癌症给药技术：技术・市场・企业

Abstract

Summary

Drug delivery remains a challenge in management of cancer. Approximately 12.5 million new cases of cancer are being diagnosed worldwide each year and considerable research is in progress for drug discovery for cancer. Cancer drug delivery is no longer simply wrapping up cancer drugs in a new formulations for different routes of delivery. The focus is on targeted cancer therapy. The newer approaches to cancer treatment not only supplement the conventional chemotherapy and radiotherapy but also prevent damage to normal tissues and prevent drug resistance.

Innovative cancer therapies are based on current concepts of molecular biology of cancer. These include antiangiogenic agents, immunotherapy, bacterial agents, viral oncolysis, targeting of cyclic-dependent kinases and tyrosine kinase receptors, antisense approaches, gene therapy and combination of various methods. Important methods of immunotherapy in cancer involve use of cytokines, monoclonal antibodies, cancer vaccines and immunogene therapy.

Several innovative methods of drug delivery are used in cancer. These include use of microparticles as carriers of anticancer agents. These may be injected into the arterial circulation and guided to the tumor by magnetic field for targeted drug delivery. Polyethylene glycol (PEG) technology has been used to overcome some of the barriers to anticancer drug delivery. Encapsulating anticancer drugs in liposomes enables targeted drug delivery to tumor tissues and prevents damage to the normal surrounding tissues. Monoclonal antibodies can be used for the delivery of anticancer payloads such as radionucleotides, toxins and chemotherapeutic agents to the tumors.

Antisense oligonucleotides have been in clinical trials for cancer for some time now. RNAi has also been applied in oncology. Small interfering RNAs (siRNAs) can be targeted to tumors and one example is suppression of H-ras gene expression indicating the potential for application in therapy of ovarian cancer. Cancer gene therapy is a sophisticated form of drug delivery for cancer. Various technologies and companies developing them are described. Nucleic acid-based cancer vaccines are also described.

Drug delivery strategies vary according to the type and location of cancer. Role of drug delivery in the management of cancers of the brain, the bladder, the breast, the ovaries and the prostate are used as examples to illustrate different approaches both experimental and clinical. Biodegradable implants of carmustine are already used in the treatment of malignant brain tumors.

The market value of drug delivery technologies and the anticancer drugs are difficult to separate. Cancer market estimates from 2007-2017 are given according to organs involved and the types of cancer as well as according to technologies. Distribution of the into major regions is also described.

Profiles of 198 companies involved in developing innovative cancer therapies and methods of delivery are presented along with their 212 collaborations. The bibliography contains over 580 publications that are cited in the report.The report is supplemented with 53 tables and 7 figures.

Table of Contents

0. Executive Summary 17

1. Introduction to cancer therapy 19

• Molecular biology of cancer 19
• The genesis of cancer 19
• Normal cell cycle and growth 19
• Oncogenes 20
• Tumor Suppressor Genes 20
• Role of microRNAs in cancer 22
• Role of Bub 1 gene in cell division 22
• Accumulation of random mutations 23
• Chromosomal instability 23
• Aneuploidy 24
• Telomeres and cancer 24
• DNA methylation and cancer 25
• Anticancer treatments based on RNA regulation of genes 25
• Hallmarks of cancer 25
• Self-sufficiency of tumor proliferation 26
• Apoptosis 26
• Therapeutic implications of apoptosis in cancer 27
• Autophagy 28
• Induction of angiogenesis 29
• Acquisition of a potential for unlimited replication 30
• Invasion and metastases 30
• Cancer biomarkers 31
• Molecular imaging of cancer 31
• Cancer genomics 32
• Gene expression profiling in cancer 32
• Cancer proteomics 33
• Limitations of genomics and proteomics for understanding cancer 33
• Cancer microenvironment 33
• Epidemiology of cancer 34
• Current management of cancer 35
• Chemotherapy 35
• Limitations of cancer chemotherapy 35
• Radiotherapy 36
• Brachytherapy 36
• Surgery 36
• Basics of drug delivery in cancer 36
• Historical landmarks in cancer drug delivery 37

