Written by leading scientists in the field of delivery of protein and peptide drugs to tumors for cancer therapy, this important book provides a broad introduction to the field, with discussion by key experts on the physiological barriers for protein and peptide drugs in tumors, and the different approaches to stabilization of these drugs in biological surroundings, as well as their enhanced delivery to tumors and inside cancer cells.
This book can be used as an advanced textbook by graduate students and young scientists and clinicians at the early stages of their career. It is also suitable for non-experts from related areas of chemistry, biochemistry, molecular biology, physiology, experimental and clinical oncology and pharmaceutical sciences, who are interested in general problems of drug delivery and drug targeting as well as in a more specialized topics of using protein and peptide drugs for tumor therapy.
Author(s): Vladimir P. Torchilin
Edition: 1
Publisher: Imperial College Press
Year: 2006
Language: English
Commentary: 33321
Pages: 392
Contents......Page 6
Contributors......Page 14
1. Introduction Vladimir Torchilin......Page 18
References......Page 23
1. Introduction......Page 26
2.1. General features of blood vessels in biological systems......Page 27
2.2. The tumor vasculature: Specialized features and angiogenesis......Page 29
3.1. Barriers limiting drug transport......Page 31
3.2. The interstitial matrix: MMPs, collagen, invasion and metastasis......Page 36
3.3. Overcoming barriers: Exploiting tumor physiology for therapeutic gain......Page 38
References......Page 46
1. Introduction......Page 54
2. Theory Underlying the EPR Effect......Page 55
3. Anatomical and Pathophysiological Abnormalities Related to EPR Effect......Page 56
4. Augmentation of the EPR Effect in Solid Tumor by Influencing Vascular Mediators......Page 59
5. Relation of Fluid Dynamics in Cancer Tissue to the EPR Effect......Page 61
6. Implications for Delivery of Drugs to Tumors......Page 62
References......Page 65
Abstract......Page 70
1. Introduction......Page 71
2. Features of PEG as Bioconjugation Polymer......Page 72
3.1. Amino group PEGylation......Page 78
3.2. Thiol PEGylation......Page 84
3.3. Carboxy PEGylation......Page 85
4. Strategies in Protein PEGylation......Page 86
5. Enzymatic Approach for Protein PEGylation......Page 91
6. PEGylated Protein Purification and Characterization......Page 93
7. Conclusion......Page 95
References......Page 96
1. Introduction......Page 102
2. Enzymes and PEG-Enzymes in Cancer Therapy......Page 104
2.1.1. PEG-asparaginase (PEG-ASNase)......Page 105
2.1.2. PEG-methioninase (PEG-METase)......Page 108
2.1.3. PEG-arginine deiminase (PEG-ADI)......Page 110
2.1.4. PEG-uricase (PEG-UK)......Page 112
3. PEG-Antibodies......Page 117
4. Conclusions......Page 120
References......Page 121
Abstract......Page 128
1. Introduction......Page 129
2. PEGylated Interferon-α......Page 131
3. PEGylated G-CSF......Page 132
4. Other PEGylated Hematopoietic Growth Factors......Page 134
5. PEGylated Lymphokines......Page 135
7. Conclusions and Outlook......Page 136
References......Page 137
7. Silencing Proteins: Nanotechnological Approaches to Deliver siRNA for Cancer Therapy Raymond M. Schiffelers, Daan J.A. Crommelin and Gert Storm......Page 144
1.2. Tumor suppressor genes......Page 145
2. RNA Interference......Page 146
2.1. Mechanism of RNA interference......Page 147
2.2. Structural requirements for siRNA......Page 148
3. Approaches for siRNA Delivery......Page 151
4.1. siRNA to silence oncogenes......Page 152
4.2. siRNA to silence mutated tumor suppressor genes......Page 155
4.3. siRNA to silence pro-angiogenic/ pro-metastatic genes......Page 156
5. Concluding Remarks......Page 158
References......Page 160
1. Proteins and Peptides as Cancer Therapeutics......Page 172
2. Stability, Delivery and Distribution Issues for Peptide and Protein Drugs......Page 173
3. Possible Solutions. Liposomes as Pharmaceutical Carriers......Page 175
4. Liposomal Proteins and Peptides for Cancer Treatment......Page 179
5. Tumor Cell Targeting Using Specific Ligand-Bearing Liposomes......Page 182
