Prokop / Weissig Intracellular Delivery III

Market Entry Barriers of Nanomedicines
1. Auflage 2016
ISBN: 978-3-319-43525-1
Verlag: Springer International Publishing
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 455 Seiten

Reihe: Fundamental Biomedical Technologies

A critical review is attempted to assess the status of nanomedicine entry onto the market. The emergence of new potential therapeutic entities such as DNA and RNA fragments requires that these new 'drugs' will need to be delivered in a cell-and organelle-specific manner. Although efforts have been made over the last 50 years or so to develop such delivery technology, no effective and above all clinically approved protocol for cell-specific drug delivery in humans exists as yet. Various particles, macromolecules, liposomes and most recently 'nanomaterials' have been said to 'show promise' but none of these promises have so far been 'reduced' to human clinical practice. The focus of this volume is on cancer indication since the majority of published research relates to this application; within that, we focus on solid tumors (solid malignancies). Our aim is critically to evaluate whether nanomaterials, both non-targeted and targeted to specific cells, could be of therapeutic benefit in clinical practice. The emphasis of this volume will be on pharmacokinetics (PK) and pharmacodynamics (PD) in animal and human studies. Apart from the case of exquisitely specific antibody-based drugs, the development of target-specific drug-carrier delivery systems has not yet been broadly successful at the clinical level. It can be argued that drugs generated using the conventional means of drug development (i.e., relying on facile biodistribution and activity after (preferably) oral administration) are not suitable for a target-specific delivery and would not benefit from such delivery even when a seemingly perfect delivery system is available. Therefore, successful development of site-selective drug delivery systems will need to include not only the development of suitable carriers, but also the development of drug entities that meet the required PK/PD profile. 

Autoren/Hrsg.

