Intracellular Delivery III (eBook)

Contents 6
Contributors 9
Introduction to Volume III 13
Part I: Introductory Chapters 14
Chapter 1: Overview of Present Problems Facing Commercialization of Nanomedicines 15
1.1 Introduction 18
1.2 Extracellular Matrix Manipulation 20
1.3 Extending the Blood Nanoparticle Circulation 22
1.4 Passive and Active Targeting 22
1.5 Differences Between Man and Mice 25
1.6 Cell-Specific Targeting 27
1.7 Subcellular Organelle-Targeted Drug Delivery 28
1.8 Towards the Improved Imaging Technique in Humans 36
1.9 New Quantitative Tools to Explore Pharmacokinetics 37
1.10 How can Academia Survive With Diminishing Funding and How it Affects Nanomedicine Patenting? 40
1.11 Analysis of Present Market Push 42
Web Citations and References 43
Web Citations 43
References 43
Chapter 2: Precision Drugs and Cell-Specific Drug Delivery 49
2.1 Introduction 50
2.2 Precision Drugs 50
2.3 Antibodies 51
2.4 Tumor Antigens 51
2.4.1 Tumor-Associated Antigens 51
2.4.2 Tumor-Specific Antigens 52
2.5 Uptake by Cells & Drug Release
2.6 Tumor Environment & Drug Access
2.7 Drug Payload 54
2.8 A Word of Caution 55
2.9 Conclusions 56
References 56
Part II: EPR Effect and ECM Modification 59
Chapter 3: Extracellular Matrix Degrading Enzymes for Nanocarrier-Based Anticancer Therapy 60
3.1 Matrix in Tumors 61
3.2 Hyaluronic Acid 63
3.2.1 HA in Tumors 63
3.2.2 Physico-Chemical Properties of Hyaluronic Acid 63
3.2.3 Hyaluronidase 64
3.2.4 Hyaluronidase as an Adjuvant 65
3.2.5 Hyaluronidase for Nanocarrier Based Anti-Cancer Therapy 65
3.2.6 Immobilized Hyaluronidase for Nanocarrier Based Anti-Cancer Therapy 66
3.2.7 Safety and Clinical Trials with Human Recombinant Hyaluronidase 68
3.3 Collagen and Collagenase 69
3.3.1 Collagen in Cancer 69
3.3.2 Collagenase for Nanocarrier Based Anti-Cancer Therapy 70
3.4 Chondroitin Sulfate Proteoglycans (CSPGs) 71
3.4.1 CSPGs in Cancer 71
3.4.2 Chondroitinase in Nanocarrier Based Anticancer Therapy 72
3.5 Conclusions and Outlook 72
References 73
Chapter 4: Nanocarrier-Based Anticancer Therapies with the Focus on Strategies for Targeting the Tumor Microenvironment 78
4.1 Introduction: Tumor Microenvironment 80
4.1.1 Angiogenic Blood Vessels 80
4.1.2 Lymphatic System and Infiltrating Immune Cells 82
4.1.3 Cancer-Associated Fibroblasts (CAF) 85
4.1.4 Non-cellular Components 90
4.2 Characteristics to be Considered to Design Nanoparticles Targeting Tumor Microenvironment 92
4.2.1 Geometry 94
4.2.1.1 Size 95
4.2.1.2 Shape 96
4.2.2 Surface Charge 100
4.2.3 pH 101
4.2.4 Modifications of Nanocarriers 101
4.2.4.1 NP Modification for Targeting 101
4.2.4.2 NP Modification to Avoid Mononuclear Phagocyte System MPS Clearance 103
4.2.4.3 NP Modification for Intracellular Fate Modulation 104
4.3 Nanovectors Targeting Tumor Microenvironment 106
4.3.1 Vasculature 106
4.3.1.1 Angiogenesis 110
4.3.1.2 Hypoxia 111
4.3.2 Immune and Lymphatic Cells 112
4.3.3 CAF 115
4.3.4 ECM 117
4.4 Conclusion and Perspectives 118
References 118
Part III: How to Extend the Circulation Time of Nanovehicles 134