2. Innovative treatments for cancer 39

• Introduction 39
• Selective estrogen receptor modulators 40
• Antiangiogenic strategies for cancer 41
• Development of antiangiogenic therapies 41
• Classification of antiangiogenic agents 41
• Examples of antiangiogenic agents 43
• Chemotherapy at lower than maximum tolerated dose 43
• Inhibitors of endothelial proliferation 43
• Inducers of apoptosis of endothelial cells of tumor vessels 43
• Lodamin 44
• Matrix metalloproteinase inhibitors 44
• Monoclonal antibodies with vasculostatic properties 45
• PPARα agonists 46
• Rapalogues as antiangiogenic agents 46
• VEGF Trap 47
• Agents that decrease the permeability of tumor blood vessels 47
• Antiangiogenic agents in clinical trials 47
• Combination of antiangiogenic with cytotoxic therapy 48
• Bacterial anticancer agents 48
• Tumor-targeted bacteria 49
• Genetically modified Salmonella typhimurium as anticancer agent 49
• TAPET (Tumor Amplified Protein Expression Therapy) 49
• Bacterial protein for targeted delivery of liposomal cancer drugs 50
• Killed but metabolically active (KBMA) bacteria 50
• Bacterial toxins targeted to tumors 50
• Immunotoxins 50
• Escherichia Coli toxins 51
• Engineered anthrax toxin 51
• Recombinant fusion toxins 52
• Type III secretion systems 53
• Induction of apoptosis in cancer by bacterial proteins 54
• Induction of immune response by bacteriolytic therapy 54
• Innovations in cell therapy for cancer 54
• Stem cell transplantation for cancer 55
• Cancer drug/gene delivery by mesenchymal stem cells 55
• Cancer immunotherapy 55
• Cytokines 56
• Cancer vaccines 56
• 5T4 as a target for cancer immunotherapy 57
• Anti-telomerase vaccine 58
• Antigen-specific cancer vaccines 58
• Carcinoembryonic antigen-based vaccines 59
• Dendritic cells for cancer vaccination 59
• Hybrid cell vaccination 60
• Lymphocyte-based cancer therapies 61
• Tumor cell vaccines 63
• Vaccines that simultaneously target different cancer antigens 64
• Concluding remarks about cancer vaccines 64
• Cancer Vaccine Consortium 64
• Innovative methods of radiation delivery 64
• Image-guided ultrasound technology for delivery of radiation 65
• Respiratory gating technology for radiation therapy 65
• Positron therapy 65
• Boron neutron capture therapy 66
• Application of drug delivery systems to BNCP 66
• Use of nanotechnology to enhance BNCT 66
• Skeletal Targeted Radiotherapy 67
• Irreversible electroporation 67
• Methods to overcome multidrug resistance (MDR) 68
• P-glycoprotein-mediated MDR 68
• MDR-associated protein gene 68
• Strategies for overcoming MDR 69
• Blocking the action of P-glycoprotein 69
• Nitric oxide inducers 69
• Managing resistance to antiapoptotic action of anticancer agents 69
• Inhibition of DNA repair 70
• Liposome formulation of drugs 70
• Modification of the chemical structure of the anticancer drug 70
• Enzyme Catalyzed Therapeutic Activation 71
• Modulation of SPARC expression 71
• Iron chelators that overcomes resistance to chemotherapeutics 71
• Proton pump inhibitors 72
• Combination of targeted drugs with different specificities 72
• Targeted cancer therapies 72
• Targeting cellular pathways 72
• Targeting antigens in virus-associated cancer 73
• Targeting HAAH for cancer therapy 73
