生物启发与仿生型高分子药物及基因递送系统 下载 pdf 百度网盘 epub 免费 2025 电子版 mobi 在线

近年来，生物活性物质控释系统的研究主要集中于：时控型药物控释系统；自调节药物控释系统；靶 药物控释系统；组织/细胞微环境响应性药物控释系统以及核酸类药物递送系统。受自然界启发，如何运用仿生的方法构建和优化药物、蛋白质和基因的递送系统已是一个新兴的发展方向和趋势，它是涉及生物学、材料学、化学、物理学、药学、工程学等学科的多学科交叉研究领域。

本书汇聚了包括美国工程院院士在内的多名国内外药物控释系统研究领域的著名科学家近年来的*研究工作。作为国际上本生物启发和仿生高分子的药物及基因递送系统的专著，本书不仅报道了药物递送领域的*进展和未来发展方向，还分别从材料与细胞相互作用、载体材料的组织/细胞微环境响应性设计、控释系统在体内环境下生物活性物质的高效释放及有效表达等不同的角度对药物递送系统的未来发展方向进行了新的诠释和展望，充分体现了前瞻性和新颖性，是该领域一部难得的、非常有价值的专著。

本书可供从事生物工程、纳米技术及材料领域的高校、科研院所、公司企业的相关研究人员使用。同时可作为生物医学工程、高分子科学及相关交叉学科的研究生及本科生教学参考书。