Chapter 5: A New Approach to Decrease the RES Uptake of Nanodrugs by Pre-administration with Intralipid® Resulting in a Reduction of Toxic Side Effects 135
5.1 Introduction 136
5.2 Current Strategies and Limitations for Reducing the RES Clearance of Nanoparticles 138
5.3 Using Intralipid® to Reduce the RES Uptake of Nanoparticles for Imaging 139
5.3.1 Treatment Protocol 140
5.3.2 Intralipid® Changes the Biodistribution and Reduces the RES Uptake of Iron-Oxide Particles 140
5.3.3 Intralipid® Increases the Blood Half-life (t1/2) of Iron-­Oxide Particles 141
5.3.4 Intralipid® Increases the Labeling of Monocytes in the Circulation and Improves the Sensitivity of Cellular MRI 141
5.4 Using Intralipid® to Reduce the RES Uptake of Anti-­cancer Nanodrugs for Improved Drug Delivery 142
5.4.1 Treatment Protocol 145
5.4.2 Intralipid® Reduces Toxic Side Effects of DACHPt/HANP in Liver, Spleen, and Kidney 145
5.4.3 Intralipid® Changes the Tissue Distribution and Blood Clearance of DACHPt/HANP 149
5.4.4 A Pilot Study: Using Multi-doses of Intralipid® to Deliver Multi- and Over-dose of Nanodrugs 150
5.4.5 Using Intralipid® to Deliver Liposome-Based Nanodrugs 152
5.5 Conclusion 152
References 153
Part IV: Differences Between In Vivo Status in Men and Mice 157
Chapter 6: Authentic Vascular and Stromal Structure in Animal Disease Model for Nanomedicine 158
6.1 Introduction 159
6.2 Vasculature in Human Pathology 159
6.2.1 Endothelial Cells for Nanomedicine 159
6.2.2 Pericytes for Nanomedicine 160
6.2.3 Vascular Structure in Human Diseases 161
6.3 Stromal Structure in Human Pathological Conditions 162
6.3.1 Stromal Cells for Nanomedicine 162
6.3.2 Stromal Structure in Human Diseases 164
6.4 Structural Discrepancy of Vasculature and Stromal Structure Between Human and Experimental Models 165
6.5 Conclusions 167
References 167
Part V: Cell-Specific Targeting 170
Chapter 7: Ligand-targeted Particulate Nanomedicines Undergoing Clinical Evaluation: Current Status 171
7.1 Introduction 173
7.2 Ligand-Targeted Particulate Nanomedicines Under Clinical Evaluation 182
7.2.1 Lipid-Based Nanomedicines 183
7.2.1.1 MBP-426 183
7.2.1.2 SGT-53 and SGT-94 184
7.2.1.3 MM-302 185
7.2.1.4 Anti-EGFR ILs-DOX 186
7.2.1.5 2B3-101 187
7.2.1.6 MCC-465 188
7.2.1.7 Lipovaxin-MM 188
7.2.2 Polymer-Based Nanomedicines 189
7.2.2.1 BIND-014 189
7.2.2.2 CALAA-01 190
7.2.2.3 SEL-068 191
7.2.3 Bacterially-Derived Minicells 191
7.2.3.1 Erbitux®EDVsPAC 191
7.2.4 Retroviral Vectors 192
7.2.4.1 Rexin-G 192
7.3 Discussion 193
7.4 Future Directions 197
References 200
Chapter 8: Anti-angiogenic Therapy by Targeting the Tumor Vasculature with Liposomes 209
8.1 Introduction 210
8.2 Liposomes for Anti-angiogenic Therapy 212
8.2.1 Cationic Liposomes 212
8.2.2 Peptides 214
8.2.2.1 RGD Motif 218
8.2.2.2 The NGR Motif 220
8.2.2.3 Others 220
Anginex 220
APRPG Peptide 221
8.2.3 Nucleic Acids Aptamer 222
8.2.4 Antibodies 224
8.2.4.1 VEGFR2 225
8.2.4.2 VCAM-1 225
8.2.4.3 E-Selectin 225
8.2.5 Sialyl LewisX 226
8.2.6 Dual-Targeting 227
8.3 Impact of Tumor Endothelial Cells on Tumor Microenvironments 229
References 230
Chapter 9: Accessing Mitochondrial Targets Using NanoCargos 237
9.1 Introduction 238