Prokop, Ales

Prokop, Aleš

Weissig, Volkmar

Inhaltsverzeichnis

1;Contents;6
2;Contributors;9
3;Introduction to Volume III;13
4;Part I: Introductory Chapters;14
4.1;Chapter 1: Overview of Present Problems Facing Commercialization of Nanomedicines;15
4.1.1;1.1 Introduction;18
4.1.2;1.2 Extracellular Matrix Manipulation;20
4.1.3;1.3 Extending the Blood Nanoparticle Circulation;22
4.1.4;1.4 Passive and Active Targeting;22
4.1.5;1.5 Differences Between Man and Mice;25
4.1.6;1.6 Cell-Specific Targeting;27
4.1.7;1.7 Subcellular Organelle-Targeted Drug Delivery;28
4.1.8;1.8 Towards the Improved Imaging Technique in Humans;36
4.1.9;1.9 New Quantitative Tools to Explore Pharmacokinetics;37
4.1.10;1.10 How can Academia Survive With Diminishing Funding and How it Affects Nanomedicine Patenting?;40
4.1.11;1.11 Analysis of Present Market Push;42
4.1.12;Web Citations and References;43
4.1.12.1;Web Citations;43
4.1.12.2;References;43
4.2;Chapter 2: Precision Drugs and Cell-Specific Drug Delivery;49
4.2.1;2.1 Introduction;50
4.2.2;2.2 Precision Drugs;50
4.2.3;2.3 Antibodies;51
4.2.4;2.4 Tumor Antigens;51
4.2.4.1;2.4.1 Tumor-Associated Antigens;51
4.2.4.2;2.4.2 Tumor-Specific Antigens;52
4.2.5;2.5 Uptake by Cells & Drug Release;53
4.2.6;2.6 Tumor Environment & Drug Access;54
4.2.7;2.7 Drug Payload;54
4.2.8;2.8 A Word of Caution;55
4.2.9;2.9 Conclusions;56
4.2.10;References;56
5;Part II: EPR Effect and ECM Modification;59
5.1;Chapter 3: Extracellular Matrix Degrading Enzymes for Nanocarrier-Based Anticancer Therapy;60
5.1.1;3.1 Matrix in Tumors;61
5.1.2;3.2 Hyaluronic Acid;63
5.1.2.1;3.2.1 HA in Tumors;63
5.1.2.2;3.2.2 Physico-Chemical Properties of Hyaluronic Acid;63
5.1.2.3;3.2.3 Hyaluronidase;64
5.1.2.4;3.2.4 Hyaluronidase as an Adjuvant;65
5.1.2.5;3.2.5 Hyaluronidase for Nanocarrier Based Anti-Cancer Therapy;65
5.1.2.6;3.2.6 Immobilized Hyaluronidase for Nanocarrier Based Anti-Cancer Therapy;66
5.1.2.7;3.2.7 Safety and Clinical Trials with Human Recombinant Hyaluronidase;68
5.1.3;3.3 Collagen and Collagenase;69
5.1.3.1;3.3.1 Collagen in Cancer;69
5.1.3.2;3.3.2 Collagenase for Nanocarrier Based Anti-Cancer Therapy;70
5.1.4;3.4 Chondroitin Sulfate Proteoglycans (CSPGs);71
5.1.4.1;3.4.1 CSPGs in Cancer;71
5.1.4.2;3.4.2 Chondroitinase in Nanocarrier Based Anticancer Therapy;72
5.1.5;3.5 Conclusions and Outlook;72
5.1.6;References;73
5.2;Chapter 4: Nanocarrier-Based Anticancer Therapies with the Focus on Strategies for Targeting the Tumor Microenvironment;78
5.2.1;4.1 Introduction: Tumor Microenvironment;80
5.2.1.1;4.1.1 Angiogenic Blood Vessels;80
5.2.1.2;4.1.2 Lymphatic System and Infiltrating Immune Cells;82
5.2.1.3;4.1.3 Cancer-Associated Fibroblasts (CAF);85
5.2.1.4;4.1.4 Non-cellular Components;90
5.2.2;4.2 Characteristics to be Considered to Design Nanoparticles Targeting Tumor Microenvironment;92
5.2.2.1;4.2.1 Geometry;94
5.2.2.1.1;4.2.1.1 Size;95
5.2.2.1.2;4.2.1.2 Shape;96
5.2.2.2;4.2.2 Surface Charge;100
5.2.2.3;4.2.3 pH;101
5.2.2.4;4.2.4 Modifications of Nanocarriers;101
5.2.2.4.1;4.2.4.1 NP Modification for Targeting;101
5.2.2.4.2;4.2.4.2 NP Modification to Avoid Mononuclear Phagocyte System MPS Clearance;103
5.2.2.4.3;4.2.4.3 NP Modification for Intracellular Fate Modulation;104
5.2.3;4.3 Nanovectors Targeting Tumor Microenvironment;106
5.2.3.1;4.3.1 Vasculature;106
5.2.3.1.1;4.3.1.1 Angiogenesis;110
5.2.3.1.2;4.3.1.2 Hypoxia;111
5.2.3.2;4.3.2 Immune and Lymphatic Cells;112
5.2.3.3;4.3.3 CAF;115
5.2.3.4;4.3.4 ECM;117
5.2.4;4.4 Conclusion and Perspectives;118
5.2.5;References;118
6;Part III: How to Extend the Circulation Time of Nanovehicles;134
6.1;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