List of Contributors XIII

Preface XIX

1 Backbone Degradable and Coiled-Coil Based Macromolecular

Therapeutics 1

Jiyuan Yang and Jindˇ rich Kopeˇ cek

1.1 Introduction 1

1.2 Water-Soluble Polymers as Carriers of Anticancer Drugs 2

1.2.1 First Generation Conjugates – Design, Synthesis, and Activity 2

1.2.2 Analysis of Design Factorshat Need Attention 2

1.2.2.1 Design of Conjugates for the Treatment of Noncancerous

Diseases 2

1.2.2.2 Combinationherapy Using Polymer-Boundherapeutics 3

1.2.2.3 New Targeting Strategies 4

1.2.2.4 Relationship Between Detailed Structure of the Conjugates andheir

Properties 5

1.2.2.5 Impact of Binding a Drug to a Polymer on the Mechanism of

Action 6

1.2.2.6 Mechanism of Internalization and Subcellular Tra?cking 7

1.2.2.7 Relationship Between the MolecularWeight of the Carrier and the

E?cacy of the Conjugate 7

1.2.3 Design of Second Generation Conjugates – Long-Circulating and

Backbone Degradable 8

1.2.3.1 RAFT Copolymerization for the Synthesis of Conjugates 8

1.2.3.2 Click Reactions for Chain Extension into Multiblock

Copolymers 10

1.2.3.3 Biological Properties of Long-Circulating Macromolecular

herapeutics 10

1.2.4 Summary of Part 2 and Future Prospects 14

1.3 Drug-Free Macromolecularherapeutics – A New Paradigm in

Drug Delivery 15

1.3.1 Biorecognition in Hybrid Polymer Systems 15

1.3.2 Coiled-Coils in Biomedical Systems 16

1.3.3 Coiled-Coil Based Drug-Free Macromolecularherapeutics: Design,

In Vitro,and In Vivo Activity 17

1.3.4 Potential, Limitations, and Future Prospect of Drug-Free

Macromolecularherapeutics 18

1.4 General Summary and Outlook 20

Acknowledgments 21

References 21

2 Dendritic Polymers as Targeting Nanoscale Drug Delivery Systems

forCancerTherapy 29

Kui Luo and Zhongwei Gu

2.1 Introduction 29

2.2 Functional Dendritic Polymers Based Drug Delivery Vehicles for

Targeting Tumorherapy via EPR E?ect 30

2.2.1 Functional Dendritic Polymers for Encapsulation of Anticancer

Drugs 32

2.2.2 Chemical Conjugation Functional Dendritic Polymers as Drug

Delivery Systems 37

2.3 Tumor Targeting Moieties Functionalized Dendritic Drug Delivery

Vehicles for Cancerherapy 45

2.4 Conclusion 54

References 54

3 Composite Colloidal Nanosystems for Targeted Delivery

and Sensing 61

Pilar Rivera Gil,Moritz Nazarenus, andWolfgang J. Parak

3.1 Introduction 61

3.1.1 Working Toolkit 62

3.1.2 Engineering a Multifunctional Carrier 63

3.2 Objective 66

3.3 Cellular Behavior of the Carrier 66

3.3.1 Intracellular Fate 66

3.3.2 Biocompatibility 69

3.4 Applications 71

3.4.1 Delivery with Multifunctional PEM Capsules 71

3.4.1.1 Magnetic Targeting and Magnetofection 71

3.4.1.2 Strategies for Controlled Opening 73

3.4.2 Intracellular Ion Sensing 75

3.5 Conclusions 77

Abbreviations 77

References 78

4 Polymeric Micelles for Cancer-Targeted Drug Delivery 85

Huabing Chen, Zhishen Ge, and Kazunori Kataoka

4.1 Introduction 85

4.2 Micelle Formulations in Clinical Development 85

4.3 ParticleSizeofMicelles 89

4.4 Morphology of Micelles 92

4.5 Targeting Design of Micelles for Enhanced Accumulation and Cell

Internalization 94

4.6 Functional Designs of Micelles 96

4.7 Design of Micelles for Gene Delivery 99

4.8 Challenge and Future Perspective 103

References 104

5 Biomimetic Polymers for In Vivo Drug Delivery 109

WenpingWang and KinamPark

5.1 Introduction 109

5.2 Commonly Used Biomimetic Polymers andheir Applications

in DDS 110

5.2.1 Polylactones andheir Modi?cations 110

5.2.1.1 Poly(lactic acid) (PLA) 110

5.2.1.2 Poly(lactic-co-glycolic acid) (PLGA) 113

5.2.1.3 Poly(ε-caprolactone) (PCL) 118

5.2.2 Dendrimer 124

5.2.2.1 Structure and Properties of Dendrimers 124

5.2.2.2 Types of Dendrimers 124

5.2.2.3 Applications of Dendrimers as Carriers in Drug Delivery

Systems 124

5.2.3 Synthetic Polypeptides 134

5.3 Challenges and Perspectives 135

References 136

6 Drug Delivery fromProtein-Based Nanoparticles 149

Dan Ding and Xiqun Jiang

6.1 Introduction 149

6.2 Preparation of Protein-Based Nanoparticles 150

6.2.1 Desolvation 150

6.2.2 Emulsi?cation 151

6.2.3 Coacervation 151

6.2.4 Polymer–Monomer Pair Reaction System 151

6.3 Drug Delivery from Albumin-Based Nanoparticles 152

6.3.1 Albumin-Based Nanoparticles as Drug Carriers 152

6.3.2 Targeting Ligand-Functionalized Albumin-Based

Nanoparticles 154

6.3.3 Nanoparticle Albumin-Bound (nab)Technology 156

6.4 Drug Delivery from Gelatin-Based Nanoparticles 156

6.4.1 Gelatin-Based Nanoparticles as Drug Carriers 158

6.4.2 Targeting Ligand-Functionalized Gelatin-Based Nanoparticles 160

6.4.3 Site-Speci?c Drug Delivery System 162

6.5 Drug Delivery from Other Protein-Based Nanoparticles 163

References 165

7 Polymeric Gene Carriers 171

Xuesi Chen, Huayu Tian, and Xiuwen Guan

7.1 Geneherapy and Gene Carriers 171

7.1.1 Geneherapy 171

7.1.1.1 he Concept of Geneherapy 171

7.1.1.2 Development and the Present Situation of Geneherapy 171

7.1.1.3 Methods and Strategies of Geneherapy 172

7.1.1.4 Research Contents and Challenges of Geneherapy 174

7.1.2 Gene Carriers 175

7.1.2.1 he Concept of Gene Carrier 175

7.1.2.2 he Necessity of the Gene Carrier 175

7.1.2.3 Requirements of Gene Carrier 176

7.1.2.4 Classi?cation of Gene Carrier 176

7.2 Polymeric Gene Carriers 178

7.2.1 Cationic Polymer Gene Carriers 178

7.2.1.1 Process of the Polycation Vector Mediated Gene Delivery 179

7.2.1.2 Categories and Research Situation of the Cationic Polymer Gene

Vector 180

7.3 PEI Grafting Modi?cation Polymeric Gene Carriers 183

7.3.1 Amino Acid Derivatives Modi?ed Polymeric Gene Carriers 183

7.3.1.1 Poly(glutamic acid) Derivatives Modi?ed PEI 184

7.3.1.2 Polyphenylalanine Derivatives Modi?ed PEI 186

7.3.2 PEG Modi?ed Hyperbranched PEI 187

7.4 Low MolecularWeight (LWM) PEI Base Polymeric Gene

Carriers 188

7.4.1 Crosslinked Polycations 188

7.4.1.1 Crosslinked Polycation OEI-CBA 188

7.4.1.2 Crosslinked Polycation OEI-PBLG-PEGDA 189

7.4.1.3 Hexachlorotriphosphazene Crosslinked Polycation 190

7.4.2 Grafted Polycations 190

7.4.2.1 Grafted Cationic Polymer MP-g-OEI 190

7.4.2.2 Graft Cationic Polymer N-PAE-g-OEI 191

7.4.2.3 Graft Cationic Polymer mPEG-b-PMCC-g-OEI 192

7.5 Targeted Shielding System for Polymeric Gene Carriers 192

7.5.1 Static Shielding System 192

7.5.1.1 Poly(glutamine acid) Shielding System and PEGylations 195

7.5.1.2 Sulfonamides Related Shielding System 195

7.5.2 Other Design Strategies of Cationic Gene Carrier 196

7.6 Conclusion 197

References 197

8 pH-Sensitive Polymeric Nanoparticles as Carriers for Cancer Therapy

and Imaging 203

Yi Li, Guang Hui Gao, Ick Chan Kwon, and Doo Sung Lee

8.1 Introduction 203

8.2 pH-Sensitive Polymers 204

8.2.1 pH-Sensitive Anionic Polymers 205

8.2.2 pH-Sensitive Cationic Polymers 207

8.2.3 pH-Sensitive Neutral Polymers 208

8.3 pH-Sensitive Polymers as Drug Carriers 209

8.3.1 pH-Sensitive Polymer–Drug Conjugates 210

8.3.2 pH-Sensitive Polymeric Micelles 210

8.3.3 pH-Sensitive Polymersomes 212

8.3.4 pH-Sensitive Polymer–Inorganic Hybrid Nanoparticles 214

8.3.5 pH-Sensitive Dendrimers 214

8.4 pH-Sensitive Polymers for Bioimaging 215

8.5 Conclusions 216

References 216

9 Charge-Reversal Polymers for Biodelivery 223

Bo Zhang, KaiWang, Jingxing Si,Meihua Sui, and Youqing Shen

9.1 Applications of Cationic Polymers in Biodelivery 223

9.2 Barriers for Cationic Polymers in In vitro and In vivo

Applications 224

9.3 Characteristic pH Gradients in Tumor Interstitium and

Endo/Lysosomes 225

9.4 Chemistry of Charge-Reversal Polymers Based on Acid-Labile

Amides 226

9.4.1 pHe-Triggered Charge-Reversal 228

9.4.2 pHL-Triggered Charge-Reversal 229

9.5 Applications of Charge-Reversal Polymers in Biodelivery

Systems 230

9.5.1 Charge-Reversal in Cancer Drug Delivery 230

9.5.2 Charge-Reversal in Gene Delivery 232

9.5.3 Charge-Reversal in Protein Delivery 235

9.5.4 Charge-Reversal Incorporated with Inorganic Materials 236

9.6 Perspectives 237

References 237

10 Phenylboronic Acid-Containing Glucose-Responsive Polymer

Materials: Synthesis and Applications in Drug Delivery 243

RujiangMa and Linqi Shi

10.1 Introduction 243

10.2 PBA-Containing Polymers Operating Under Physiological

Conditions 244

10.3 Chemically Crosslinked PBA-Based Gels 247

10.4 Self-Assembled PBA-Based Polymer Micelles 253

10.5 Self-Assembled PBA-Based Polymersomes 266

10.6 Perspectives 271

References 272

11 Extracellular pH-Activated Nanocarriers for Enhanced Drug

Delivery to Tumors 277

You-Yong Yuan, Cheng-QiongMao, Jin-Zhi Du, Xian-Zhu Yang,

and JunWang

11.1 Introduction 277

11.2 Passive and Active Tumor Targeting 278

11.3 Targeting the Extracellular pH (pHe) in Tumors 279

11.4 Extracellular pH-Induced Drug Delivery to Tumors 280

11.5 Ligand Exposure by a Shielding/Deshielding Method 281

11.6 Surface Charge Reversing Nanoparticles 283

11.6.1 Enhanced Cellular Uptake by Surface Charge Reversing

Nanoparticles 283

11.6.2 Overcoming MDR by Surface Charge Reversing Nanoparticles 287

11.6.3 Enhanced Delivery of siRNA by Surface-Charge Reversing

Nanoparticles 295

11.7 Conclusion 300

References 300

12 Stimulation-Sensitive Drug Delivery Systems 305

Xintao Shuai and Du Cheng

12.1 Introduction 305

12.2 pH-Sensitive Delivery Systems 306

12.2.1 pH-Sensitive Micellar Delivery Systems 306

12.2.2 pH-Sensitive Polymer–Drug Conjugates 307

12.2.3 pH-Sensitive Dendrimers 308

12.2.4 pH-Sensitive Liposomes 310

12.3 hermo-Sensitive Delivery Systems 311

12.4 Biomolecule-Sensitive Delivery Systems 314

12.4.1 Enzyme-Sensitive Nanocarriers 315

12.4.2 Reduction–Responsive Conjugates 316

12.5 Other Environmentally Sensitive Nanocarriers 318

12.6 Outlook 319

References 320

Index 331

顾忠伟，四川大学国家医学材料工程技术研究中心，教授博导，973首席科学家，自七十年代中期以来，致力于生物医用高分子材料及其药物/生物活性物质控制释放系统的基础和应用基础研究，并在这一领域内积累了较丰富的理论基础知识和实践经验，掌握了这一领域的科学前沿和发展方向。先后三次出任国家973计划项目首席科学家并负责其子项目，曾主持“七.五”、“八.五”、“九.五”国家重点攻关、国家自然科学基金重点和面上、国家新药研究基金、北京市自然科学基金、国家科技部、国家计生委及国际合作项目等近30项科研项目。曾获得两项部委科技奖励；在国内外重要学术期刊上发表论文共180余篇（其中SCI源刊论文160余篇），以及80篇国际及全国学术会议报告摘要，并在世界生物材料大会、亚洲生物材料大会、中国材料学会年会、全国高分子年会等国内外学术会议上作了60余次大会或邀请报告；主持和参与组织生物材料国际及全国学术会议20余次，多次参与有关我国生物材料发展规划和建议讨论并执笔。现为J. Reproductive Medicine 杂志副主编，Biomed. Mater. 、Int. J Med. Eng. & Inf.、Biomatter等杂志编委。

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编辑推荐

《先进功能材料丛书》是由师昌绪院士主编的“十二五”规划重点图书。

近年来，生物活性物质控释系统的研究主要集中于：时控型药物控释系统；自调节药物控释系统；靶向药物控释系统；智能型药物控释系统以及核酸类药物输送系统。受自然界天然传递系统的启发，如何运用仿生的方法构建和优化药物、蛋白质和基因的运输系统将是一个新兴的发展方向和趋势，它是涉及生物学、材料学、化学、物理学、药学、工程学等学科的多学科交叉研究领域。

（1)国际上**本生物启发和仿生聚合物系统的药物传递的专著；

(2)包括美国工程院院士在内的多名国内外药物控释系统研究领域的著名科学家共同编写；

（3）反应了国际上***的研究成果。

前言

In recent years, the rapid development of polymer science and advances in mod-ern medicine, pharmacy, biology, and ngineering have fostered the emergence of a new ?eld focused on the theory and technology underlying drug delivery.his inter-disciplinary ?eld is called drug delivery systems (DDS). It shows great promise and has become a hotspot in biomedical material research, especially in biomedical polymers.

he successful development of advanced, e?cient DDS depends on the design and construction of the materials and micro devices involved.he research fron-tier focuses mainly on targeted delivery, especially cell and molecular targeting,and on controlled release stimulated by the tissue or cellular microenvironment.he complex in vivo physiological and pathological environment often obscures the e?ects of active targeting. In this way, producing a highly e?cient system capable of active targeting in vivo is the key to improving the e?cacy of DDS.Drug release systems capable of biological sensing are called bioinspired and biomimetic delivery systems. hey automatically adjust the drug release in response to external stimuli, such as changes in temperature, pH, magnetic ?elds, ultrasound, and electric ?elds. hey have received a considerable amount

of attention from researchers and pharmaceutical companies worldwide. Drug release systems that can be switched on and o? via self-feedback upon changes in the chemical or physical signals given o? by a lesion or intelligent carrier have drawn particular interest. Systems that can undergo rapid stimuli-responsive controlled release under in vivo microenvironment conditions would be far more useful to actual clinical treatment regimens.

his book embodies the wisdom and achievements of renowned experts and research teams in this ?eld from China, the United States, Germany, Japan, and Korea. he discussion provided herein covers the most important, active, and cutting-edge parts of this ?eld, re?ecting the latest developments and trends in DDS research.he chief editor, Professor ZhongweiGu, studied under the pioneer biomedical polymers in China–Professor Xin-De Feng (Academician of Chinese Academy of Sciences). Gu entered this ?eld in the 1970s and has become a well-known professor of polymer biomaterials in China. It is our hope that this book will promote scienti?c research and biomedical applications in the vibrant and exciting area. Young academics and professionals interested in DDSmay also ben-e?t from this treatise.

We would like to thank all our editors for their hard work and dedication. We would also like to thank John Wiley & Sons Publishing Company and Chemical Industry Press for their forward-looking strategic vision and the timely publica-

tion of this book.

August 2014 Professor Ren-Xi Zhuo

Academician of Chinese Academy of Sciences

IUS-BSE Fellow

Wuhan University

Wuhan, China