9.2 Mitochondrial Dysfunctions in Various Diseases 242
9.3 NanoCargo Intracellular Uptake Mechanisms for Targeting Mitochondria 245
9.4 Detection Techniques for Nanoparticle Internalization into Mitochondria 248
9.4.1 Fluorescence Based Detection 248
9.4.2 Mass Spectrometry Based Detection 254
9.4.3 Transmission Electron Microscopy (TEM) Based Methods 255
9.4.4 Miscellaneous Methods 255
9.5 Conclusions 256
References 256
Chapter 10: Redox-Responsive Nano-Delivery Systems for Cancer Therapy 263
10.1 Introduction 264
10.2 Stimuli-Responsive Systems and Cancer 265
10.2.1 Hypoxia 266
10.2.2 Low Extracellular pH 266
10.2.3 Redox-Responsive Systems 267
10.2.4 Abnormal Tumor Vasculature 267
10.2.5 Tumor Targeting Strategy 268
10.3 Illustrative Examples of Redox-Responsive Delivery Systems 269
10.3.1 Polymeric Systems 269
10.3.2 Lipid-Based Systems 270
10.3.3 Hybrid Systems 272
10.4 Conclusions and Future Perspective 273
10.5 Summary 275
References 276
Part VI: Improved Imaging 278
Chapter 11: Nano-emulsions for Drug Delivery and Biomedical Imaging 279
11.1 Introduction 281
11.2 Formulation Processes 282
11.2.1 Generalities 282
11.2.2 High-Pressure Methods 283
11.2.3 Ultrasounds-Based Methods 284
11.2.4 Low-Energy Methods 286
11.3 Applications of Nano-emulsions for Drug Delivery and Biomedical Imaging 288
11.3.1 Nano-emulsions as Nanomedicines 288
11.3.2 Clinical Applications of Nano-emulsions 294
11.3.3 Nano-emulsions in Biomedical Imaging 297
11.3.3.1 Nano-emulsions in X-ray Imaging 297
11.3.3.2 Nano-emulsions in Magnetic Resonance Imaging (MRI) 298
11.3.3.3 NEs as Fluorescent Probes in Fluorescent Imaging 298
11.3.3.4 Nano-emulsions as Multimodal Imaging Probes and Theragnostics 301
11.4 Conclusion 303
References 303
Chapter 12: The Tumor Microenvironment in Nanoparticle Delivery and the Role of Imaging to Navigate Roadblocks and Pathways 307
12.1 Introduction 308
12.2 Nanoplatforms 308
12.3 Tumor Microenvironment 310
12.3.1 Tumor Vasculature 310
12.3.2 Tumor Lymphatics 313
12.3.3 The Extracellular Matrix 313
12.3.4 Stromal Cells 314
12.4 NP Delivery in Tumors 314
12.5 Improving Tumor Delivery of Nanoparticles 316
12.5.1 Optimization of Circulation Time 316
12.5.2 NP Extravasation 316
12.5.3 NP Shape and Size 316
12.5.4 TME Modification Strategies 318
12.6 TME Targeting Strategies 319
12.7 Molecular Imaging in Optimizing NP Delivery and in Theranostics 321
12.8 Conclusion 324
References 324
Chapter 13: Microscopic Mass Spectrometry for the Precise Design of Drug Delivery Systems 329
13.1 Introduction 330
13.2 Principle of Microscopic Mass Spectrometry (MMS) 333
13.3 MMS for Analysis of Drugs Delivered Via Active Targeting 334
13.4 MMS for a Passive Targeting 338
13.5 Conclusion and Future Prospect 342
References 342
Part VII: Quantitative PK Treatment, Systems Biology and Drug Discovery 344
Chapter 14: Pharmacokinetics and Pharmacodynamics of Nano-Drug Delivery Systems 345
14.1 Introduction 346
14.2 The Pharmacokinetics and Pharmacodynamics of Systemically-Administered Nano-DDSs 348
14.2.1 PK and PD of Nano-DDSs in the Systemic Circulation 349
14.2.2 PK and PD of Nano-DDSs in the Tissues 352
14.2.3 Intracellular PK and PD of Nano-DDSs 353
14.3 Targeted Delivery of Analgesic Peptides to the Brain Using Bolavesicle-Based Nano-DDSs 354
14.4 Targeted Delivery of Antigenic Peptides to the Endoplasmic Reticulum of the Antigen-­Presenting Cells for Anti-Cancer Vaccination 356
14.5 Rational Design of Nano-DDSs 359
14.6 Conclusion 362
References 363
Chapter 15: PBPK Modelling of Intracellular Drug Delivery Through Active and Passive Transport Processes 367
15.1 An Introduction to Physiologically Based Pharmacokinetic Modelling 368
15.2 Intracellular Drug Delivery in PBPK Modelling 371
15.2.1 Organ-Plasma Partitioning 371
15.2.2 Passive Transport: Permeability-Surface Area Products 373
15.2.3 Active Transport: First Order Kinetics and Michaelis-­Menten Kinetics 373
15.3 Cross-Species Extrapolation 374
15.4 Discussion 375
References 377
Chapter 16: Exploiting Nanocarriers for Combination Cancer Therapy 379
16.1 Introduction 381
16.2 Drug Combinations for Cancer Treatment 381
16.2.1 A Brief History of Combination Cancer Therapy 381
16.2.1.1 Combinations of Independently Active Drugs 381
16.2.1.2 Rational Drug Combinations Targeting a Shared Mechanism of Action 383
16.2.1.3 Molecularly Targeted Therapies 383
16.2.1.4 Large-Scale Screens, Nucleic Acid Therapies, and Beyond 384
16.2.2 Challenges in Delivering Drug Combinations to Tumors 384
16.2.2.1 Co-delivery 384
16.2.2.2 Stoichiometry/Ratiometric Dosing 385
16.2.2.3 Drug Sequence and Timing 385
16.2.2.4 Compounding and Overlapping Toxicity 387
16.3 Nanoparticle Formulations to Optimize Anti-cancer Combination Therapies 387
16.3.1 Mesoporous Silica Nanoparticles 388
16.3.2 Self-Assembly Copolymer Carriers – Micelles 388
16.3.3 Nanotechnology Approaches to Enhance Co-delivery 389
16.3.4 Nanotechnology Solutions: Stoichiometry/Ratiometric Dosing 391
16.3.5 Nanotechnology Approaches to Tailor Drug Combination Timing and Sequence 395
16.3.6 Nanotechnology Approaches to Limit Compounding and Overlapping Toxicity 396
16.3.7 Combining Nucleic Acid Therapies with Other Drug Combinations 396
16.4 Limitations to Developing Combination Chemotherapeutics, Tumor-Specific Targeting, and Enabling Approaches 397
16.5 Outlook and Conclusions 399
References 400
Part VIII: Market Situation and Commercialization of Nanotechnology 407
Chapter 17: The Commercialization of Medical Nanotechnology for Medical Applications 408
17.1 Introduction 409
17.2 Historical Advancement of Medical Nanotechnology 411
17.2.1 Diagnostics 414
17.2.2 Imaging 415
17.2.3 Pharmaceuticals 415
17.2.4 Therapeutics 417
17.3 Biomaterials 417
17.3.1 Biosensors 417
17.3.2 Tissue Engineering 418
17.3.3 Medical Devices and Accessories 419
17.4 Entrepreneurship 420
17.5 The Commercialization Process 422
17.6 Risk and Hazard Assessment 427
17.7 Securing Intellectual Property and Licensing (IP Strategy) 430
17.8 Valuation and Technology Transfer 435
17.9 Funding and Financing 436
17.10 Regulatory Approval 440
17.11 Market Acceptance/Adoption 441
17.12 Success 443
17.13 Lessons Learned 444
17.14 Future of Medical Nanotechnology Commercialization 446
17.15 Summary 446
References 447
Index 453