6.1.1;5.1 Introduction;136
6.1.2;5.2 Current Strategies and Limitations for Reducing the RES Clearance of Nanoparticles;138
6.1.3;5.3 Using Intralipid® to Reduce the RES Uptake of Nanoparticles for Imaging;139
6.1.3.1;5.3.1 Treatment Protocol;140
6.1.3.2;5.3.2 Intralipid® Changes the Biodistribution and Reduces the RES Uptake of Iron-Oxide Particles;140
6.1.3.3;5.3.3 Intralipid® Increases the Blood Half-life (t1/2) of Iron-­Oxide Particles;141
6.1.3.4;5.3.4 Intralipid® Increases the Labeling of Monocytes in the Circulation and Improves the Sensitivity of Cellular MRI;141
6.1.4;5.4 Using Intralipid® to Reduce the RES Uptake of Anti-­cancer Nanodrugs for Improved Drug Delivery;142
6.1.4.1;5.4.1 Treatment Protocol;145
6.1.4.2;5.4.2 Intralipid® Reduces Toxic Side Effects of DACHPt/HANP in Liver, Spleen, and Kidney;145
6.1.4.3;5.4.3 Intralipid® Changes the Tissue Distribution and Blood Clearance of DACHPt/HANP;149
6.1.4.4;5.4.4 A Pilot Study: Using Multi-doses of Intralipid® to Deliver Multi- and Over-dose of Nanodrugs;150
6.1.4.5;5.4.5 Using Intralipid® to Deliver Liposome-Based Nanodrugs;152
6.1.5;5.5 Conclusion;152
6.1.6;References;153
7;Part IV: Differences Between In Vivo Status in Men and Mice;157
7.1;Chapter 6: Authentic Vascular and Stromal Structure in Animal Disease Model for Nanomedicine;158
7.1.1;6.1 Introduction;159
7.1.2;6.2 Vasculature in Human Pathology;159
7.1.2.1;6.2.1 Endothelial Cells for Nanomedicine;159
7.1.2.2;6.2.2 Pericytes for Nanomedicine;160
7.1.2.3;6.2.3 Vascular Structure in Human Diseases;161
7.1.3;6.3 Stromal Structure in Human Pathological Conditions;162
7.1.3.1;6.3.1 Stromal Cells for Nanomedicine;162
7.1.3.2;6.3.2 Stromal Structure in Human Diseases;164
7.1.4;6.4 Structural Discrepancy of Vasculature and Stromal Structure Between Human and Experimental Models;165
7.1.5;6.5 Conclusions;167
7.1.6;References;167
8;Part V: Cell-Specific Targeting;170
8.1;Chapter 7: Ligand-targeted Particulate Nanomedicines Undergoing Clinical Evaluation: Current Status;171
8.1.1;7.1 Introduction;173
8.1.2;7.2 Ligand-Targeted Particulate Nanomedicines Under Clinical Evaluation;182
8.1.2.1;7.2.1 Lipid-Based Nanomedicines;183
8.1.2.1.1;7.2.1.1 MBP-426;183
8.1.2.1.2;7.2.1.2 SGT-53 and SGT-94;184
8.1.2.1.3;7.2.1.3 MM-302;185
8.1.2.1.4;7.2.1.4 Anti-EGFR ILs-DOX;186
8.1.2.1.5;7.2.1.5 2B3-101;187
8.1.2.1.6;7.2.1.6 MCC-465;188
8.1.2.1.7;7.2.1.7 Lipovaxin-MM;188
8.1.2.2;7.2.2 Polymer-Based Nanomedicines;189
8.1.2.2.1;7.2.2.1 BIND-014;189
8.1.2.2.2;7.2.2.2 CALAA-01;190
8.1.2.2.3;7.2.2.3 SEL-068;191
8.1.2.3;7.2.3 Bacterially-Derived Minicells;191
8.1.2.3.1;7.2.3.1 Erbitux®EDVsPAC;191
8.1.2.4;7.2.4 Retroviral Vectors;192
8.1.2.4.1;7.2.4.1 Rexin-G;192
8.1.3;7.3 Discussion;193
8.1.4;7.4 Future Directions;197
8.1.5;References;200
8.2;Chapter 8: Anti-angiogenic Therapy by Targeting the Tumor Vasculature with Liposomes;209
8.2.1;8.1 Introduction;210
8.2.2;8.2 Liposomes for Anti-angiogenic Therapy;212
8.2.2.1;8.2.1 Cationic Liposomes;212
8.2.2.2;8.2.2 Peptides;214
8.2.2.2.1;8.2.2.1 RGD Motif;218
8.2.2.2.2;8.2.2.2 The NGR Motif;220
8.2.2.2.3;8.2.2.3 Others;220
8.2.2.2.3.1;Anginex;220
8.2.2.2.3.2;APRPG Peptide;221
8.2.2.3;8.2.3 Nucleic Acids Aptamer;222
8.2.2.4;8.2.4 Antibodies;224
8.2.2.4.1;8.2.4.1 VEGFR2;225
8.2.2.4.2;8.2.4.2 VCAM-1;225
8.2.2.4.3;8.2.4.3 E-Selectin;225
8.2.2.5;8.2.5 Sialyl LewisX;226
8.2.2.6;8.2.6 Dual-Targeting;227
8.2.3;8.3 Impact of Tumor Endothelial Cells on Tumor Microenvironments;229
8.2.4;References;230
8.3;Chapter 9: Accessing Mitochondrial Targets Using NanoCargos;237
8.3.1;9.1 Introduction;238
8.3.2;9.2 Mitochondrial Dysfunctions in Various Diseases;242
8.3.3;9.3 NanoCargo Intracellular Uptake Mechanisms for Targeting Mitochondria;245
8.3.4;9.4 Detection Techniques for Nanoparticle Internalization into Mitochondria;248
8.3.4.1;9.4.1 Fluorescence Based Detection;248
8.3.4.2;9.4.2 Mass Spectrometry Based Detection;254
8.3.4.3;9.4.3 Transmission Electron Microscopy (TEM) Based Methods;255
8.3.4.4;9.4.4 Miscellaneous Methods;255
8.3.5;9.5 Conclusions;256
8.3.6;References;256
8.4;Chapter 10: Redox-Responsive Nano-Delivery Systems for Cancer Therapy;263
8.4.1;10.1 Introduction;264
8.4.2;10.2 Stimuli-Responsive Systems and Cancer;265
8.4.2.1;10.2.1 Hypoxia;266
8.4.2.2;10.2.2 Low Extracellular pH;266
8.4.2.3;10.2.3 Redox-Responsive Systems;267
8.4.2.4;10.2.4 Abnormal Tumor Vasculature;267
8.4.2.5;10.2.5 Tumor Targeting Strategy;268
8.4.3;10.3 Illustrative Examples of Redox-Responsive Delivery Systems;269
8.4.3.1;10.3.1 Polymeric Systems;269
8.4.3.2;10.3.2 Lipid-Based Systems;270
8.4.3.3;10.3.3 Hybrid Systems;272
8.4.4;10.4 Conclusions and Future Perspective;273
8.4.5;10.5 Summary;275
8.4.6;References;276
9;Part VI: Improved Imaging;278
9.1;Chapter 11: Nano-emulsions for Drug Delivery and Biomedical Imaging;279
9.1.1;11.1 Introduction;281
9.1.2;11.2 Formulation Processes;282
9.1.2.1;11.2.1 Generalities;282
9.1.2.2;11.2.2 High-Pressure Methods;283
9.1.2.3;11.2.3 Ultrasounds-Based Methods;284
9.1.2.4;11.2.4 Low-Energy Methods;286
9.1.3;11.3 Applications of Nano-emulsions for Drug Delivery and Biomedical Imaging;288
9.1.3.1;11.3.1 Nano-emulsions as Nanomedicines;288
9.1.3.2;11.3.2 Clinical Applications of Nano-emulsions;294
9.1.3.3;11.3.3 Nano-emulsions in Biomedical Imaging;297
9.1.3.3.1;11.3.3.1 Nano-emulsions in X-ray Imaging;297
9.1.3.3.2;11.3.3.2 Nano-emulsions in Magnetic Resonance Imaging (MRI);298
9.1.3.3.3;11.3.3.3 NEs as Fluorescent Probes in Fluorescent Imaging;298
9.1.3.3.4;11.3.3.4 Nano-emulsions as Multimodal Imaging Probes and Theragnostics;301
9.1.4;11.4 Conclusion;303
9.1.5;References;303
9.2;Chapter 12: The Tumor Microenvironment in Nanoparticle Delivery and the Role of Imaging to Navigate Roadblocks and Pathways;307
9.2.1;12.1 Introduction;308
9.2.2;12.2 Nanoplatforms;308
9.2.3;12.3 Tumor Microenvironment;310
9.2.3.1;12.3.1 Tumor Vasculature;310
9.2.3.2;12.3.2 Tumor Lymphatics;313
9.2.3.3;12.3.3 The Extracellular Matrix;313
9.2.3.4;12.3.4 Stromal Cells;314
9.2.4;12.4 NP Delivery in Tumors;314
9.2.5;12.5 Improving Tumor Delivery of Nanoparticles;316
9.2.5.1;12.5.1 Optimization of Circulation Time;316
9.2.5.2;12.5.2 NP Extravasation;316
9.2.5.3;12.5.3 NP Shape and Size;316
9.2.5.4;12.5.4 TME Modification Strategies;318
9.2.6;12.6 TME Targeting Strategies;319
9.2.7;12.7 Molecular Imaging in Optimizing NP Delivery and in Theranostics;321
9.2.8;12.8 Conclusion;324
9.2.9;References;324
9.3;Chapter 13: Microscopic Mass Spectrometry for the Precise Design of Drug Delivery Systems;329
9.3.1;13.1 Introduction;330
9.3.2;13.2 Principle of Microscopic Mass Spectrometry (MMS);333
9.3.3;13.3 MMS for Analysis of Drugs Delivered Via Active Targeting;334
9.3.4;13.4 MMS for a Passive Targeting;338
9.3.5;13.5 Conclusion and Future Prospect;342
9.3.6;References;342
10;Part VII: Quantitative PK Treatment, Systems Biology and Drug Discovery;344
10.1;Chapter 14: Pharmacokinetics and Pharmacodynamics of Nano-Drug Delivery Systems;345
10.1.1;14.1 Introduction;346
10.1.2;14.2 The Pharmacokinetics and Pharmacodynamics of Systemically-Administered Nano-DDSs;348
10.1.2.1;14.2.1 PK and PD of Nano-DDSs in the Systemic Circulation;349
10.1.2.2;14.2.2 PK and PD of Nano-DDSs in the Tissues;352
10.1.2.3;14.2.3 Intracellular PK and PD of Nano-DDSs;353
10.1.3;14.3 Targeted Delivery of Analgesic Peptides to the Brain Using Bolavesicle-Based Nano-DDSs;354
10.1.4;14.4 Targeted Delivery of Antigenic Peptides to the Endoplasmic Reticulum of the Antigen-­Presenting Cells for Anti-Cancer Vaccination;356
10.1.5;14.5 Rational Design of Nano-DDSs;359
10.1.6;14.6 Conclusion;362
10.1.7;References;363
10.2;Chapter 15: PBPK Modelling of Intracellular Drug Delivery Through Active and Passive Transport Processes;367
10.2.1;15.1 An Introduction to Physiologically Based Pharmacokinetic Modelling;368
10.2.2;15.2 Intracellular Drug Delivery in PBPK Modelling;371
10.2.2.1;15.2.1 Organ-Plasma Partitioning;371
10.2.2.2;15.2.2 Passive Transport: Permeability-Surface Area Products;373
10.2.2.3;15.2.3 Active Transport: First Order Kinetics and Michaelis-­Menten Kinetics;373
10.2.3;15.3 Cross-Species Extrapolation;374
10.2.4;15.4 Discussion;375
10.2.5;References;377
10.3;Chapter 16: Exploiting Nanocarriers for Combination Cancer Therapy;379
10.3.1;16.1 Introduction;381
10.3.2;16.2 Drug Combinations for Cancer Treatment;381
10.3.2.1;16.2.1 A Brief History of Combination Cancer Therapy;381
10.3.2.1.1;16.2.1.1 Combinations of Independently Active Drugs;381
10.3.2.1.2;16.2.1.2 Rational Drug Combinations Targeting a Shared Mechanism of Action;383
10.3.2.1.3;16.2.1.3 Molecularly Targeted Therapies;383
10.3.2.1.4;16.2.1.4 Large-Scale Screens, Nucleic Acid Therapies, and Beyond;384
10.3.2.2;16.2.2 Challenges in Delivering Drug Combinations to Tumors;384
10.3.2.2.1;16.2.2.1 Co-delivery;384
10.3.2.2.2;16.2.2.2 Stoichiometry/Ratiometric Dosing;385
10.3.2.2.3;16.2.2.3 Drug Sequence and Timing;385
10.3.2.2.4;16.2.2.4 Compounding and Overlapping Toxicity;387
10.3.3;16.3 Nanoparticle Formulations to Optimize Anti-cancer Combination Therapies;387
10.3.3.1;16.3.1 Mesoporous Silica Nanoparticles;388
10.3.3.2;16.3.2 Self-Assembly Copolymer Carriers – Micelles;388
10.3.3.3;16.3.3 Nanotechnology Approaches to Enhance Co-delivery;389
10.3.3.4;16.3.4 Nanotechnology Solutions: Stoichiometry/Ratiometric Dosing;391
10.3.3.5;16.3.5 Nanotechnology Approaches to Tailor Drug Combination Timing and Sequence;395
10.3.3.6;16.3.6 Nanotechnology Approaches to Limit Compounding and Overlapping Toxicity;396
10.3.3.7;16.3.7 Combining Nucleic Acid Therapies with Other Drug Combinations;396
10.3.4;16.4 Limitations to Developing Combination Chemotherapeutics, Tumor-Specific Targeting, and Enabling Approaches;397
10.3.5;16.5 Outlook and Conclusions;399
10.3.6;References;400
11;Part VIII: Market Situation and Commercialization of Nanotechnology;407
11.1;Chapter 17: The Commercialization of Medical Nanotechnology for Medical Applications;408
11.1.1;17.1 Introduction;409
11.1.2;17.2 Historical Advancement of Medical Nanotechnology;411
11.1.2.1;17.2.1 Diagnostics;414
11.1.2.2;17.2.2 Imaging;415
11.1.2.3;17.2.3 Pharmaceuticals;415
11.1.2.4;17.2.4 Therapeutics;417
11.1.3;17.3 Biomaterials;417
11.1.3.1;17.3.1 Biosensors;417
11.1.3.2;17.3.2 Tissue Engineering;418
11.1.3.3;17.3.3 Medical Devices and Accessories;419
11.1.4;17.4 Entrepreneurship;420
11.1.5;17.5 The Commercialization Process;422
11.1.6;17.6 Risk and Hazard Assessment;427
11.1.7;17.7 Securing Intellectual Property and Licensing (IP Strategy);430
11.1.8;17.8 Valuation and Technology Transfer;435
11.1.9;17.9 Funding and Financing;436
11.1.10;17.10 Regulatory Approval;440
11.1.11;17.11 Market Acceptance/Adoption;441
11.1.12;17.12 Success;443
11.1.13;17.13 Lessons Learned;444
11.1.14;17.14 Future of Medical Nanotechnology Commercialization;446
11.1.15;17.15 Summary;446
11.1.16;References;447
12;Index;453