6. Transmembrane Delivery of Protein and Peptide Drugs into Tumor Cells......Page 184
References......Page 188
9. Folate-Mediated Delivery of Protein and Peptide Drugs into Tumors Joseph A. Reddy, Christopher P. Leamon and Philip S. Low......Page 200
1. Introduction......Page 201
2. Methods for Coupling FA to Proteins and Peptides......Page 202
3. Cytotoxicity Studies of Folate Linked Toxins......Page 205
4. Folate Targeted Immunotherapy......Page 209
6. Folate-mediated Targeting of Adenovirus......Page 212
7. In vivo Fate of Folate-protein Conjugates......Page 214
8. Folate-targeted Peptidic Imaging Agent......Page 215
9. Conclusions and Outlook......Page 217
References......Page 218
1. Introduction......Page 222
2.1. Structure......Page 223
3.1. Structure......Page 224
3.2. Clathrin-mediated endocytosis......Page 225
3.4. Tissue distribution......Page 226
4. In vivo Application of Proteins Drugs, General Considerations......Page 227
5.1. Chemical coupling......Page 228
5.2. Recombinant production of conjugates......Page 229
6.1. Ribosomal inhibitors......Page 230
6.2. Ribonucleases......Page 231
6.3. Diphtheria toxin and Pseudomonas exotoxin......Page 232
References......Page 234
Abstract......Page 242
1. Introduction......Page 243
2.2. TAT-related peptides......Page 244
3. Mechanism of PTD-Mediated Transduction......Page 245
4. Delivery of Anti-Cancer Therapies Using Protein Transduction Domains......Page 246
4.1.1. p53 tumor suppressor......Page 247
4.1.3. p21 and p27 tumor suppressors......Page 249
4.1.5. NF2/merlin tumor suppressor......Page 251
4.2.1. Caspase activation......Page 252
4.2.3. S100 family proteins......Page 254
4.2.5. Activating transcription factor 2......Page 255
4.3.1. Ras signaling pathways......Page 256
4.3.2. HER-2 pathway......Page 257
4.4.1. RasGAP-derived peptide......Page 258
4.4.2. Repair of mitochondrial DNA......Page 259
4.5.1. Cancer cell vaccines......Page 260
4.5.2. Cancer cell migration......Page 261
References......Page 262
1. Introduction......Page 272
2. Natural Cyokines......Page 273
3. Cryptic Protein Fragments......Page 279
4.1. Monoclonal antibodies (mAb)......Page 281
4.2. Recombinant antibodies......Page 284
6.1. Vascular targeting peptides......Page 286
6.2. Function-blocking peptides......Page 288
References......Page 290
Abstract......Page 302
1. Introduction......Page 303
2.1. Lipid absorption from the small intestine......Page 304
3. Lymphatic Vessels Functioning as Transport Routes for Malignant Cells......Page 307
4.1. Contribution of lymphatic transport to the increased absorption of water-insoluble drugs into the systemic circulation......Page 308
4.2. Evaluation and assessment of intestinal lymphatic transport......Page 310
4.3.1. Diffusion and partition behaviour of water-insoluble drugs......Page 312
4.3.2. Lipid solubility of water-insoluble drugs......Page 313
5. Utilization of Lymphatic System in the Delivery of Drugs, Including Proteins and Peptides to Metastatic Tumors......Page 314
6. Clinical Signi.cance......Page 317
References......Page 318
Abstract......Page 326
1. Introduction......Page 327
2. Biology of the BBB, BBB-Transport Systems, and BTB......Page 328
3. Overview of Drug Delivery and Distribution......Page 331
4. Chemical Modification, Glycosylation, Pegylation, and Other Delivery Approaches......Page 332
5. Nanoparticle Drug Delivery Approaches......Page 335
6. Liposomal Drug Delivery Approaches......Page 337
8. Immunoglobulin-Based Delivery Approaches......Page 340
9. Vector-Mediated Delivery Approaches......Page 343
References......Page 345
1. Cancer Gene Therapy......Page 352
1.1. Identifying the target gene/pathway for cancer therapy......Page 353
1.2. Selection of gene therapy vector......Page 355
2. Protein-Based Cancer Gene Therapy......Page 356
2.1.1. Toxic proteins......Page 357
2.1.2. Tumor suppressor proteins......Page 360
2.1.3. Antiangiogenic proteins......Page 365
2.2. Enhancement of the immune response......Page 368
3.1. Tumor targeting and gene transduction......Page 370
References......Page 374
Index......Page 388
