Polymer-based Nanostructures: Medical Applications

by Violeta Malinova (Contribution by), Harry Kroto (Editor), Pavel Broz (Editor), Wolfgang Meier (Contribution by), Paul O'Brien (Editor)

Overview

Nanotechnology is about small things and medicine usually deals with bigger things — with patients and their diseases. The ultimate goal of all medical sciences is the healing of diseases whenever possible, otherwise the abatement of suffering. The first step of a successful medical treatment is the correct diagnosis of the disease or disease condition, based on clinical knowledge and experience and on diagnostic tools that give insight into macroscopic, microscopic, and biochemical properties of the disease process. Nanomaterials can improve currently available diagnostic applications in medicine and especially polymer—based nanostructures have an enormous potential to revolutionize the way how clinicians diagnose diseases correctly and efficiently. The second step when treating patients is a powerful and specific therapy that is low in side effects, that can prolong the survival of the patient or that can lower the burden of the disease. Again, polymer—based nanostructures are very promising novel tools that might change the way how certain diseases are being treated. This book combines both viewpoints and presents successful applications of nanotechnological constructs in medicine and the science behind the tools. Supramolecular nanometre—sized structures such as nanoparticles or vesicles built out of new synthetic polymeric materials have aroused enormous interest in recent years — both in chemical and pharmaceutical labs as well as in clinical medicine. They promise to be useful for novel or improved diagnostic and therapeutic applications for important diseases such as arteriosclerosis, cancer, infections, or autoimmune disorders. In the first part of this book, renowned researchers provide a detailed insight into both chemical and biological/pharmacological basics that have to be managed for successful applications of these nanostructures in human beings. In the second part, invited authors review the main literature in both diagnostic and therapeutic applications with polymer—based nanostructures that have already reached clinical practice or will enter it in the next few years. Key features include: —Multidisciplinary: The book is written by both clinicians from world—wide leading UniversityHospitals as well as researchers coming from natural sciences. Special effort was invested into comprehensibility across the traditional borders of medicine, pharmacology, and chemistry. —State—of—the—art: The book is filled with exciting contributions from some of the leading research groups in the field. This guarantees a clear emphasis on ongoing research and ground—breaking applications and projects —Structure: The book can be read from the beginning to the end, starting with basics that help to understand the current diagnostic and therapeutic applications of polymer—based nanostructures in medicine, ending with innovative multifunctional and "smart" nanostructures that might be the future of medicine. The way leads from solid foundations to nowadays applications and further to more futuristic approaches —References: The internationally renowned authors of the chapters have put great efforts into choosing only the most important and competitive papers for the reference lists. All major projects in this field are included — perfect for students or researchers that want to search the main literature thus avoiding the need to search through huge electronic databases

Product Details

ISBN-13:	9780854049561
Publisher:	RSC
Publication date:	02/10/2010
Series:	Nanoscience & Nanotechnology Series , #9
Pages:	388
Product dimensions:	6.30(w) x 9.20(h) x 1.00(d)

About the Author

Dr Pavel Broz MD is at the UniversityHospital Basel, Switzerland.

Read an Excerpt

Polymer-Based Nanostructures

Medical Applications

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By Pavel Broz

The Royal Society of Chemistry

Copyright © 2010 Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85404-956-1

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CHAPTER 1

Polymer Materials for Biomedical Applications

VIOLETA MALINOVA AND WOLFGANG MEIER

University of Basel, Basel, Switzerland

1.1 Introduction

Polymers are the most versatile class of biomaterials, being extensively applied in diverse medical fields such as tissue engineering, implantation, artificial organs, medical devices, prostheses, contact lenses, dental materials and pharmaceutical vehicles. Compared with other types of biomaterials, such as metals and ceramics, polymers can be synthesized in different compositions with a wide variety of structures and properties which permit specific applications.

The recent progress in nanotechnology as well as the active research at the interface of polymer chemistry and biomedicine has opened novel opportunities to use nano-sized polymeric systems in bioengineering, molecular biology, diagnostics, and therapeutics. In this chapter we aim to summarize the types of polymer-based nanostructures applied in biomedical fields and outline the basic criteria for polymer selection.

1.2 Polymers as biomaterials

Polymers used as biomaterials can be naturally occurring, synthetic of combination of both. Natural polymers are abundant, usually biodegradable and offer good biocompatibility. A majority of drug delivery systems have been based on proteins (e.g. collagen, gelatine, and albumin) and polysaccharides (e.g. starch, dextran, hyaluronic acid, and chitosan). For example, chitosan and its derivatives have shown excellent biocompatibility, biodegradability, low immunogenicity, and biological activities. The principal disadvantage of natural polymers is associated with their structural complexity, which often makes modification and purification difficult. On the other hand, synthetic polymers are available in a wide variety of compositions with readily controlled physicochemical, chemical, mechanical, and biological properties. Advanced polymerization techniques, processing, and blending provide ways for optimizing the polymer mechanical characteristics, diffusive and biological properties. A primary drawback of the majority of synthetic materials is the general lack of biocompatibility, although poly(ethylene oxide) (PEO) and poly(lacticco-glycolic) acid are notable exceptions.

1.2.1 Natural and Synthetic Polymers

The role of natural and synthetic polymers of macroscopic dimensions (mm to cm) in biomedical applications such as fabrication of prostheses, implants, and soft contact lenses is well established. During the last two decades an extensive research has been dedicated to understanding the function of nano-structured polymers as biomaterials. Indeed, polymeric nanostructures are predominantly used to design intelligent systems for drug formulations. Polymer therapeutics can be broadly classified into polymer–drug conjugates, polymer–protein conjugates and novel nano-vehicles such as self-assembled block copolymer micelles, vesicles, DNA/polycation complexes ("polyplexes"), block ionomer complexes, micro (nanogels) and nanocapsules (-spheres) (Figure 1.1).

Usually, all subclasses utilize specific water-soluble or biodegradable polymers, either bioactive themselves or an inert parts of drug, gene or protein delivery systems. Polymer–protein conjugates are widely employed for biomedical applications. Covalent attachment of a synthetic polymer to biopolymers such as proteins, enzymes, antibodies, usually improves the stability, solubility, and biocompatibility of both components as well as extends the circulation time of the system. Poly(ethyleneoxide) (PEO) (commonly referred to as poly(ethyleneglycol) (PEG)) has become the prototypical "biocompatible" polymer for conjugation with therapeutic peptides, proteins, and anti-bodies ("PEGylation"). Several PEGylated proteins are in clinical use. The concept of polymer–drug conjugates is based on the "Ringsdorf's model" implying a drug, a polymeric carrier, and a cleavable covalent link between the two. Careful tailoring of the polymer–drug linker is essential for the creation of polymer-based drug delivery system, since the latter has to be inert during transport and allow drug liberation at an appropriate rate. Further elaboration of this model included the incorporation of a targeting motif to ensure delivery of the therapeutic at the desired biological site. It is important to mention that the polymer–drug conjugates provide an ideal opportunity for simultaneous delivery of a combination of drugs. A number of polymer–drug conjugates are in clinical trials, others are already on the market.

Compared to this first generation polymer therapeutics, the new generation nanosized materials are more advanced (Figure 1.1b). They offer high drug loading capacity, adequate stability in the bloodstream, long circulating properties, and can be designed to enable selective drug targeting with a suitable drug release profile. Polymeric micelles with non-covalently (physical entrapment) or covalently (chemical conjugation) incorporated drugs are extensively studied as promising nanoscopic therapeutics due to their attractive features approaching the requirements for selective dug delivery. Some of these systems are presently in phase I or phase II clinical trials. Besides the core-shell type of self-assembly structure typical for polymeric micelles, depending on the polymer composition and the preparation conditions, amphiphilic block copolymers can also form vesicular structures. These are commonly called "polymersomes", and reflect the structure of liposomes meaning that a bilayer structure enclosing an aqueous interior is present. Compared with lipid vesicles which possess a number of pharmacokinetic limitations, polymersomes are considered to be more rigid, stable and versatile, and less permeable. These synthetic shells are being used to encapsulate, protect, target, and release various hydrophilic drugs, proteins, and nucleic acids. Furthermore, it was demonstrated by Discher et al. that the polymeric vesicles can simultaneously carry hydrophobic drugs (in the bilayer) as well as hydrophilic drugs (in the interior).

1.2.2 Complicated Polymer Architectures

Modern polymer chemistry is producing an increasing number of complicated polymer architectures, including multivalent polymers, branched polymers, graft polymers, dendrimers and dendronized polymers, block copolymers, stars, hybrid glyco- and peptide derivatives, carbon nanotubes, and nanofibers (Figure 1.2). In terms of biomedical applications these materials are still at relatively early development stages. However, their unique structural and mechanical properties hold a great promise for drug delivery, bioimaging and tissue engineering research. Their potential advantages include better defined chemical composition, tailored surface multivalency, and creation of defined three-dimensional architecture within either synthetic water-soluble macromolecules or new supramolecular systems such as polymeric nanotubes. Dendrimers and dendronized polymers are particularly attractive for immobilization of drugs, imaging agents, and targeting moieties since they combine the features of monodisperse nanoscale geometry with high end-group density on their surface.

1.3 Factors Influencing the Polymer's Applicability in Biomedical Fields

Despite the broad diversity of polymer structures available, the choice of a polymer for biomedical applications remains a challenging task due to the number of criteria it has to satisfy. An additional complication arises from the fact that the polymer–body interactions are currently not well understood.

Materials at the nanometer scale possess unique physicochemical properties including small size, high surface area, chemical composition (e.g. purity, crystallinity, electronic properties), surface structure (e.g. surface reactivity, functionality), solubility, shape, and aggregation. Being of the same size as biological entities the polymeric nanomaterials can readily interact with biomolecules on both the cell surface and within the cell. Due to these properties the nanomaterials can exhibit toxic effect and may represent a considerable hazard for the human body. Polymer biocompatibility or toxicity (term referred to drugs) is a measure of non-specific, unwanted harm that the polymer may elicit towards cells, organs, or indeed the patient as a multi-organ system. It should be noted, however, that the material biocompatibility has to be defined only in the precise context of material use. For example, for blood-contact applications, biocompatibility is determined basically by specific interactions with blood and its components. For applications not involving blood contact, the choice of material depends on its tissue biocompatibility. Indeed, a polymer may be biocompatible in one application but bioincompatible in another. In any case, however, the biocompatibility is an essential characteristic of material for its biomedical utilization.

The general cytotoxicity, hematoxicity, carcinogenicity, teratogenicity, and immunogenicity of many polymer materials has been defined. Features such as polymer molecular weight, molecular weight distribution, charge, hydrophobicity and more delicate physicochemical properties, including surface and bulk properties have a profound effect on the polymer biocompatibility, biodistribution, elimination, and metabolism. It is important that a molecular mass of a polymer is correctly chosen to satisfy the requirements for certain application. For instance, the molecular masses of non-biodegradable polymers have to be limited to <40 kDa to ensure eventual renal elimination. It is also known that high molecular weight polymers cannot cross the blood– brain barrier and are not resorbed after oral administration. Individual macromolecules of different chain length present in a polymer sample might significantly affect the polymer biological activity (e.g. toxicity, efficacy). Therefore, the polymer polydispersity index (ratio Mw/Mn; where Mw is the weight average molecular weight; and Mn is the number average molecular weight) is a crucial characteristic of the polymer. Depending on the mechanism of polymerization, some synthetic polymers have very narrow polydispersity. For example, PEG has an Mw/Mn ~1.01. New synthetic methods (e.g. living free-radical polymerizations) and dendrimer chemistry are moving towards the production of synthetic macromolecules that, like proteins, are monodisperse.

It is important to point out that polycations, as a rule, are significantly more toxic than water soluble natural polymers and polyanions. Nevertheless, a few polycation-based therapeutics have been developed and tested in clinical applications. For instance, chitosan has been incorporated in a number of oral and injectable drug therapeutics and vaccines. An example of a successful synthetic polycation-based polymer therapeutic is "polyoxidonium", a partially N-alkylated, partially N-oxidized biodegradable copolymer of poly(1,4-ethylenepiperaside). Polyanions are less cytotoxic, but can cause anticoagulant activity and can also stimulate cytokine release. The few well-known examples of systemically administered anionic polymers include heparin and its synthetic analogs, e.g. highly sulfated glycosaminoglycans. One example of a synthetic polyanion administered in the body is poly (dicarboxylatophenoxyphosphazene) (PCPP), evaluated in clinical trials as immunoadjuvant in a number of preventive vaccines, such as influenza and also as drug carrier.

The biocompatibility of a polymer depends also on the specific adsorption of proteins to the polymer surface and the subsequent cellular interactions. These interactions with the surrounding medium are governed mostly by the distribution of functional groups on the biomaterial's surface. For instance, if blood contact is desired, the surface must be nonthrombogenic. The surface load and energy should then be considered, because they regulate the fluid–material interactions within the host. In general, a high charge density or/and hydrophilicity are required to reduce protein adsorption and thus to promote thromboresistance of the surface. Hydrophilic surfaces are essential in applications such as controlled drug delivery and sutures, where a regulated hydrolytic-degradation rate and optimum diffusion characteristics are desirable. Various chemical and physical approaches have been used to optimize specific polymer surface properties and thus improve the polymer biocompatibility. Material bulk properties such as permeability, diffusional characteristics and degradation rate must also be considered when selecting polymers for a certain application. Certainly, the polymer bulk properties are determined by its microstructural design. Concerning the permeability, for example, it is known that elastomers are usually permeable to gases and hydrophobic molecules, e.g. polyoleffin-based microporous membranes are highly permeable to oxygen. Hydrogels are permeable to water and water-soluble molecules, which is important for drug delivery and dialysis.

For many pharmaceutical applications biodegradable polymers are required. The degradation of the material is needed to ensure its removal from the body through renal clearance. It is essential that non-toxic low molecular weight products are generated as a result of the polymer degradation. Biodegradable polymers (also called bioerodible or bioresorable) may be of natural or synthetic origin (Figure 1.3).

Due to the physicochemical limitations of natural polymers, the synthetic polymers are preferred materials for specific applications. Their biodegradability can be tuned by varying the chemical structure of the polymer. Incorporation of hydrolytically labile groups (e.g. ester, orthoester, anhydride, carbonate, amide, urea, and urethane) (Figure 1.4) into the polymer backbones, and/or grafting side chains with different hydrophilicity or crystallinity can influence the kinetics of biodegradation, as well as the physical and mechanical properties. For example, degradation of synthetic polymer can be limited to 1 week or 1 month, depending on the desired application.

Biodegradation can be of enzymatic, chemical, or microbial origin, and these may operate either separately or simultaneously and are often influenced by many other factors (Table 1.1).

Poly(ester)s, poly(orthoester)s, poly(anhydride)s, poly(phosphazene)s, poly(phosphoester)s, poly(amide)s and few natural polymers (i.e. proteins, polysaccharides), as well as networks, copolymers, blends, and micro/nanoobjects based on these polymers, have been commonly studied and used as biodegradable biomaterials. Poly(ester)s, namely, poly(caprolactone) (PCL), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and their copolymers, poly(lactic acid-co-glycolic acid) (PLGA), are one of the best defined biomaterials with regard to design and performance.

The ability to design polymers with controlled degradation profile, mechanical and processing properties has opened opportunities for the development of modern polymer-based drug delivery devices such as biodegradable micro/nanoparticles. The latter are particularly attractive with their potential to provide a more effective alternative for release of bioactive molecules then liposomes. Polymer particles are more stable and offer longer-term release of cancer therapeutics in vivo.

Furthermore, novel "smart" biomaterials with improved biological action (e.g. for triggered drug release) are now emerging as a new generation of therapeutics. These "intelligent" systems are based on polymers that undergo structural changes in response to various physical, chemical, and biological stimuli such as pH, temperature, and electrical and optical fields. The use of smart polymers allows a controlled drug release at a predetermined time/or place.

Although the polymer biocompatibility and biodegradability are criteria of primary concern for biomedical applications, the manufacturing process also needs to be considered. The polymeric devices must be prepared by aseptic processing and sterilized before medical use. The sterilization method (wet or dry heat, radiation, or chemical treatment) should not cause structural changes or lead to chain scission, cross-linking or a significant alteration in mechanical properties.

Despite their great potential as biomaterials, currently only a small number of polymers have been administrated in the human body and an even smaller subset of them has been clinically validated for systematic administration. Examples of approved water-soluble or amphiphilic neutral polymers include PEG, poly(vinylpyrrolidone) (PVP) and its copolymers, copolymers of N-(2-hydroxypropyl)methacrylamide (PHPMA), and poly(ethylene oxide)-b-poly(propylene oxide)-b-poly (ethylene oxide) (PEO-PPO-PEO) block copolymers (Pluronic®). These polymers have been utilized in a broad range of applications including preparation of soluble polymer–drug conjugates (PHPMA, PEG), surface modification of proteins, liposomes and nanoparticles (PEG, PHPMA, Pluronic®) and the preparation of micellar drug formulations (Pluronic®). Examples of clinically validated water-insoluble, biodegradable polymers include PLGA, poly(orthoesters) (POE), and polyisohexylcyanoacrylate (PIHCA). These polymers have been used for the preparation of nanoparticles, biodegradable implants and viscous injectable materials. In addition, the amphiphilic poly(styrene-co-maleic acid) copolymer conjugated with neocarzinostatin (SMANCS) dissolved in lipid contrast medium Lipiodol has proven effective in several clinical trials for the treatment of cancer.

(Continues...)

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Excerpted from Polymer-Based Nanostructures by Pavel Broz. Copyright © 2010 Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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Table of Contents

1 Basics

Chapter 1 Polymer Materials for Biomedical Applications Violeta Malinova Wolfgang Meier 3

1.1 Introduction 3

1.2 Polymers as biomaterials 3

1.2.1 Natural and Synthetic Polymers 4

1.2.2 Complicated Polymer Architectures 6

1.3 Factors Influencing the Polymer's Applicability in Biomedical Fields 6

References 12

Chapter 2 Strategies for Transmembrane Passage of Polymer-based Nanostructures Emmanuel O. Akala 16

2.1 Introduction 16

2.1.1 Peptides and Proteins Delivery 17

2.1.2 Gene Delivery 20

2.1.3 General Vaccines Delivery 21

2.2 Nanoparticles 22

2.3 Strategies for Transmembrane Passage of Polymer-based Nanostructures 24

2.3.1 Gastrointestinal Transepithelial Permeability of Polymer-based Nanostructures 24

2.3.2 Mechanisms of Transepithelial Transport of Nanoparticles 25

2.3.3 Strategies for Transepithelial Permeability of Polymer-based Nanostructures through the Paracellular Pathway 27

2.3.4 Strategies for Transepithelial Permeability of Polymer-based Nanostructures through the Transcellular Pathway 28

2.3.5 Strategy Based on the Understanding and the Use of the Right Animal Model and Conversion of Epithelial Cells to M Cells 35

2.3.6 Strategies for Gastrointestinal Delivery of Nanoparticles Using Bio-(Muco-) Adhesion Mechanism 40

2.3.7 The Use Permeability or Absorption Enhancers as a Strategy for Transepithelial Permeability of Nanoparticles 49

2.3.8 Strategy Based on the Influence of Particle Size on Transepithelial Permeability of Nanoparticles 53

2.3.9 Strategies Based on the Influence of Particle Surface Properties (Charge and Hydrophobicity) on Transepithelial Permeability of Nanoparticles 56

2.3.10 Strategies Based on Protein Transduction 57

2.4 Strategy for Permeability of Nanostructures Across Other Mucosal Epithelia 61

2.4.1 Transepithelial Permeability of Polymer-based Nanostructures Across the Lung Epithelium 61

2.4.2 Nasal Route 64

2.4.3 Ophthalmic Route 64

2.5 Strategies for Permeability of Polymer-based Nanostructures Across the Blood–Brain Barrier 66

2.5.1 Surfactant 67

2.5.2 Surface Charge 68

2.5.3 Particle Size 68

2.5.4 Antibody for Targeting the Blood–Brain Barrier 69

2.5.5 Lectin for Targeting the Blood–Brain Barrier 69

2.5.6 Nanogel for Targeted Delivery of Drugs Aand Macromolecules to the Brain 69

References 70

Chapter 3 Nanoparticle Engineering for the Lymphatic System and Lymph Node Targeting Seyed M. Moghimi 81

3.1 Introduction 81

3.2 Nanoparticle Size 83

3.3 Nanoparticle Surface Engineering 85

3.3.1 Surface Modification with Serum 85

3.3.2 Surface Manipulation with Block Copolymers 87

3.4 Recent Trends in Vesicular Surface Engineering 91

3.5 Platform Nanotechnologies 95

3.6 Conclusions 95

References 96

Chapter 4 Strategies for Intracellular Delivery of Polymer-based Nanosystems Jaspreet K. Vasir Chiranjeevi Peetla Vinod Labhasetwar 98

4.1 Introduction 98

4.2 Barriers to Cellular Transport of Nanosystems 99

4.3 Nanosystem–Cell Interactions and Cellular Internalization 100

4.4 Intracellular Trafficking of Nanosystems 107

4.5 Challenges 111

References 112

Chapter 5 Strategies for Triggered Release from Polymer-based Nanostructures Violeta Malinova Lucy Kind Mariusz Grzelakowski Wolfgang Meier 114

5.1 Introduction 114

5.2 Stimuli Applied for Triggered Release 117

5.2.1 Temperature 117

5.2.2 pH 131

5.2.3 Other Stimuli 146

References 158

2 Polymer-Based Nanostructures for Diagnostic Applications

Chapter 6 Polymeric Nanoparticles for Medical Imaging Egidijus E. Uzgiris 173

6.1 Introduction 173

6.1.1 Polymeric Particles in Medical Imaging 173

6.1.2 MRI Contrast Agents 175

6.2 Type I, Linear Chains, Polylysine Backbone 181

6.2.1 Motivation 181

6.2.2 Synthesis and Conformation 182

6.2.3 Role of Electric Dipole Centers on the Polymer Chain 186

6.2.4 Scaling Law 187

6.2.5 Trans-endothelial Transport: the New Mechanism 190

6.2.6 Tumor Assessment 192

6.3 Type I, Linear Chains, Dextran Backbone 193

6.3.1 Motivation and Early Results 193

6.3.2 DOTA-lmked Dextran 194

6.3.3 New DTPA-dextran Constructs 196

6.3.4 Dextran Constructs for Nuclear and Optical Imaging 196

6.3.5 Summary 197

6.4 Type II, Dendrimers and Globular Particles 197

6.4.1 Introduction 197

6.4.2 Structures and Synthesis of Principal Classes of Dendrimers for Imaging 198

6.4.3 Principal Characteristics of DTPA-dendrimers 198

6.4.4 The DOTA-linked Dendrimer, Gadomer 17 199

6.4.5 Dendrimer Elimination and Safety 202

6.4.6 Applications 203

6.4.7 Other Constructs, Targeting, and CT 206

6.5 Globular Agents and Endothelial Pore Size Distribution 208

6.5.1 Tumor Endothelial Leakiness, Large Pore Dominance Model 208

6.5.2 Theoretical 208

6.5.3 Pore Size Distribution in Rat Mammary Tumors 209

6.5.4 PEG-linked Gd-DTPA-polylysine 211

6.6 Iron Oxide Nanopaiticles 212

6.6.1 Summary Overview 212

6.6.2 Developments 213

6.6.3 Labeling of Cells 216

6.6.4 Cell Trafficking 218

6.6.5 Cell Labeling II and Detection Limits 218

6.6.6 Lymphography 224

6.6.7 Gene Expression 226

6.6.8 Targeting 227

6.6.9 Tumor Assessment 229

References 231

Chapter 7 Polymeric Vesicles/Capsules for Diagnostic Applications in Medicine Margaret A. Wheatley 237

7.1 Introduction 238

7.2 Ex vivo Diagnostics 238

7.2.1 Polymeric Nanoparticles 238

7.3 Diagnostic Imaging 239

7.3.1 X-Ray 239

7.3.2 Magnetic Resonance Imaging-contrast 241

7.3.3 Ultrasound Contrast Agents 243

7.3.4 Optical Imaging 248

7.3.5 Radionuclide Imaging 249

7.4 Conclusion 251

References 251

3 Polymer-Based Nanostructures for Therapeutic Applications

Chapter 8 Polymeric Micelles for Therapeutic Applications in Medicine Vladimir P. Torchilin 261

8.1 Introduction 261

8.2 Solubilization by Micelles 264

8.3 Polymeric Micelles 267

8.4 Micelle Preparation, Morphology, and Drug Loading 271

8.5 Drug-loaded Polymeric Micelles In vivo: Targeted and Stimuli-sensitive Micelles 279

8.6 Other Applications of Polymeric Micelles 285

8.6.1 Micelles in Immunology 285

8.6.2 Micelles as Carriers of Contrast Agents 286

8.7 Conclusion 290

References 291

Chapter 9 Anti-Cancer Polymersomes Shenshen Cai David A. Christian Manu Tewari Tamara Minko Dennis E. Discher 300

9.1 Introduction 300

9.2 Polymersome Structure and Properties 301

9.3 Controlled Release Polymersomes 304

9.4 Small Molecule Chemotherapeutics for Shrinking Tumors 306

9.5 Efforts to Target Polymersomes 309

9.6 Conclusions and Opportune Comparisons to Copolymer Micelles 310

References 310

4 Polymer-Based Nanostructures with an Intelligent Functionality

Chapter 10 Polymer-based Nanoreactors for Medical Applications An Ranquin Caroline De Vocht Patrick Van Gelder 315

10.1 Introduction 315

10.2 The Nanoreactor Toolbox 317

10.2.1 Polymers 317

10.2.2 Channels and Enzymes used in Nanoreactors 318

10.2.3 Preparation Methods 321

10.3 Functionalized Reactors 323

10.3.1 Targeting Nanoreactors to Different Tissues 323

10.3.2 Controlling the Activity of the Nanoreactor 325

10.4 Applications 326

10.4.1 Cancer Therapy 326

10.4.2 Diagnostic Tools 327

10.4.3 Brain Delivery 327

10.4.4 Enzyme Replacement Therapy 327

10.4.5 Biosensors 328

10.4.6 Production of Crystals 328

10.5 Open Questions 329

10.5.1 Toxicity 329

10.5.2 Polymer Chemistry 329

10.5.3 Vesicle Shape 330

10.5.4 Endocytotic Mechanisms 330

References 330

Chapter 11 Nanoparticles for Cancer Diagnosis and Therapy Yong-Eun Lee Koo Daniel A. Orringer Raoul Kopelman 333

11.1 Introduction 333

11.1.1 Cancer Facts/Problems 333

11.1.2 Nanoparticle Advantages for Cancer Therapy and Imaging 335

11.2 Nanoparticles for Therapy 338

11.2.1 Chemotherapy 338

11.2.2 Radiotherapy 340

11.2.3 Photo-dynamic Therapy 340

11.2.4 Thermotherapy 342

11.3 Nanoparticles for Imaging 342

11.3.1 Magnetic Resonance Imaging 342

11.3.2 Optical Imaging 343

11.3.3 X-Ray Computed Tomography 345

11.3.4 Bimodal Imaging: MRI and Fluorescence Imaging 345

11.4 Multitasking Nanoparticles for Integrated Imaging and Therapy 346

11.5 Summary and Future Challenges 349

11.6 Acknowledgements 350

References 350

Subject Index 354