• Targeting mitochondrial membranes 74
• Targeting tumor lymphatics 75
• Targeting tyrosine kinase receptors 75
• Inhibitors of bcr-abl tyrosine kinase 76
• Inhibition of multiple tyrosine kinases 76
• Inhibitors of ErbB tyrosine kinase 76
• Targeting the Hedgehog signaling pathway 77
• Targeting oncogenes 77
• Targeting miRNA for cancer therapeutics 78
• miRNAs as basis of cancer therapeutics 78
• Targeting the transferrin receptor-mediated endocytosis pathway 79
• Targeting cancer stem cells 79
• Targeting glycoproteins 79
• Tagging cancer with sugars 80
• Anticancer agents based on glycobiology 80
• Targeting cell surface glycoproteins 80
• Biofusion for targeted cancer therapy 80
• Targeted drug delivery of anticancer agents with controlled activation 81
• Targeted delivery of anticancer agents with ReCODE"! technology 82
• Enhancing the effects of radiation and chemotherapy 82
• Sensitizing agents for chemotherapy 82
• Tesmilifene for chemosensitization 82
• CoFactor to enhance the efficacy of chemotherapy 82
• Enzyme-enhanced chemotherapy 83
• Sensitizing agents for radiotherapy 83
• IPdR 83
• Manipulation of tumor oxygenation 84
• Hypoxia-based methods to enhance chemotherapy and radiotherapy 84
• Hyperbaric oxygen and radiation 85
• HIF-1 antagonists to enhance radiotherapy 85
• Nonsteroidal antiinflammatory drugs enhance tumor radiosensitivity 85
• ONCONASE as radiosensitivity enhancer 85
• Hyperthermia and chemotherapy/radiation therapy 86
• Techniques for hyperthermia 86
• Trimodality therapy: radiation, chemotherapy, and hyperthermia 86
• Photodynamic therapy 87
• Novel anticancer agents 89
• Anti-EphA2 antibodies 89
• Antioxidants 89
• Brostallicin 89
• Agents disrupting folate metabolism 90
• Pemetrexed 90
• Cytotoxic ribonucleases 90
• DNA hypomethylating agents 91
• Histone-based cancer therapy 91
• Histone deacetylase inhibitors 91
• Modulation of p300/CBP histone acetyltransferase activity 92
• Simulation of endogenous histone for anticancer therapy 92
• HSP90 inhibitors 93
• Ion channel blockers 93
• IOT-101 93
• Endovion 93
• LPAAT-beta inhibitors 94
• P13-kinase inhibitors 94
• PARP inhibitors 94
• Targeted destruction of BRCA2 deficient tumors by PARP inhibitors 95
• Prodrugs 95
• Enzyme-activated prodrugs 95
• Ascorbic acid as a prodrug for cancer 96
• Prolarix 96
• Protein kinase G activation 96
• Proteasome inhibitors 97
• Recombinant human insulin-like growth factor binding protein-3 97
• Second generation nucleosides 98
• Targeting topoisomerase IB 98
• Telomerase inhibitors 98
• Therapeutic strategies based on the P53 pathway 99
• Development of targeted anticancer therapies 100
• In vivo models for molecularly anticancer drugs 100
• Checkpoint activation as a strategy against cancer 100
• Deletion-specific targeting for cancer therapy 101
• Combining novel anticancer approaches 101
• Personalized therapy of cancer 102
• Challenges of cancer classification 104
• Design of future cancer therapies 104
• Personalized drug development in oncology 105
• Role of molecular imaging 105
• Role of molecular imaging in targeted cancer therapy 106
• Screening for personalized anticancer drugs 107
• Targeting pathways for personalized cancer therapy 107

3. Drug delivery systems for cancer 109

• Introduction 109
• Routes of drug delivery in cancer 109
• Intravenous delivery systems for cancer therapy 110
• Oral delivery of anticancer agents 111
• Oral UFT 111
• 5-FU combined with eniluracil 112
• Oral paclitaxel 113
• Oral fluoropyrimidines 113
• Oral satraplatin 114
• Oral PXD101 114
• ARRY-142886 114
• High dose pulse administration of calcitrol 114
• Oral gefitinib vs intravenous docetaxel 114
• Transdermal drug delivery 115
• Delivery of the photosensitizer drug δ-amino levulinic acid 115
• Transdermal delivery of the methotrexate 115
• Transdermal delivery of peptide cancer vaccines 116
• Intradermal delivery of cancer vaccines by adenoviral vectors 116
• Pulmonary delivery of anticancer agents 116
• Regional intra-arterial delivery of chemotherapy 117
• Gas embolotherapy of tumors 117
• Drug delivery to lymph nodes 118
• Intraperitoneal macrophages as drug delivery vehicle 118
• Challenges of cancer drug delivery 118
• Tumor blood vessel pore barrier to drug delivery 119
• Improvement of drug transport in tumors 119
• Delivery of anticancer drugs to nuclear targets 119
• Innovative formulations for drug delivery in cancer 120
• Cancer targeting with polymeric drugs 120
• Linking anticancer drugs to polyglutamate 121
• Bacterial ghosts as drug delivery systems for anticancer drugs 122
• Microparticles as therapeutic delivery systems in cancer 122
• Subcutaneous injection of microspheres carrying anticancer drugs 123
• Intravascular delivery systems using microparticles 123
• Tumor embolization with drug-eluting beads 123
• Tumor embolization with radioactive microparticles 124
• Microparticles heated by magnetic field 124
• Magnetic targeted microparticle technology 124
• Release of drugs from micelles by ultrasound 125
• Release of drugs from biSphere by ultrasound 125
• Release of drugs from microcapsules by laser 126
• Chemoembolization 126
• Anticancer drugs bound to carbon particles 126
• Anticancer drugs bound to protein microspheres 126
• Nanoerythrosomes 126
• Micronized droplets of olive oil 127
• Nanobiotechnology-based drug delivery for cancer 127
• Nanoparticle formulations for drug delivery in cancer 128
• Anticancer drug particles incorporated in liposomes 128
• Bacterial nanoparticles for encapsulation and chemotherapy delivery 130
• Encapsulating drugs in hydrogel nanoparticles 130
• Exosomes 130
• Folate-linked nanoparticles 131
• Lipid based nanocarriers 131
• Micelles for drug delivery in cancer 131
• Nanoparticle formulations of paclitaxel 133
• Nanoparticles containing albumin and antisense oligonucleotides 133
• Non-aggregating nanoparticles 133
• Pegylated nanoliposomal formulation 134
• Perfluorocarbon nanoparticles 134
• Protosphere nanoparticle technology 134
• Nanoparticles for targeted delivery of drugs into the cancer cells 135
• Antiangiogenic therapy using nanoparticles 136
• Carbon magnetic nanoparticles for targeted drug delivery in cancer 137
• Carbon nanotubes for targeted drug delivery to cancer cells 137
• Fullerenes for enhancing tumor targeting by antibodies 137
• Gold nanoparticles for drug delivery in cancer 138
• Iron oxide magnetic nanoparticle formulation for drug delivery 139
• Lipoprotein nanoparticles targeted to cancer-associated receptors 139
• Magnetic nanoparticles for remote-controlled drug delivery to tumors 139
• Nanocell for targeted drug delivery to tumor 140
• Nanodroplets for site-specific cancer treatment 141
• Phage nanoparticles as antibody-drug conjugates 141
• Polymer nanoparticles for targeted drug delivery in cancer 141
• Polymersomes for targeted cancer drug delivery 141
• Targeted drug delivery with nanoparticle-aptamer bioconjugates 142
• Dendrimers for anticancer drug delivery 143
• Application of dendrimers in boron neutron capture therapy 143
• Application of dendrimers in photodynamic therapy 144
• Dendrimer-based synthetic vector for targeted cancer gene therapy 144
• Devices for nanotechnology-based cancer therapy 145
• Convection-enhanced delivery with nanoliposomal CPT-11 145
• Nanocomposite devices 145
• Nanoengineered silicon for brachytherapy 146
• Nanoparticles combined with physical agents for tumor ablation 146
• Carbon nanotubes for laser-induced cancer destruction 146
• Nanoparticles and thermal ablation 146
• Nanoparticles combined with ultrasound radiation of tumors 147
• Nanoparticles as adjuncts to photodynamic therapy of cancer 147
• Nanoparticles for boron neutron capture therapy 148
• RNA nanotechnology for delivery of cancer therapeutics 148
• Nanocarriers for simultaneous delivery of multiple anticancer agents 149
• Combination of diagnostics and therapeutics for cancer 149
• Biomimetic nanoparticles targeted to tumors 149
• Dendrimer nanoparticles for targeting and imaging tumors 149
• Gold nanorods for diagnosis plus photothermal therapy of cancer 150
• Magnetic nanoparticles for imaging as well as therapy of cancer 150
• pHLIP nanotechnology for detection and targeted therapy of cancer 151
• Radiolabeled carbon nanotubes for tumor imaging and targeting 151
• Targeted therapy with magnetic nanomaterials guided by antibodies 151
• Ultrasonic tumor imaging and targeted chemotherapy by nanobubbles 151
• Polyethylene glycol technology 152
• Enzon' s PEG technology 152
• Debiopharm' s PEG biconjugate drug delivery platform 153
• Nektar PEGylation 153
• PEG Intron 153
• Single-chain antibody-binding protein technology 154
• Liposomes for anticancer drug delivery 154
• Antibody-targeted liposomes for cancer therapy 155
• AlZA' s Stealth liposomes 155
• Boron-containing liposomes 156
• DepoFoam technology 156
• Hyperthermia and liposomal drug delivery 156
• Liposomal doxorubicin formulation with N-octanoyl-glucosylceramide 157
• Liposome-nucleic acid complexes for anticancer drug delivery 157
• Non-pegilated liposomal doxorubicin 157
• Tumor-selective targeted drug delivery via folate-PEG liposomes 157
• Ultrasound-mediated anticancer drug release from liposomes 158
• Companies developing liposome-based anticancer drugs 158
• Emulsion formulations of anticancer drugs 159
• Albumin-based drug carriers 159
• Anticancer drugs that bind to tumors 160
• Monoclonal antibodies 160
• Murine monoclonal antibodies 160
• Humanized MAbs 160
• Actions and uses of monoclonal antibodies in cancer 161
• Targeted antibody-based cancer therapy 161
• Antibody - cytokine fusion proteins 161
• Antibody J591 for targeted delivery of anticancer therapy 162
• Anti-Thomsen-Friedenreich antigen MAb 162
• Combining MAbs with anti-CD55 antibody 162
• MAbs targeted to alpha fetaprotein receptor 163
• MAbs targeted to tumor blood vessels 163
• MAbs targeted to HAAH 163
• MAbs for immune activation 163
• Delivery of cancer therapy with MAbs 164
• Antibody-directed enzyme prodrug therapy 165
• Chemically programmed antibodies 165
• Combining diagnostics with therapeutics based on MAbs 166
• Radiolabeled antibodies 166
• Clinical development of MAbs for treatment of cancer 167
• Advantages and limitations of MAbs for cancer therapy 172
• Monoclonal T cell receptors 173
• Radiolabeled somatostatin receptor antagonists 173
• Strategies for drug delivery in cancer 173
• Direct introduction of anticancer drugs into the tumor 175
• Injection into the tumor 175
• Antineoplastic drug implants into tumors 175
• Tumor necrosis therapy 176
• Injection into the arterial blood supply of cancer 176
• Electrochemotherapy 178
• Pressure-induced filtration of drugs across vessels to the tumor 178
• Improving drug transport to tumors 178
• Carbohydrate-enhanced chemotherapy 178
• Dextrans as macromolecular anticancer drug carriers 179
• In situ production of anticancer agents in tumors 179
• Targeted drug delivery in cancer 179
• Affibody molecules for targeted anticancer therapy 181
• Fatty acids as targeting vectors 181
• Genetic targeting of the kinase activity in cancer cells 181
• Heat-activated targeted drug delivery 182
• Novel transporters to target photosensitizers to cancer cell nuclei 182
• Photodynamic therapy of cancer 183
• Radionuclides delivered with receptor targeting technology 183
• Targeting ligands specific for cancer cells 184
• Targeting abnormal DNA in cancer cells 184
• Targeting using a bispecific antibody 184
• Targeted chemotherapy using transporters 185
• Targeted generation of intracellular reactive oxygen species 185
• Targeted cytotoxic peptides 185
• Targeted delivery to receptors found in tumors 186
• Targeted delivery by tumor-activated prodrug therapy 186
• Targeting glutathione S-transferase 188
• Targeting tumors by exploiting leaky blood vessels 188
• Transmembrane Carrier Systems 189
• Transferrin-oligomers as targeting carriers in anticancer drug delivery 189
• Ultrasound and microbubbles for targeted anticancer drug delivery 189
• Ultrasound for targeted delivery of chemotherapeutics 190
• Vitamin B12 and folate for targeting cancer chemotherapy 190
• Drug delivery in relation to circadian rhythms 192
• Implants for systemic delivery of anticancer drugs 192
• Drug-eluting polymer implants 193
• Angiogenesis and drug delivery to tumors 193
• Antiangiogenesis strategies 193
• Targeting tumor endothelial cells 194
• Methods for overcoming limitations of antiangiogenesis approaches 194
• Vascular targeting agents 195
• Alpha-emitting antibodies for vascular targeting 196
• Angiolytic therapy 196
• Anti-phosphatidylserine antibodies as VTA 196
• AS1404 197
• Cadherin inhibitors 197
• Combretastatin A4 Prodrug 198
• Drugs to induce clotting in tumor vessels 198
• Selective permeation of the anticancer agent into the tumor 198
• Targeted delivery of tissue factor 199
• Vascular targeting agents versus antiangiogenesis agents 200
• ZD6126 200
• Delivery of proteins and peptides for cancer therapy 201
• CELLECTRA"! electroporation device 201
• Emisphere' s eligen"! system 202
• Diatos Peptide Vector intra-cellular/intra-nuclear delivery technology 202
• Lytic peptides and cancer 202
• Modification of proteins and peptides with polymers 203
• Peptide-based targeting of cancer biomarkers for drug delivery 203
• Peptide-cytokine complexes as vascular targeting agents 204
• Peptide-polymer conjugates with radionuclides 204
• Transduction of proteins in vivo 205
• Tumor targeting by stable toxin (ST) peptides 205
• Cell-based cancer vaccines 205
• Autologous tumor cell vaccines 205
• Vaccines that simultaneously target different cancer antigens 206
• Delivery systems for cancer vaccines 206
• A computational approach to integration of drug delivery methods for cancer 207

4. Antisense, RNAi and Gene Therapy for Cancer 209

• Basics of antisense therapy 209
• Antisense cancer therapy 209
• Mechanisms of anticancer effect of antisense oligonucleotides 210
• Selected antisense drugs in development for cancer 210
• Antisense targeted to ribonucleotide reductase 210
• Targeting C-myb with LR3001 211
• Immune modulatory oligonucleotide 211
• Ribozyme therapy 211
• Antisense drug delivery issues 212
• Strategies to overcome delivery problems of antisense oligonucleotides 212
• Oral delivery of oligonucleotides 212
• Iontophoretic delivery of oligonucleotides 213
• Delivery across the blood-brain barrier 213
• Receptor-mediated endocytosis 213
• Liposomes-mediated oligonucleotide delivery 214
• Antisense delivery in microspheres 214
• Antisense nanoparticles 214
• Peptide nucleic acid delivery 215
• Neugene™ antisense drugs 215
• Delivery of ribozymes 215
• Combination of antisense and electrochemotherapy 216
• Aptamers for combined diagnosis and therapeutics of cancer 216
• Antisense and RNAi 217
• Basics of RNAi 217
• Comparison of antisense and RNAi 217
• RNAi applications in oncology 218
• Delivery of siRNA by nanoparticles 219
• Delivery of siRNA by nanosize liposomes 219
• Lipid nanoparticles for delivery of anticancer siRNAs 220
• Polymer nanoparticles for targeted delivery of anticancer siRNA 220
• Companies developing cancer therapies based on antisense and RNAi 220
• DNA interference 221
• Cancer gene therapy 222
• Basics of gene therapy 222
• Strategies for cancer gene therapy 222
• Gene transfer techniques as applied to cancer gene therapy 223
• Viral vectors 223
• Non-viral vectors 224
• A polymer approach to gene therapy for cancer 225
• Direct gene delivery to the tumor 225
• Injection into tumor 225
• Reversible electroporation 226
• Hematopoietic gene transfer 227
• Genetic modification of human hematopoietic stem cells 227
• Gene-based strategies for immunotherapy of cancer (immunogene therapy) 228
• Cytokine gene therapy 229
• Nucleic acid-based cancer vaccines 232
• DNA cancer vaccines 232
• Methods of delivery of DNA vaccines 233
• RNA vaccines 233
• Viral vector-based cancer vaccines 234
• Genetically modified cancer cells vaccines 234
• GVAX cancer vaccines 235
• Genetically modified dendritic cells 235
• Use of hematopoietic stem cells for targeted cancer therapy 236
• Companies involved in nucleic acid-based vaccines 236
• Monoclonal antibody gene transfer 237
• Transfer and expression of intracellular adhesion-1 molecules 238
• Other gene-based techniques of immunotherapy of cancer 238
• Fas (Apo-1) 238
• Chemokines 238
• Major Histocompatibility Complex (MHC) Class I 239
• IGF (Insulin-Like Growth Factor) 239
• Inhibition of immunosuppressive function 239
• Delivery of toxic genes to tumor cells for eradication (molecular chemotherapy) 239
• Gene-directed enzyme prodrug therapy 239
• Combination of gene therapy with radiotherapy 240
• Multipronged therapy of cancer with microencapsulated cells 241
• Correction of genetic defects in cancer cells (mutation compensation) 241
• Targeted gene therapy for cancer 242
• Transcriptional targeting for cancer gene therapy 242
• Targeted epidermal growth factor-mediated DNA delivery 242
• Gene-based targeted drug delivery to tumors 243
• Targeting gene expression to hypoxic tumor cells 243
• Targeting gene expression by progression-elevated gene-3 promoter 244
• Targeted delivery of retroviral particles hitchhiking on T cells 244
• Targeting tumors with genetically modified T cells 244
• Targeting tumors by genetically engineered stem cells 245
• Tumor-targeted gene therapy by receptor-mediated endocytosis 245
• Targeted site-specific delivery of anticancer genes by nanoparticles 246
• Immunolipoplex for delivery of p53 gene 246
• Combination of electrogene and electrochemotherapy 246
• Virus-mediated oncolysis 247
• Targeted cancer treatments based on oncolytic viruses 247
• Oncolytic gene therapy 247
• Cytokine-induced killer cells for delivery of an oncolytic virus 248
• Facilitating oncolysis by targeting innate antiviral response by HDIs 248
• Oncolytic HSV 248
• Oncolytic adenoviruses 249
• Oncolytic Coxsackie virus A21 251
• Oncolytic vesicular stomatitis virus 251
• Oncolytic measles virus 251
• Oncolytic paramyxovirus 252
• Oncolytic reovirus 252
• Oncolytic vaccinia virus 252
• Cancer terminator virus 252
• Monitoring of viral-mediated oncolysis by PET 253
• Companies developing oncolytic viruses 253
• Bacteria as novel anticancer gene vectors 254
• Apoptotic approach to improve cancer gene therapy 254
• Concluding remarks on cancer gene therapy 255
• Cancer gene therapy companies 256

5. Delivery strategies according to cancer type and location 259

• Introduction 259
• Bladder cancer 259
• Intravesical drug delivery 259
• Intravesical agents combined with systemic chemotherapy 259
• Targeted anticancer therapy for bladder cancer 260
• Prodrug EOquin for bladder cancer 260
• Antisense treatment of bladder cancer 261
• Gene therapy for bladder cancer 261
• Brain tumors 262
• Methods for evaluation of anticancer drug penetration into brain tumor 262
• Innovative methods of drug delivery for glioblastoma multiforme 262
• Anticancer agents with increased penetration of BBB 263
• Intranasal perillyl alcohol 264
• Combination of chemotherapy with radiotherapy 264
• Local delivery of chemotherapeutic agents into the tumor 264
• Carmustine biodegradable polymer implants 264
• Fibrin glue implants containing anticancer drugs 265
• Biodegradable microspheres containing 5-FU 265
• Magnetically controlled microspheres 266
• Convection-enhanced delivery 266
• Receptor-directed cytotoxin therapy 266
• Delivery of a modified diphtheria toxin conjugated to transferrin 266
• Convection-enhanced delivery with nanoliposomal CPT-11 267
• Monoclonal antibodies targeted to brain tumors 267
• Liposomes for drug delivery to brain tumors 267
• Use of nanoparticles for drug delivery in glioblastoma multiforme 268
• Lipid-coated microbubbles as a delivery vehicle for taxol 268
• Targeted antiangiogenic/apoptotic/cytotoxic therapies for brain tumors 269
• Multiple targeted drugs for brain tumors 269
• Introduction of the chemotherapeutic agent into the CSF pathways 270
• Intraventricular chemotherapy for meningeal cancer 270
• Intrathecal chemotherapy 270
• Increasing the permeability of blood-tumor barrier to anticancer drugs 271
• BBB disruption 271
• Tyrosine kinase inhibitor increases topotecan penetration into CNS 271
• Intra-arterial chemotherapy 272
• Interstitial delivery of dexamethasone for reduction of peritumor edema 272
• Photodynamic therapy for chemosensitization of brain tumors 272
• Nanoparticles for photodynamic therapy of brain tumors 273
• Innovative delivery of radiotherapy to brain tumors 273
• GliaSite Radiation Therapy System 273
• Boron neutron capture therapy for brain tumors 274
• Cell therapy for glioblastoma multiforme 274
• Mesenchymal stem cells to deliver treatment for gliomas 274
• Gene therapy for glioblastoma multiforme 274
• Single-chain antibody-targeted adenoviral vectors 276
• Intravenous gene delivery with nanoparticles into brain tumors 276
• Neural stem cells for drug/gene delivery to brain tumors 276
• Peptides targeted to glial tumor cells 277
• Targeting normal brain cells with an AAV vector encoding interferon-β 277
• Treatment of medulloblastoma by suppressing genes in Shh pathway 278
• Antiangiogenic gene therapy 278
• Anticancer drug delivery by genetically engineered MSCs 279
• RNAi gene therapy of brain cancer 279
• Ligand-directed delivery of dsRNA molecules targeted to EGFR 279
• Virus-mediated oncolytic therapy of brain cancer 279
• Breast Cancer 282
• Combination targeted treatment stops breast cancer growth 282
• Therapies for breast cancer involving innovative methods of drug delivery 282
• Injectable biodegradable polymer delivery system for local chemotherapy 283
• MammoSite brachytherapy 283
• Monoclonal antibodies for breast cancer 283
• Breast cancer vaccines 284
• HER-2 DNA AutoVac™ vaccine 285
• Recombinant adenoviral ErbB-2/neu vaccine 285
• Gene vaccine for breast cancer 286
• Gene therapy for breast cancer 286
• Intratumoral injection of Ad5CMV-p53 287
• Antisense therapy for breast cancer 287
• Inhibitors of growth factors FGF2 and VEGF 287
• Drug delivery for cancer of the cervix and the uterus 288
• Gene therapy for cervical cancer 288
• Delivery of chemoradiation therapy 288
• Cervical cancer vaccines 288
• Leukemia 289
• Clofarabine 289
• Malignant melanoma 289
• Targeted therapies for melanoma 289
• Immunotherapy for malignant melanoma 290
• Gene therapy for malignant melanoma 291
• Neuroblastoma 292
• Genetically modified NSCs for treatment of neuroblastoma 292
• Non-small cell lung cancer 293
• Intratumoral administration of anticancer drugs through a bronchoscope 294
• Aerosol delivery of anticancer agents for lung cancer 294
• Aerosol gene delivery for lung cancer 294
• Ovarian cancer 295
• Innovative drug delivery for ovarian cancer 295
• Intraperitoneal delivery 295
• Gene Therapy for ovarian cancer 296
• Pancreatic cancer 297
• Targeted chemotherapy for pancreatic cancer 297
• Local anticancer drug delivery for pancreatic cancer 297
• Vaccine for pancreatic cancer 298
• Gene therapy for pancreatic cancer 298
• Adenovirus-mediated transfer of vasostatin gene 298
• Rexin-G™ for targeted gene delivery in pancreatic cancer 298
• Targeted Expression of BikDD gene 299
• Prostate cancer 299
• PACLIMER Microspheres 300
• PRX302 300
• Brachytherapy for cancer of prostate 300
• Capridine-beta 301
• LHRH for prostate cancer 301
• LHRH analogs 301
• Histrelin implant 302
• Immunomodulatory drugs 302
• MAbs for prostate cancer 302
• Targeted therapies for prostate cancer 303
• Delivery of cisplatin to prostate cancer by nanoparticles 303
• Delivery of siRNAs to prostate cancer with aptamer-siRNA chimeras 303
• Delivery of siRNA for prostate cancer with metastases 303
• Nanoparticulate delivery of suicide DNA to prostate tumors 303
• PSA-activated protoxin that kills prostate cancer 304
• Targeted drug delivery with nanoparticle-aptamer bioconjugates 304
• Targeting oncogene MDM2 in prostate cancer 305
• Vascular targeting of prostate cancer 305
• Gene therapy for cancer of prostate 305
• Experimental studies 305
• Tumor suppressor gene therapy in prostate cancer 305
• Clinical trials 306
• Combined approaches 306
• Combined autovaccination and hyperthermia 307
• Hepatocellular carcinoma 307

6. Cancer drug delivery markets 309

• Introduction 309
• Global markets for drug delivery 309
• Estimation of cancer drug delivery markets 309
• Methods used for market estimation 309
• Cancer epidemiology 310
• Cost of patient care in cancer 311
• Market forecasts 2007-2017 312
• Cancer drug market 312
• Markets for leukemia 313
• Markets for brain tumors 313
• Geographical distribution of cancer markets 313
• Factors affecting future cancer markets 314
• Market share according to cancer drug delivery technologies 314
• Antiangiogenesis therapies 315
• Antineoplastic drug implants for systemic administration 315
• Antisense therapy and RNAi 316
• Cancer vaccines 316
• Gene therapy 316
• Liposomes for anticancer drugs 316
• Monoclonal antibodies 317
• Strategic aspects of cancer drug delivery 317
• Unmet needs in cancer drug delivery 317
• Future prospects of cancer drug delivery 318
• Cancer drug delivery and pharmacogenomics 318
• Drug delivery for cancer in the postgenomic era 319
• Role of nanobiotechnology in development of cancer drug delivery markets 319
• Expansion of cancer drug delivery markets in developing countries 319
• Drivers for the development of drug delivery technologies in cancer 319

7. References 321

Tables

• Table 1 1: Estimated new cases of cancer in the US at most involved organs - 2007 34
• Table 1 2: Historical landmarks in drug delivery for cancer 37
• Table 2 1: Innovative strategies against cancer 39
• Table 2 2: A classification of antiangiogenic therapies 42
• Table 2 3: Antiangiogenic agents in clinical trials 47
• Table 2 4:Approaches to cancer therapy based on bacteria 48
• Table 2 5: Cell therapy technologies used for cancer 54
• Table 2 6: Non-nucleic acid cancer vaccines without genetic modification 56
• Table 2 7: Cellular pathways as targets for anticancer therapies 73
• Table 2 8: Examples of anticancer agents that target mitochondrial membranes 74
• Table 2 9: Drugs targeting oncogenes 78
• Table 2 10: Cancer therapies based on the P53 99
• Table 2 11: Promise of personalized therapy in cancer 102
• Table 2 12: Companies developing personalized therapy for cancer 103
• Table 3 1: Routes of drug delivery in cancer 110
• Table 3 2: Systemic intravenous drug delivery systems for chemotherapy of cancer 110
• Table 3 3: Microparticles as therapeutic delivery systems in cancer 122
• Table 3 4: Classification of nanobiotechnology approaches to drug delivery in cancer 127
• Table 3 5: Liposome-based anticancer drug delivery 158
• Table 3 6: Approved monoclonal antibodies for cancer 160
• Table 3 7: Anticancer agents linked to monoclonal antibodies 164
• Table 3 8: Monoclonal antibodies in clinical trials for cancer 167
• Table 3 9: Strategies for drug delivery in cancer 174
• Table 3 10: Implant systems for delivery of anticancer drugs into tumors 175
• Table 3 11: Systemic delivery of drugs targeted to the tumor 180
• Table 3 12: Methods of delivery of antiangiogenesis therapies 194
• Table 3 13: Companies developing vascular targeting agents 195
• Table 4 1: Mechanisms of anticancer effect of antisense oligonucleotides 210
• Table 4 2: Methods of delivery of oligonucleotides for cancer therapy 212
• Table 4 3: Companies developing antisense and RNAi therapies for cancer 221
• Table 4 4: Strategies for cancer gene therapy 222
• Table 4 5: Companies developing nucleic acids/genetically modified cells-based cancer vaccines 236
• Table 4 6: Enzyme/prodrug combinations employed in suicide gene therapy 240
• Table 4 7: Mutation compensation strategies used clinically 242
• Table 4 8: Companies developing oncolytic viruses 254
• Table 4 9: Companies involved in cancer gene therapy 256
• Table 5 1: Innovative methods of drug delivery for glioblastoma multiforme 262
• Table 5 2: Strategies for gene therapy of malignant brain tumors 275
• Table 5 3: Therapies for breast cancer involving innovative methods of drug delivery 282
• Table 5 4: Gene therapy for malignant melanoma 291
• Table 5 5: Targeted treatment of non-small-cell lung cancer 293
• Table 5 6: Clinical trials of gene therapy in ovarian cancer 296
• Table 5 7: Methods of drug delivery in pancreatic cancer 297
• Table 5 8: Pharmacological strategies under investigation for cancer of the prostate 299
• Table 5 9: Clinical trials in gene therapy for prostate cancer 306
• Table 5 10: Drug delivery for hepatocellular carcinoma 307
• Table 6 1: Worldwide drug delivery market growth 2007 to 2017 309
• Table 6 2: Estimated worldwide prevalence of cancer according to type of cancer 310
• