomaterials

9.4 Imprinted Drug Delivery Nanodevices

9.5 Imprinted Nanosorbents for Sample Preparation

9.6 Imprinted Nanocomposites for Biosensors

9.7 Biolabeling With Imprinted Polymeric Nanostructures

9.8 Conclusions

References

Further Reading

Chapter 10. Poly(lactic-co-glycolic acid) (PLGA) matrix implants

Abstract

10.1 Introduction

10.2 Implantable Drug Delivery Systems

10.3 Ability to Sustain and to Control Drug Delivery

10.4 The Issue of Biocompatibility

10.5 Poly(Lactide-co-Glycolic Acid) (PLGA)

10.6 Biodegradability

10.7 PLGA Matrix Implants

10.8 Successful Case Studies

10.9 Problems to Overcome and Opportunities

10.10 Conclusions

References

Chapter 11. Hydrogels for biomedical applications

Abstract

11.1 Hydrogels: Concepts and Definitions

11.2 Classification of Hydrogels

11.3 Applications of Hydrogels

11.4 Hydrogel Technical Features

11.5 Metabolism and Hydrogels

11.6 Regulation of Hydrogels

11.7 Potential Risks of Hydrogels

11.8 Nanoparticle Biosafety

11.9 Final Remarks

References

Further Reading

Chapter 12. Silk-based matrices for bone tissue engineering applications

Abstract

12.1 Introduction

12.2 Global Perspective on Orthopaedic Trauma Management

12.3 Rising Needs for Bone Grafts

12.4 Ideal Scaffold for Bone Tissue Engineering

12.5 Lacunae of Current Materials and Practices for Bone Regeneration

12.6 Bioderived and Synthetic Materials for Bone Tissue Engineering

12.7 Context and Structure of the Chapter

12.8 Various Sources of Silk

12.9 Silk From Silkworms

12.10 Spider Silk

12.11 Benign Aspects of Silk for Bone Tissue Engineering

12.12 Processing Silk Into Various Formats

12.13 Silk Composites for Bone Tissue Engineering

12.14 Beyond the Classic Mulberry Silk Fibroin

12.15 Recent Trends in Bone Tissue Engineering

References

Chapter 13. Implantable drug delivery systems: An overview

Abstract

13.1 Introduction

13.2 Classification of Implantable Drug Delivery Systems

13.3 Design Approaches

13.4 Current Therapeutic Applications

13.5 Current Challenges and Future Perspectives

13.6 Conclusion

Acknowledgments

References

Chapter 14. Nanobionics and nanoengineered prosthetics

Abstract

14.1 Introduction

14.2 History

14.3 Definition

14.4 Types and Classifications

14.5 Manufacture

14.6 Nanobiomaterials

14.7 Applications

14.8 Ethical Issues

14.9 Safety Issues Pertinent to Nanobionics and Prosthetics

14.10 Conclusion

References

Further Reading

Index

Copyright

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List of Contributors

Noor A. Al Halabi,     RAK Medical and Health Sciences University, Ras al Khaimah, United Arab Emirates

Ghufran A. Alsalloum,     RAK Medical and Health Sciences University, Ras al Khaimah, United Arab Emirates

Promita Bhattacharjee,     Indian Institute of Technology, Kharagpur, West Bengal, India

Murali M. Bommana,     Impax Labs, Middlesex, NJ, United States

Camila Cubayachi,     School of Pharmaceutical Sciences of Ribeirao Preto, University of São Paulo, Ribeirao Preto, SP, Brazil

Luciana F. Dalmolin,     School of Pharmaceutical Sciences of Ribeirao Preto, University of São Paulo, Ribeirao Preto, SP, Brazil

Serap Evran,     Ege University, Izmir, Turkey

Luciane R. Feksa

Feevale University, Novo Hamburgo, RS, Brazil

Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil

Abdelkarim Guaadaoui,     University Mohammed Premier, Oujda, Morocco

Prerak Gupta,     Indian Institute of Technology Guwahati, Guwahati, Assam, India

Imane Himri,     University Mohammed Premier, Oujda, Morocco

M. Joseph Christakiran,     Indian Institute of Technology Guwahati, Guwahati, Assam, India

Alexey Kopylov,     Chemistry Department of Lomonosov Moscow State University, Moscow, Russian Federation

Anoop Kumar

Translational Health Science & Technology Institute (THSTI), Faridabad, India

Indo-Soviet Friendship College of Pharmacy (ISFCP), Moga, Punjab, India

Sevinc Kurbanoglu,     Ankara University, Ankara, Turkey

Camila N. Lemos,     School of Pharmaceutical Sciences of Ribeirao Preto, University of São Paulo, Ribeirao Preto, SP, Brazil

Renata F.V. Lopez,     School of Pharmaceutical Sciences of Ribeirao Preto, University of São Paulo, Ribeirao Preto, SP, Brazil

Piotr Luliński,     Medical University of Warsaw, Warsaw, Poland

Aline B. Machado,     Feevale University, Novo Hamburgo, RS, Brazil

Biman B. Mandal,     Indian Institute of Technology Guwahati, Guwahati, Assam, India

Cristina D. Muller,     Feevale University, Novo Hamburgo, RS, Brazil

Arunachalam Muthuraman,     JSS University, Mysuru, India

Samit K. Nandi,     West Bengal University of Animal and Fishery Sciences, Kolkata, West Bengal, India

Sibel A. Ozkan,     Ankara University, Ankara, Turkey

Canan Ozyurt,     Ege University, Izmir, Turkey

Francieli Pereira,     School of Pharmaceutical Sciences of Ribeirao Preto, University of São Paulo, Ribeirao Preto, SP, Brazil

Karel Petrak,     NangioTx Inc., New York, NY, United States

Jonathan Pillai,     Translational Health Science & Technology Institute (THSTI), Faridabad, India

Danielle N. Ramos,     School of Pharmaceutical Sciences of Ribeirao Preto, University of São Paulo, Ribeirao Preto, SP, Brazil

Sangram Raut,     Texas Christian University, Fort Worth, TX, United States

Virgínia C. Rech

Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil

Franciscan University, Santa Maria, RS, Brazil

António J. Ribeiro

University of Coimbra, Coimbra, Portugal

Institute for Molecular and Cell Biology, Porto, Portugal

Ana C. Santos

University of Coimbra, Coimbra, Portugal

Institute for Molecular and Cell Biology, Porto, Portugal

Joana A.D. Sequeira,     University of Coimbra, Coimbra, Portugal

João Serra,     Tecnimede Group – SA, Dois Portos, Portugal

Monika Sobiech,     Medical University of Warsaw, Warsaw, Poland

Eduardo A. Troian,     Feevale University, Novo Hamburgo, RS, Brazil

Ozge Ugurlu,     Ege University, Izmir, Turkey

Bengi Uslu,     Ankara University, Ankara, Turkey

Francisco Veiga,     University of Coimbra, Coimbra, Portugal

Fabian Viegas,     Feevale University, Novo Hamburgo, RS, Brazil

Hemant K.S. Yadav,     RAK Medical and Health Sciences University, Ras al Khaimah, United Arab Emirates

Elena Zavyalova,     Chemistry Department of Lomonosov Moscow State University, Moscow, Russian Federation

Series Preface: Pharmaceutical Nanotechnology

Alina M. Holban, University of Bucharest, Bucharest, Romania

Due to its immense applicative potential, nanotechnology is considered the leading technology of the 21st century. The science and engineering of nanometer-sized materials is currently employed for the development of numerous scientific, industrial, ecological, and technological fields. Biology, medicine, chemistry, pharmacy, agriculture, food industry, and material science are the main fields which have benefited from the great technological progress developed in nanoscience.

In the pharmaceutical field, nanotechnology has revolutionized traditional drug-design concept and the art of drug delivery. The idea of a highly specific nanoscale drug for the targeted therapy of diseases is now considered a feasible treatment for severe health conditions.

Some scientists believe that the pharmaceutical domain has been reborn by the important contribution of nanotechnology. The field of pharmaceutical nanotechnology has the potential to offer innovative solutions for all diagnosis, therapy, and prophylaxis domains. Application of nanotechnology tools in pharmaceutical research and design is likely to result in moving the industry from a blockbuster drug model to personalized medicine. The current main focus of clinicians is to treat patients individually, not their general diagnosed diseases, which are usually difficult to diagnose or incorrectly diagnosed. There are compelling applications in the pharmaceutical industry where suitable nanotechnology tools can be successfully utilized. By designing and modifying drugs at nanoscale, pharmaceutical nanotechnology could be useful not only for the development of completely new therapeutic solutions, but also to add value to existing products. This possibility opens perspectives of success for pharmaceutical companies in existing markets, but also for new markets.

Scientists have manifested an impressive interest on the field of pharmaceutical nanotechnology research in recent years. However, we face today a true dilemma of data unavailability, due to the multitude of existing information which can be highly inaccurate and contradictory. This is because of the lack of an efficient model for sorting the plethora of nanotechnology tools and information that exists, and strategically correlate those with potential opportunities into different segments of pharmaceutical research and design.

This series is trying to cover the most relevant aspects regarding the great progress of nanotechnology in the pharmaceutical field and to highlight the currently emerging trend of pharmaceutical nanotechnology towards the personalized medicine concept.

The 10 volumes of this series are structured to wisely offer relevant information regarding basic concepts and also to reveal the newest approaches and perspectives in pharmaceutical nanotechnology.

Nanoscale Fabrication, Optimization, Scale-Up and Biological Aspects of Pharmaceutical Nanotechnology, introduces the readers into the amazing field of nanoscale design. Also, this volume facilitate understanding of the biological requirements of nanostructured pharmaceutical formulations for advanced drugs.

In Design and Development of New Nanocarriers, the most recent progress made on the field of nano-delivery is discussed. Modern nanostructured drug carriers employ innovative solutions for the detection and treatment of various diseases in a personalized and efficient manner.

Design of Nanostructures for Theranostics Applications, highlights the impressive impact of nanotechnology in the development of combined diagnosis and therapy concept: theranostics.

Design of Nanostructures for Versatile Therapeutic Applications, offers a dynamic solution for immune modulation, treatment of diseases by natural-based products and infection control, while employing nanostructured solutions to achieve top results.

Nanostructures for the Engineering of Cells, Tissues and Organs: From Design to Applications, is a highly investigated and debated field; tissue engineering, is dissected through this volume. Here is shown how nanotechnology has advanced research and applications in the manipulation and engineering of cells and tissues in vitro.

Organic Materials as Smart Nanocarriers for Drug Delivery, deals with the specific world of organic nanomaterials, revealing their wide applications, types, and advantages in drug delivery.

In the volume entitled: Inorganic Frameworks as Smart Nanomedicines, the main focus is to discuss the variety and properties of inorganic nanostructures for therapy and drug delivery in the context of improved personalized medicine.

Lipid Nanocarriers for Drug Targeting, deals with recently developed lipid nanostructures and the advances made in drug targeting.

Drug Targeting and Stimuli-Sensitive Drug Delivery Systems, dissects smart stimuli-responsive nanosystems employed to specifically detect various biochemical conditions and control the release of drugs.

Fullerens, Graphenes and Nanotubes: A Pharmaceutical Approach, reveals major findings made on widely applied drug-design nanosystems, namely fullerens, graphenes and nanotubes. The impact of these nanostructures in pharmaceutical research is highlighted.

All 10 volumes are nicely illustrated and chapters are organized into a logical manner to be accessible to a wide audience. The series is a valuable resource of new and comprehensive scientific proof on the intriguing and emerging field of pharmaceutical nanotechnology, which could be of a great use for scientists, engineers, pharmaceutical representatives, clinicians, and any non-specialist interested user.

Preface

Alexandru M. Grumezescu, http://www.grumezescu.com, University Politehnica of Bucharest, Bucharest, Romania

The aim of this reference book is to present the novel progress from recent years in the field of pharmaceutical nanotechnology, with special attention to engineering of cell, tissues, and organs. The book provides an up-to-date overview about organ targeting and cell targeting using nanotechnology. Different biomedical applications are presented with pros and cons, as follows: nanobionics and nanoengineered prosthetics, molecular nanoconstructions and nanodevices for diagnostics and therapy, precision medicine and drug targeting, brain targeting and many others.

The book entitled Nanostructures for the Engineering of Cells, Tissues and Organs: From Design to Applications, contains 14 chapters, prepared by outstanding researchers from United Arab Emirates, Portugal, Poland, Russian Federation, Brazil, United States, India, Turkey, and Morocco.

Chapter 1, Cell and organ drug targeting: Types of drug delivery systems and advanced targeting strategies, prepared by Himri Imane et al., gives an up-to-date overview about the targeted delivery of drugs to diseased tissue without affecting the original characteristics of the tissue. It highlights a smart approach to increase the therapeutic index of a drug to specifically deliver the therapeutic molecule in its active form, not only into target tissue, nor even to target organs, but more importantly, into the targeted cells.

Chapter 2, Cell-penetrating peptides in nanodelivery of nucleic acids and drugs, prepared by Canan Ozyurt et al., summarizes the use of cell-penetrating peptides in enhancing the gene transfer efficiency of nonviral vectors. Besides the clinical potential of currently known cell-penetrating peptides, they also discuss the limitations and the need for designing novel cell-penetrating peptides.

Chapter 3, The current perspectives of nanoparticles in cellular and organ-specific drug targeting in biological system, prepared by Arunachalam Muthuraman, focuses on the cellular and organ-specific action of nanoparticles in a biological system. In addition, it also emphasizes the possible mechanism to overcome the limitation of nanoparticles. Furthermore, the interaction between nanoparticle and cells are explained by the cellular uptake and the action on subcellular compartments process. It also covers the factors affecting nanoparticle action i.e., activity on cell membranes, ion channels, cytoskeletal proteins, mitochondria, and nucleus; interaction with proteins, lipids, DNA and small molecules; alteration of cellular signaling, genomic, proteomic and metabonomic processes in the biological system. The detailed overview of this chapter can deliver successful nanomedicine in various disorders including cancer, vascular, and neurodegenerative disorders.

Chapter 4, Precision medicine and drug targeting: The promise versus reality of target-specific drug delivery, prepared by Karel Petrak, give an up-to-date overview about precision medicine, which is an initiative is to improve disease treatment and prevention by taking into account individual variability in genes, environment, and lifestyle for each person. Successful application of the new knowledge generated by precision medicine will ultimately require the availability of precision drugs; drugs that act exclusively on the disease molecular targets without impacting adversely on the rest of the body. This review examines the recent progress in developing such site-specific targeting drug systems.

Chapter 5, Brain targeting of payload using mild magnetic field: Site specific delivery, prepared by Murali Mohan Bommana et al., reviews the applications of magnetic nanoparticles in brain-targeting and diagnostic applications.

Chapter 6, Nanoparticles influence in skin penetration of drugs: In vitro and in vivo characterization, prepared by Camila Nunes Lemos et al., presents the recent progress of the nanoparticle characteristics affecting skin drug penetration, their possible penetration pathways, in addition to in vitro and in vivo techniques commonly used in assessing penetration and distribution of drugs into the skin where nanoparticles are used as topical delivery systems.

Chapter 7, DNA aptamer-based molecular nanoconstructions and nanodevices for diagnostics and therapy, prepared by Elena Zavyalova et al., provides a thorough discussion of DNA aptamer-based nanoconstructions and nanodevices. The challenges and the opportunities in the field are also discussed.

Chapter 8, Nanobiodevices for electrochemical biosensing of pharmaceuticals, prepared by Sevinc Kurbanoglu et al., presents the recent progress of nanobiodevices for electrochemical biosensing of pharmaceuticals related to different biorecognition parts, such as enzymes, DNA, tissues, bacteria, yeast, antibodies, antigens, liposomes, and organelles. Nanobiodevices such as Lab-on-a-chip platforms in biosensors and their applications in pharmaceutical analysis are discussed

Chapter 9, Imprinted polymeric nanoparticles as nanodevices, biosensors and biolabels, prepared by Monika Sobiech et al., presents the recent advances in synthetic approaches for fabrication of imprinted nanomaterials, together with diversity of formats for possible applications in pharmaceutical science. The physicochemical behavior of imprinted nanostructures are discussed in context of their practical utility. Finally, the current limits and future prospects for the imprinted nanomaterials were pointed out.

Chapter 10, Poly(lactic-co-glycolic acid) (PLGA) matrix implants, prepared by Joana A. D. Sequeira et al., begins offering a brief review about poly(esters) in general, with special emphasis on PLGA. It discusses current methods used to produce PLGA matrix implants, focusing on PLGA matrix implants for the delivery of therapeutic peptides. Commercially successful examples are revealed, and a reflection is made on future directions and potentialities.

Chapter 11, Hydrogels for biomedical applications, prepared by Luciane Rosa Feksa et al., reports recent progress in the field of hydrogels used for biomedical purposes, demonstrating that most of the definitions are still under construction. In this context, new drug delivery systems, wound dressings, and contact lenses are being developed, although not limited to these applications. Because they are considered recent technology, there is still little information or studies regarding their behavior in biological systems. Finally, comments are made about the marketing of products containing nanomaterials.

Chapter 12, Silk-based matrices for bone tissue engineering applications, prepared by Promita Bhattacharjee et al., gives an overview of the field from a perspective of materials and fabrication. Silk is a biopolymer with several characteristics, including excellent biocompatibility and mechanical strength that make it a potential candidate for various tissue engineering applications. A growing trend is observed towards designing mineralized nanofibrous and composite scaffolds.

Chapter 13, Implantable drug delivery systems: An overview, prepared by Anoop Kumar et al., starts with a review of various types of implantable drug delivery systems from biomaterial-based to electro-mechanical systems. Furthermore, design approaches to optimal drug delivery, including methods to tailor drug release profiles and the mechanism of release kinetics, are presented. Potential therapeutic applications and biocompatibility related issues are briefly discussed. Finally, this chapter concludes with a summary of future perspectives of implantable drug delivery systems, particularly in their applicability to precision and personalized medicine.

Chapter 14, Nanobionics and nanoengineered prosthetics, prepared by Hemant K.S. Yadav et al., focuses on the impact of nanotechnology on medical bionic devices. The contributors discuss the engineering and manufacture of prosthetics, their uses and applications, and recent advances in this field.

Chapter 1

Cell and organ drug targeting

Types of drug delivery systems and advanced targeting strategies

Imane Himri and Abdelkarim Guaadaoui,    University Mohammed Premier, Oujda, Morocco

Abstract

One of the big expectations of nanomedicines is progression in optimized and targeted delivery of drugs to diseased tissue without affecting the original characteristics of the tissue. Accordingly, a smart approach to increase the therapeutic index of a drug is to specifically deliver the therapeutic molecule in its active form, not only into target tissue, nor even to target organs, but more importantly, into the targeted cells.

Drug therapy is based on the prototype that drug will selectively define its pharmacological activity to make the diseased person free from negative side effects and decrease the symptoms and/or cause of the disease. However, the real obstruction associated with systemic drug administration is the lack of target-specific affinity toward a pathological site, resulting in systemic toxicity and countless other side effects, as well as higher dosage requirement for efficacy. As a consequence, it is of major importance that a drug is delivered directly to its site of action within the target cell, while keeping the molecule intact. Drug delivery systems can specifically target tissue and organs of interest as well as different type of cells.

Keywords

Brain; cancer; dendrimer; drug; eye; liposomes; lung; nanocarrier; nanoparticle; neoplastic disease; PEGylation; targeting

Chapter Outline

1.1 Introduction 1

1.2 Drug Targeting: What, Why and How? 2

1.2.1 Definition and Reasons for Drug Targeting 2

1.2.2 Drug Targeting Strategies 4

1.2.3 Properties Influencing Drug Targeting 20

1.3 Cellular Targeting: Normal Cells and Abnormal Cells 30

1.4 Organ Targeting 31

1.4.1 Drug Delivery to Brain 31

1.4.2 Drug Delivery to Lung 32

1.4.3 Drug Delivery to Eye 35

1.4.4 Drug Delivery to Neoplastic Disease 37

1.5 Conclusion 39

Glossary 39

Abbreviations 40

References 41

1.1 Introduction

Nanotechnology is a multidisciplinary branch which consists of manufacturing nanometer-sized structures and materials. It combines the elements of molecular biology, engineering and chemistry. Nanotechnology is one of the most dynamically developing branches of science and technology (Niemirowicz and Car, 2012). In the past two decades, nanotechnology has been developing quickly and is widely used in medical sciences, specifically for disease diagnosis and treatment (Desai, 2012; Gao, 2016).

Delivering drugs or biocompounactives to the target site is a major problem in the treatment of many diseases (Wilczewska et al., 2012). Reducing the size of a selected material to nanometric scale makes it possible to utilize them in numerous potential applications, including drug targeting (Niemirowicz and Car, 2012).

Recent developments in nanotechnology have shown that nanostructures have great potential as drug carriers. Due to their small sizes, nanocarriers exhibit unique physicochemical and biological properties that make them a favorable material for biomedical applications (Wilczewska et al., 2012). The pharmacokinetic behavior of the drug-loaded nanocarriers depends on the nanosystems and the modes of targeting (passive or active) (Martin Schäffler et al., 2014).

1.2 Drug Targeting: What, Why and How?

1.2.1 Definition and Reasons for Drug Targeting

Drug targeting is a nano-biotechnological method of delivering a biocompounactive (bioactive compound) or an active pharmaceutical ingredient to a patient, in order to increase its concentration in the intended site of action, in a specific part of diseased tissue, and avoiding interaction with healthy tissues. This nano-pharmaceutical method requires various disciplines (biologists, chemists, engineers, etc.) and is believed to improve efficacy, while reducing side effects (maximum efficacy with minimal toxicity).

The drug discovery process has been accelerated with the development of modern technology in pharmaceutical chemistry and molecular biology (i.e., drug design, combinatorial chemistry, high throughput screening, etc.). Nevertheless, this increase in complexity does not necessarily offer more efficient drugs, even if these molecules often possess physicochemical and/or biological characteristics that make their use suboptimal in humans (Bertrand and Leroux, 2012; Chang et al., 2015).

In fact, new drug candidates often exhibit many problems and challenges such as: (1) poor solubility, (2) insufficient in vitro stability (shelf life), (3) too low bioavailability, (4) too short in vivo stability (half-life), (5) strong side effect, (6) need for targeted delivery, (7) regulatory issues/hurdles, and/or (8) lack of large-scale production (Muller and Keck, 2004; Chang et al., 2015). Consequently, the introduction of biotechnological methods for the production of drugs delivery brought a revolution to this biopharmaceutical field for advanced drug development (Muller and Keck, 2004).

In chemotherapy, for example, which remains the main form of treatment for cancer, only a small portion of drugs administered typically reach the organ to be affected (the tumor) since there is no clinically available antineoplastic drug that acts selectively on the tumor mass. For this reason, the scientific research is focused towards the development of novel cancer therapies and drug delivery strategies, such as drug targeting, that would enhance the therapeutic efficacy of drugs while reducing their side effects (Basile et al., 2012).

Moreover, to reach the site of action, the biocompounactive has to transit many biological barriers, such as organs, cells, and intracellular compartments (blood, kidney, liver, spleen, etc.), where it can be inactivated or express undesirable effects on organs and tissues that are not involved in the pathological process. As a result, to achieve a required therapeutic concentration of an active pharmaceutical ingredient in a certain body compartment or certain tissue, one has to administer the drug in large quantities (thus increasing the cost of the therapy), the great part of which, even in the best case scenario, is wasted in normal tissues; cytotoxic and/or antigenic/immunogenic agents can become the cause of many negative side effects. Drug targeting can bring a solution to all these problems (Torchilin, 2010; Bertrand and Leroux, 2012).

The main goal of drug targeting is to localize, target, prolong, and have a protected drug interaction with the diseased tissue (Fig. 1.1). Drug targeting may resolve many problems currently associated with systemic drug administration (orally or as injectables), such as: (a) pharmaceuticals biodistribution, (b) the necessary dose of a drug, (c) lacking affinity between drug-pathological site, (d) the adverse side effects, etc. (Torchilin, 2000; Mishra et al., 2013).

Figure 1.1 Reasons for drug targeting as referred by Agnihotri et al. (2011)-modified.

1.2.2 Drug Targeting Strategies

1.2.2.1 Common approaches of targeted drug delivery

Targeted drug delivery is the ability of the drug to accumulate in the target tissue or organ selectively and quantitatively, independent of the site and methods of administrations. The aim of targeted drug delivery is to obtain high local concentrations of drug in the target area without any side effects in normal tissues, together with low systemic exposure (Fallis, 2002; Hirsjärvi et al., 2011; Mishra et al., 2013).

Targeting may have spatial and temporal properties which deliver the right amount of drug to the right place (double-targeting) (Goodman et al., 2008; Shaji and Lal, 2013). Consequently, targeted drug delivery presents many advantages, the most important of which are (Fallis, 2002):

(1) simplification of administration protocols;

(2) drastic reduction in the cost of therapy and drug quantity required to achieve a therapeutic effect; and

(3) sharp increase in drug concentration in the required sites without negative effects on nontarget areas.

Currently, the principal strategies of drug targeting include many schemes (Torchilin, 2000). Among these various approaches, passive and active targeting seem to be most advanced, and could be relied onto achieve organ-based targeting (first order), specific cell-based targeting in an organ (second order) and cell organelle-based targeting (third order) (Torchilin, 2000, 2010; Danhier et al., 2010). Both passive and active drug targeting reduce toxic side effects, increase efficacy, and enhance delivery of poorly soluble or sensitive therapeutic molecules (Hirsjärvi et al., 2011).

1.2.2.1.1 Passive drug targeting

In the human body, some molecules (i.e., hormones, growth-factors) have a natural tendency to target their receptors (sites of action) by the action of physicochemical and pathophysiological factors. This process is called passive targeting, and can also be applied to drugs (Garnett, 2001). In fact, passive drug targeting can benefit from the presence of (1) physicochemical modifications under diseased conditions, like internal stimuli (pH, temperature, etc.) (X. Zhang et al., 2010), and (2) modified physiologies, such as structural changes (i.e., leaky vasculature) in the microenvironment of inflammatory tissues (Crielaard et al., 2012).

Passive drug targeting (or enhanced permeation and retention (EPR) effect–mediated targeting) is based on the longevity of the pharmaceutical carrier in the blood and its accumulation in pathological sites with compromised vasculature (Torchilin, 2010). For example, drugs can penetrate the tumor vasculature through its leaky endothelium and, in this way, accumulate in several solid tumors. This is called the enhanced permeation and retention (EPR) effect (Hirsjärvi et al., 2011; Nakamura et al., 2016). The EPR effect is specifically responsible for passive drug targeting in cancer tissues (Greish, 2010; Torchilin, 2011; Maeda, 2012).

Drug targeting systems will be stimulated by such modifications to release the drug only at the diseased site and spare the untargeted tissues. However, the targeting potential of such a strategy is relatively low and often associated with partial nonspecific localization of therapeutics in the normal tissues, which needs to be considered while employing such therapies. (Thanki et al., 2015; Nakamura et al., 2016).

Additionally, passive drug targeting relies on the basic defense mechanism of the reticulo-endothelial system (RES), which is part of the immune system, consisting on the phagocytic cells, such as monocytes and macrophages. Drugs or drug carriers can be taken up by the RES in the liver, spleen, lung, lymph nodes, etc. by opsonization (via C3, C4, and C5 complements) and phagocytosis processes (Nie, 2010). In this case, the passive targeting strategy may be designed outside the RES (i.e., RES blockade), and can be explored for conditions wherein the RES is the target site of action (Allen and Chonn, 1987; Lammers et al., 2012; Liu et al., 2015).

Another approach to prolong drugs’ blood circulation time is by employing polymers, such as polyethylene glycol (PEG). PEGylation of therapeutic agents is an established technology used to enhance the bioavailability and prolongs blood circulation of an active pharmaceutical ingredient in the body of patients (Mohs et al., 2014). PEGylation is a process by which one or more PEG-chains are attached to a biocompounactive. PEGs are hydrophilic polymers that are nontoxic, nonimmunogenic, nonantigenic, and FDA approved. The PEG-drug conjugates have several advantages: a prolonged residence in body (stealth characteristics), a decreased degradation by metabolic enzymes, and a decreased uptake by mononuclear phagocyte system (MPS) cells. By these favorable properties, PEGylation improves pharmacokinetics and enhances the potentials of therapeutic agents (Harris and Chess, 2003; Veronese and Pasut, 2005; Huynh et al., 2010; Gokarn et al., 2012; Salmaso and Caliceti, 2013).

1.2.2.1.2 Active drug targeting

Unlike passive targeting, which is a nonspecific strategy, active drug targeting is a specific approach that involves interactions between specific biological pairs/systems, such as ligand-receptor, antigen-antibody, and enzyme-substrate. In active targeting, therapeutics can be also transported specifically to relevant cells through stimuli responsive nanocarriers (temperature, ultrasound, magnetic field) (Fleige et al., 2012; Kong et al., 2012; Mura et al., 2013).

Active targeting strategy is based on the anchoring (attachment) of active agents or ligands to the surface of drug delivery system (DDS), which is selectively and specifically recognized by the target in concern. Attaching these active agents/ligands can be mediated by various mechanisms and facilitates greater uptake. This approach provides selectivity, recognizability and potential to interact (bind) with pathological cells and specific tissues in the body (Nishioka and Yoshino, 2001; Minko et al., 2004; Torchilin, 2010; Kong et al., 2012).

It is imperative that, in physiological conditions, very high-binding affinity moiety-receptors are required. In tumor cells for example, receptors are (highly) overexpressed relative to normal cells, and molecular targets are usually employed toward such overexpression of surface receptors for site-specific delivery of therapeutics. Using DDSs exerts precise effects also on cells with low expression (Allen, 2002; Danhier et al., 2010; Lipson et al., 2012; Muro, 2012).

Appropriate modifications and functionalization on the pharmaceuticals/drugs or drug nanocarriers for specific affinity to receptors/markers on targeted cells, tissues, or organs can involve the use of several targeting components. These include peptides, antibodies and their fragments, sugar residues, lectins, vitamins (i.e., folate), transferrin, mRNAs, etc. The targeting moieties will enable the drug/drug carriers to efficiently reach only the intended sites of action and avoid nonspecific accumulations and related side effects (Torchilin, 2000; Ferris et al., 2011; Mahon et al., 2012; Morachis et al., 2012; Wang et al., 2013; De Oliveira et al., 2016).

Active targeting could be divided into organ level, cellular level, and subcellular level, depending upon the extent of penetration. For intracellular/subcellular targeting, the active form of the therapeutic substance must reach the intracellular target for its mechanism of action. The targets in question may be located on the plasma membrane or cell components such as endosome, lysosome, endoplasmic reticulum, nucleus, mitochondria, or even mRNA-binding complexes (Harris et al., 2010; Heller et al., 2012; Lammers et al., 2012; Thanki et al., 2015).

1.2.2.1.3 Other approaches’ classification

Combination targeting:

An active targeting process is the more efficient way to obtain targeting and it provides the widest opportunities. But to yield better results, passive and active targeting approaches are often combined (i.e., PEG-coupled transferrin) (Arima et al., 2012; Krukemeyer et al., 2012; Schleich et al., 2014). The advantages of each approach need to be weighed prior to designing nanocarriers for active or passive targeting (Torchilin, 2010; Hirsjärvi et al., 2011; Allen and Cullis, 2013). As an example, EPR effect permits inherent passive accumulation of nanocarriers in tumors, therefore there is a need for active targeting strategy to evade the RES system and/or reach the specific (intra)cellular target (Bae and Park, 2011).

Additionally, a combination of active targeting techniques is used to provide additional benefits of targeting, and this is evident from various examples of multifunctional nanocarriers in the literature. This multifunctionality includes modifications of the surface of nanocarriers with the targeting ligands (Du et al., 2012; Lee and Nan, 2012; Xun et al., 2013). Polymer- or liposome-antibody fragment conjugates (immunopolymers or immunoliposomes) present an example of this combination between polymer- or liposome-based drug delivery and antibody-mediated targeting, for improving stability, solubility, immunocompatibility, pharmacokinetics, etc. (Sapra and Shor, 2013; Srivastava et al., 2014).

For increasing targeting efficiency, a combination between nonphysical/biochemical-based approaches with physical-based approaches is established. For example, ultrasound exposure improves the targeted therapy effects of some galactosylated nanoparticles by increasing vascular permeability on hepatocellular carcinoma (cellular targeting) (Wei et al., 2013). The same method is used for gene therapy with microbubbles for enhancing the delivery of nucleic acid (NA)-containing particles in ultrasound-targeted region (intracellular targeting) (Cool et al., 2013).

Physical targeting:

Physical targeting is a physical/biophysical stimuli-based approach with topical (local) characteristic, where the therapeutic agents are administered systemically. For drug targeting, we distinguish endogenous physical stimuli such as temperature, pH, redox potentials, etc., and exogenous physical stimuli, which demands the employment of an external driving force (i.e., magnetic, ultrasound) for preferential localization and destabilization of nanocarriers (Torchilin, 2000; Florence, 2012).

A variety of (bio-) physical approaches have been widely explored for their immense potential to preferentially localize drug carriers in the targeted areas; biocompatible physical targeting systems have emerged as interesting material in biological application (Watanabe et al., 2013; Chen et al., 2016).

As mentioned previously, the microenvironment of pathological tissues may present abnormal pH value and/or temperature, which could be specifically exploited as endogenous stimulus for biophysical targeting. In chemotherapy, physical targeting systems are designed to degrade at (low) acidic pH and/or elevated temperatures (hyperthermia) (Torchilin, 2000; Giustini et al., 2010; Huang and Hainfeld, 2013; Weerakkody et al., 2013).

As example of exogenous stimulus, magnetically modulated drug targeting, is a particular system wherein the drug in concern is immobilized on ferromagnetic nanoparticles and allowed to circulate in the patient body (physiological medium). The external magnetic field is applied at the diseased tissue/organ which accumulates the circulating nanoparticles at the desired site of action. The method using ultrasound energy may be similarly established (external ultrasound field guided targeting) (Issa et al., 2013; Hu et al., 2014).

Physical targeting approaches may eliminate the multiple chemical processing steps and reduce the number of components required in conventional preparation of drug targeting systems (core formation, bioconjugation with targeting ligands, etc.), thereby improving the chances of reproducibility (biophysicochemical properties) and decreasing difficulties in predicting behavior (mechanism of action) of physical targeting systems in a site of action (Desai, 2012; Florence, 2012; Hu et al., 2014).

Finally, it should be noted that there are other classifications of approaches, according to targeting-based strategies. We can find a distinction on the basis of:

(1) The purpose (subject) of targeting, such as disease-based approaches (cancer, infections), route-based approaches (oral, parenteral, nasal, transdermal, etc.), disease- or location-based approaches (brain, lung, skin) and order- or level-based approaches (organelle, cell, tissue or organ);

(2) The mode of target, such as local-targeting, in which a biocompounactive is applied directly into the affected zone; and systemic targeting that requires active or passive targeting mechanism to carry the therapeutic agents to the intended site; and

(3) The carrier- or ligand-based targeting (peptide, vitamin, transferrin, antibody, inorganic components, etc.) with different characteristics (size, density, etc.) and interactions (drug, physiological microenvironment, etc.).

1.2.2.2 Drug targeting systems

A conventional application of drugs is characterized by the lack of selectivity, poor biodistribution, and limited effectiveness (Nevozhay et al., 2007). In fact, approximately 95% of all new potential therapeutics have poor pharmacokinetic and biopharmaceutical properties, hence there is a need to develop suitable drug systems that distribute, in a very efficient way, the therapeutically active drug molecule only to the site of action, without affecting healthy tissue or organ (Agnihotri et al., 2011).

Drugs can be incorporated into nanosystems or nanocarriers, which can carry therapeutic drugs and deliver them to the target site. The incorporation of drug molecules into nanosystems can protect a drug against degradation, as well as offer possibilities of targeting and controlled release. The drug targeting systems involve (nano-)technology, designed to maximize therapeutic efficacy of drugs by controlling their biodistribution profile (Agnihotri et al., 2011; Wilczewska et al., 2012; Yamashita and Hashida, 2013; Gao, 2016).

Nanocarriers, as DDSs, are designed to improve the pharmacological and therapeutic properties of conventional drugs (Wilczewska et al., 2012). The major advantages of using such systems are improving the solubility, protecting cargoes from rapid degradation or clearance, and enhancing drug concentration in target tissues; therefore, the required doses of drugs are lower (Nevozhay et al., 2007; Gao, 2016). In comparison with the traditional form of drugs, nanocarrier-drug conjugates are more effective and selective. They can reduce the toxicity and other adverse side effects in normal tissues. The way of conjugating the drugs or other biocompounactives to the nanocarriers is highly important for a targeted therapy. A drug may be entrapped or encapsulated into the nanocarriers, or it can be adsorbed or covalently attached to its surface (Wilson et al., 2010; Wilczewska et al., 2012; Masood, 2015).

Nanocarriers, especially nanoparticles, are interesting because they are easy to synthesis and have numerous applications. In addition, the surface of nanoparticles is fairly easily conjugated with specific ligands or antibodies for recognition and binding to target cells (Faraji and Wipf, 2009; Paulo et al., 2011). There is a need for further improved particulate carrier systems, with as many as possible of the following ideal characteristics and properties (Muller and Keck, 2004; Agnihotri et al., 2011; Hahn et al., 2011; Gujral and Khatri, 2013):

(1) easy or reasonably simple to be produced and qualified, at a large scale and cost effective, and acceptable by regulatory authorities;

(2) eontoxic, nonimmunogenic (biocompatible) and physicochemically stable in vivo and in vitro (minimal drug leakage during transit);

(3) resistant to aggregation, able to cross biophysiological barriers, and have prolonged circulation times in the body (resistant to RES uptake);

(4) release the drug moiety inside the target with controllable and predictable rate;

(5) have high sensitivity and selectivity for the target, and maintain the specificity of the surface ligands (stability in biofluids);

(6) biodegradable or readily eliminated from the body without any problem after drug delivery; and

(7) applicable to as many drugs as possible.

Various kinds of nanoparticulate platforms for the targeted delivery of drugs have gained increasing attention in the biomedical field (Gao, 2016) and are currently under development using emerging novel nanomaterials (Park, 2014). Some of those pharmaceutical carriers have already made their way into clinic, whereas others are still under preclinical development (Torchilin, 2012). These include drug carrier systems such as polymer nanoparticles, liposomes, dendrimers, micelles, inorganic nanoparticles, nanogels, carbon nanotubes, etc. (Torchilin, 2007; Agnihotri et al., 2011; Srikanth and Kessler, 2012; Gujral and Khatri, 2013; Rani and Paliwal, 2014). Some chosen examples of the main drug targeting systems are presented here.

1.2.2.2.1 Lipid-based nanosystems

In the past few years, lipids have been of major interest and importance in field of DDS. Reports on different lipid-based nanosystems have increased immensely, with a major focus on liposomes and solid lipid nanoparticles (SLNs) (Pathak and Thassu, 2009; Mehnert and Mäder, 2012; Ramteke et al., 2012; Kawadkar et al., 2013).

Liposomes:

Liposomes represent an important class of nanocarriers known as vesicular DDSs. They are the first to be investigated as drug carriers and have since received a lot of attention as pharmaceutical carriers of great potential (Torchilin, 2005; Wilczewska et al., 2012). Liposomes are spherical, self-closed structures, with one or several aqueous compartments surrounded by one or many concentric bilayered (phospho)lipid membranes (Torchilin, 2005; Faraji and Wipf, 2009; Gujral and Khatri, 2013). These small, artificially designed vesicles are nano/microparticular or colloidal carriers with a size ranging from 20 nm to 10 µm (Wilczewska et al., 2012; Rani and Paliwal, 2014). A drug is incorporated in liposomes through the encapsulation process. Additionally, the interactions of liposomes with cells can be realized by adsorption, fusion, endocytosis, and lipid transfer (Wilczewska et al., 2012; Yamanaka and Yasuda, 2012; Alekseeva et al., 2015).

Liposomes are being investigated on a large scale due to their attractive biological properties and favorable characteristics. The structural similarity to human cell membrane components (phospholipids) makes liposomes biocompatible and provides a unique opportunity to deliver pharmaceuticals into cells, or even inside individual cellular compartments, without undesirable side reactions (Torchilin, 2005; Moro et al., 2010). Due to their amphiphilic nature, liposomes can entrap both hydrophilic and hydrophobic pharmaceutical agents. Hydrophilic biocompounactives remain encapsulated in the aqueous interior, and hydrophobic ones may diffuse in the phospholipid membrane. Finally, the high loading capacities provide a flexibility in designing and an ease of modification of liposomes, which makes them an appealing solution for increasing the drug delivery advantages in various applications (Agarwal et al., 2000; Nobs et al., 2004; Faraji and Wipf, 2009; Chen et al., 2010).

Different methods have been suggested to prepare liposomal vesicles of different sizes and properties. Depending on the number of bilayers and size, liposomes are classified into (1) multilamellar vesicles, formed by several concentric bilayers (0.5–5 µm); and (2) uni-lamellar vesicles which consist of a single bilayer, with two different sizes: small (around 100 nm) and large (from 200 to 800 nm) (Torchilin, 2005; Gujral and Khatri, 2013). Other types of liposomes are based on their charge, so are distinguished neutral, cationic and anionic liposomes (Jain et al., 2010; Balazs and Godbey, 2011). Both positively and negatively charged liposomes are extensively researched for their application in gene therapy (Srinivasan and Burgess, 2009; Kapoor and Burgess, 2012a; Kapoor et al., 2012; Zhi et al., 2013; Yang et al., 2016).

Variants of liposomes can be designed to adhere to cellular membranes for delivering a drug payload or simply to transfer drugs following endocytosis (Faraji and Wipf, 2009). For that, new varieties of liposomes have been developed, such as stealth liposomes (incorporating PEG) (Nag and Awasthi, 2013; Luo et al., 2016), immunoliposomes (attaching antibodies to the surface) (Rothdiener et al., 2010; Paszko and Senge, 2012; Saeed et al., 2016), proteoliposomes (incorporating a crude mitochondrial membrane fraction) (Ciancaglini et al., 2012; Bolean et al., 2015), transferosomes (elastic/deformable liposomes) (Rajan et al., 2011; Ghanbarzadeh and Arami, 2013; Ali et al., 2015), LeciPlex (containing methyl-ammonium bromide and soybean lecithin) (Date et al., 2011; Shah et al., 2015), magnetoliposomes (encapsulating maghemite nanocrystals) (Sabaté et al., 2008; Soenen et al., 2009; Monnier et al., 2014), etc. Such formulations may prevent liposomes, and accordingly, have longer circulation times and increased duration of action in targeted tissues/cell compartments (Wilczewska et al., 2012; Gujral and Khatri, 2013). Other liposome formulations are rapidly taken up by macrophages, and this can be exploited either for macrophage-specific delivery of drugs, or for passive drug targeting (Torchilin, 2012; Rani and Paliwal, 2014; Bozzuto and Molinari, 2015; Deng et al., 2016).

Liposomes are still being investigated for various novel applications. They are used for delivering peptides and proteins (Reddy and Couvreur, 2011; Storka et al., 2015), and treating various diseases (Wilczewska et al., 2012; Kim, 2016), but gene delivery and cancer therapy are the principal areas of interest for liposomal drugs (Torchilin, 2005; Thanki et al., 2015). In fact, liposomes have been widely studied to deliver the NAs (Khatri et al., 2008; Balazs and Godbey, 2011; Buyens et al., 2012; Kapoor and Burgess, 2012a; Allen and Cullis, 2013; Chen et al., 2013; Vhora et al., 2015). Generally, lipids are associated with NAs either via surface complexation or encapsulation of hydrophilic NA molecules within the aqueous core. Biophysical properties of liposomes can be modulated to achieve high NA entrapment, efficient cellular uptake, and endosomal escape (Kapoor and Burgess, 2012b; Angart et al., 2013). For example, cationic liposomes interact electrostatically with NAs to form lipid-NA complexes known as lipoplexes (Balazs and Godbey, 2011; Cool et al., 2013), which protect NA from nuclease degradation, enhance cellular transfection, and facilitate NA release from the intracellular vesicles before they reach the destructive lysosomal compartments (Brand and Nicholls, 2011). Lately, the focus has been diverted towards anionic liposomes for efficient gene delivery (Srinivasan and Burgess, 2009; Balazs and Godbey, 2011; Kapoor and Burgess, 2012a,b; Aoki et al., 2015).

Moreover, liposomes are used as thermo-responsive carriers (Ponce et al., 2006; McDaniel et al., 2013). The usefulness of pH-sensitive liposomes has been well exhibited in a wide variety of applications, especially in nanomedicine (Culver et al., 2014). Liposomal delivery systems, modified with pH-responsive, were developed to deliver NA therapeutics and peptides (Q. Zhang et al., 2013; Aoki et al., 2015; Q. Zhang et al., 2015) and used to explore multiple possibilities to treat cancer. The acidic microenvironment of tumors, due to increased glycolysis, permits pH-triggered drug release from liposomes (Karanth and Murthy, 2007; Ferreira et al., 2013; Liu et al., 2014). Various immunoliposomes were also reported for efficient management of cancer (Rochlitz and Mamot, 2009; Herrmann et al., 2012; Nishikawa et al., 2012; Limasale et al., 2015).

It was determined that conventional liposomes present some negative points, such as rapid clearance (rapidly captured by the RES) (Yokoyama, 2005). However, problems associated with lower circulation half-life and stability in blood have been resolved (Hong et al., 2002; Bertrand et al., 2010) by functionalized liposomes containing one or many specific substances (proteins, antigens, PEG, magnetic compounds, etc.). Functionalization of liposomes is a promising approach for targeted delivery of therapeutics, and can be achieved via many techniques (ligand-binding, chemical modification, etc.) (Zhang et al., 2009; Nicolas et al., 2013; Naumovska et al., 2014; Vabbilisetty and Sun, 2014). This approach facilitates the targeting and uptake (Kelly et al., 2011; Jain et al., 2013). It was observed that modified liposomes were more efficient in uptake and localization into the targeted tissues, compared to unmodified/conventional liposomes. The circulation times of these particles can be greatly increased simply by hydrophilic surface modification (Faraji and Wipf, 2009; Yoshizawa et al., 2011). Multifunctional liposomes which can conjugate a variety of ligands were also reported to act selectively on particular tissues, especially for targeting cancer cells (Biswas et al., 2011; Perche and Torchilin, 2013; Xiang et al., 2013; Balducci et al., 2014; He et al., 2014; Rengan et al., 2014).

For example, a breast cancer study shows that conjugation of a lipophilic cationic ligand to the liposomes induces more apoptosis compared to unconjugated liposomes, and the amount of drug required for an effective therapeutic response by functionalized liposomes was less compared to nonfunctionalized liposomes (Patel et al., 2010b). The same results were obtained for induction of immune response; the coated-liposomes (with lectin or IgA) showed higher immune response in comparison to nonconjugated formulation (Behera et al., 2011; Gupta and Vyas, 2011; Q. Zhang et al., 2016).

Solid lipid nanoparticles:

Solid lipid nanoparticles are one of the major types of lipid-based nanoparticles that have attracted special interest during recent decades. They are submicron colloidal carriers ranging from 50 nm to 1 µm (Faraji and Wipf, 2009; Asawale et al., 2014; Mahajan et al., 2015). This system possesses a solid biodegradable lipid core matrix (dispersed in water) which is stabilized by a shell of various surfactants/emulsifiers (i.e., soy lecithin or poloxamer) (Nair et al., 2011; Wilczewska et al., 2012). Generally, SLNs are made of a solid hydrophobic core with a monolayer of phospholipids coating. The solid core contains the drug dissolved or dispersed in the solid high-melting fat matrix. The hydrophobic chains of phospholipids are embedded in the fat matrix (Ramteke et al., 2012; Asawale et al., 2014; Nikam et al., 2014). Nair et al. (2011) and Mahajan et al. (2015) have provided an overview of lipids and surfactants used for preparation of SLNs (Table 1.1). Several production methods of SLNs are detailed in the literature (Faraji and Wipf, 2009; Ekambaram et al., 2012; Ramteke et al., 2012; Yadav et al., 2013; Mahajan et al., 2015).

Table 1.1

SLNs were developed at the beginning of the 1990s to overcome the limitations of other traditional colloidal carriers, like liposomes and polymeric nanoparticles (PNPs), and have been reported as an alternative DDS (Vishvajit et al., 2010; Nair et al., 2011; Ekambaram et al., 2012; Yadav et al., 2013). SNLs are frequently studied for their effective delivery (L. Zhang et al., 2010; Wong et al., 2012; Mahajan et al., 2015). They have the potential to carry lipophilic or hydrophilic drugs, or diagnostics (Ramteke et al., 2012; Nikam et al., 2014). Several studies investigated the potential of SLNs to improve the oral bioavailability of poorly water soluble drugs (Ekambaram et al., 2012; Thukral et al., 2014), but they can be also used to deliver drugs orally, topically, or via inhalation (Faraji and Wipf, 2009). SLN formulations for various application routes (parenteral, oral, dermal, ocular, pulmonar, rectal) have been developed and thoroughly characterized in vitro and in vivo (Nikam et al., 2014; Sanap, 2014).

SLN combine the advantages of different colloidal carriers and simultaneously avoid some of their disadvantages (Nair et al., 2011; Ekambaram et al., 2012). SLNs are attractive for their potential to improve performance of neutraceuticals, pharmaceuticals, and other materials (Asawale et al., 2014; Aditya and Ko, 2015). They offer possibility to develop new prototypes in drug targeting because of their characteristics including an excellent reproducibility and physical stability (due to their relatively rigid core), enhanced bioavailability and biocompatibility, protection of incorporated labile drugs from degradation inside the gut, controlled release along with good tolerability, less toxicity (ease of biodegradation), etc. However, some disadvantages have been observed, such as poor drug loading capacity (limited by the lipid matrix structure and/or the solubility of drug in the lipid), drug expulsion after crystallization, and generally a relatively high water content of the dispersions (70%–99.9%) (Nair et al., 2011; Ramteke et al., 2012; Wilczewska et al., 2012; Nikam et al., 2014; Sanap, 2014). Despite these disadvantages, it has been proven that an SLN is more beneficial than a colloidal DDS because of its more controlled and targeted properties (Mahajan et al., 2015; Kalaycioglu and Aydogan, 2016).

So, SLNs hold great promise for reaching the goal of controlled and site-specific drug delivery (Asawale et al., 2014). They are at the forefront of the rapidly developing field of nanotechnology with several potential applications in (targeted) drug delivery system (TDDS), clinical medicine and other science (Vishvajit et al., 2010; Ekambaram et al., 2012). SLNs have shown great potential for insulin delivery (Dolatabadi et al., 2015; Ansari et al., 2016); they are used to improve the diffusion of the drugs across the blood–brain barrier (BBB) (Ramalingam and Ko, 2015; Singh et al., 2015; Kuo and Cheng, 2016) and enhance permeation through skin, especially for skin cancer treatment (Geetha et al., 2015; Kelidari et al., 2015; Akbari et al., 2016). Some SLN formulations were prepared as novel anticancer chemotherapeutics (Peters and Brown, 2015; Talluri et al., 2015) and for treatment of tuberculosis (Gaspar et al., 2016).

The next generation of carrier systems based on the solid lipid matrix, nanostructured lipid carriers (NLCs) and lipid drug conjugates (LDCs) were designed as modified SLNs to improve their colloidal stability and drug loading capacity, and decrease drug leakage during shelf life of the product. NLCs comprise both liquid and solid lipids, which leads to a special nanostructure that makes them comparatively more versatile than conventional SLNs. Three structural models of NLCs have been proposed (imperfect, multiple, and amorphous types) (Muller and Keck, 2004; Chen et al., 2010; Wilczewska et al., 2012; Naseri et al., 2015; Beloqui et al., 2016). LDCs are insoluble drug-lipid conjugates prepared by salt formation or by covalent linking followed by homogenization. They were developed in order to expand the applicability of lipid-based carriers to lipophobic drug molecules (Muller and Keck, 2004; Yadav et al., 2013; Khatak and Dureja, 2015). These lipid nanoparticles have potential applications in the drug delivery field, clinical medicine, cosmetics (especially dermal applications), etc. (Kelidari et al., 2015; Naseri et al., 2015).

Both SLNs and NLCs have also been reported to be amenable to functionalization with attachment of targeting moieties (ligands, antibodies, PEG, magnetics, etc.). Modifications are reported either by functionalizing the lipid or the surfactant (employed in stabilization) (Rostami et al., 2014; Campos et al., 2015; Devi et al., 2015; López-Garcia and Ganem-Rondero, 2015; Neves et al., 2016). Several studies reported improved drug bioavailability and therapeutic efficacy of functionalized SLNs/NLCs compared to nonfunctionalized nanoparticles (Yu et al., 2010; Alukda et al., 2011; Soni et al., 2014; Luo et al., 2015; Arranja et al., 2016).

1.2.2.2.2 Polymer-based nanosystems

Polymeric nanoparticles:

PNPs are solid colloidal particles occurring in multiple nanoforms with a diameter ranging from 10 to 100 nm (Vauthier and Bouchemal, 2009; Niemirowicz and Car, 2012; Masood, 2015). According to their structural organization, PNPs are classified as nanocapsule and nanosphere (Fig. 1.2) (Vauthier and Bouchemal, 2009; Kumari et al., 2010). Based on their chemical composition, PNPs can originate from natural polymers (i.e., gelatin, chitosan, albumin, DNA) (Sharma et al., 2006; Saraogi et al., 2011; Charoenphol and Bermudez, 2014; Ghaz-Jahanian et al., 2015), synthetic ones (i.e., poly-caprolactone: PCL; poly-methyl methacrylate: PMMA) (Martínez et al., 2011; Niemirowicz and Car, 2012), or semisynthetic polymers (Niemirowicz and Car, 2012; Wilczewska et al., 2012). Depending on their in vivo behavior, PNPs may be classified as biodegradable (i.e., poly-L-lactide: PLA; polyglycolide: PGA) (Kumari et al., 2010; Kumar et al., 2013; X. Zhang et al., 2013), or nonbiodegradable (i.e., polyurethane) (Fritzen-Garcia et al., 2009).

Figure 1.2 Forms of nanocapsule and nanosphere with adsorbed or entrapped drug as referred by Kumari et al. (2010).

A few decades ago, PNPs emerged as a promising and viable technology platform for targeted and controlled drug delivery (Cheng et al., 2013). A targeted delivery system based on PNPs as a drug carrier is becoming a system of choice, and presents many pivotal characteristics, which include stability and prolonged circulation in blood, biodegradability, nontoxicity, and biocompatibility (Des Rieux et al., 2006). PNPs are widely investigated for their distinctive size and shape properties for tissue penetration via active and passive targeting, specific cellular/subcellular trafficking pathways, and easy control of cargo release by sophisticated material engineering (Masood, 2015); thus making these carriers useful for the treatment of chronic diseases (Panyam and Labhasetwar, 2003). In cancer, for example, targeted PNPs can be used to deliver chemotherapies to tumor cells with greater efficacy and reduced cytotoxicity on peripheral healthy tissues (Chan et al., 2010).

Many studies have reported that hydrophilic and hydrophobic biocompounactives are delivered by using PNPs as carriers (Anand et al., 2010; Nanjwade et al., 2010). Drugs can be encapsulated on the PNP structure during a polymerization step (nanocapsule) or can be immobilized on PNP surfaces after a polymerization reaction (nanosphere) (Qiu and Bae, 2006; Mora-Huertas et al., 2010; Nicolas et al., 2013; Moulton and Wallace, 2014).

Also, PNPs are of great interest for drug delivery, since they can be tailored from a range of polymers (Ungaro et al., 2012). A number of different polymers have been investigated for formulating nanoparticles by using several methods (Pal et al., 2011; Rao and Geckeler, 2011; Moulton and Wallace, 2014). However, biodegradable polymers are the main materials frequently used as drug delivery vehicles in nanopharmacology because of their good bioavailability, better encapsulation, control release, complete degradation inside the human body, and less toxic properties with negligible side effects (Kumari et al., 2010; Niemirowicz and Car, 2012).

These polymers consist of ester groups that hydrolyze and cause polymer degradation in aqueous environments, thereby releasing the entrapped material. Drugs may be released by desorption, diffusion, or nanoparticle erosion in the target tissue. The rate of degradation and release is controlled, based on polymer properties (i.e., molecular weight, crystallinity, end groups, etc.) (Torchilin, 2008, 2012).

Several polymers have been demonstrated in nanomedicine to improve the performance of the therapeutic agents. The use of biodegradable PNPs for controlled drug delivery has shown significant therapeutic potential (Chan et al., 2010). Synthetic biodegradable polymers, such as PCL, polyacrylamide, and polyacrylate, are well-known materials for the synthesis of nanoparticles (Kalaria et al., 2009), and poly(D,L-lactic-co-glycolic acid) (PLGA) polymer seems to be the most studied for drug delivery application (Jain, 2000; Betancourt et al., 2007). Nevertheless, detailed nanotoxicity studies are needed to ensure the safety of PNPs (Cenni et al., 2008; Kawaguchi et al., 2009; Soenen et al., 2011).

Additionally, recent progress in the field of TDDS is based upon the rational design of polymers tailored for particular drugs (Masood, 2015). PNPs can be chemically conjugated and modified to targeting drugs/ligands. They are usually coated with nonionic surfactants in order to reduce immunological and intermolecular interactions (Torchilin, 2008). Moreover, the engineering of multifunctional PNPs (combining several properties in one particle) can enhance the therapeutic efficacy of nanoparticulate drugs, and provide a promising method for treatment and/or diagnosis of many chronic diseases (Torchilin, 2012). For example, sophisticated PNPs have been aggressively pursued for responding to dual/multiinternal and/or external stimuli, such as pH/temperature or redox, temperature/enzyme, temperature/pH/magnetic, pH/redox/magnetic, etc. (Cheng et al., 2013; Zan et al., 2014; Guragain et al., 2015).

Dendrimer nanocarriers:

Dendrimers, referred to as the polymers of the 21st century are a novel class of synthetic materials, based on well-defined cascade macromolecules that are characterized by their three-dimensional and extensively branched globular nanopolymeric architectures, which provide a high degree of surface functionality and versatility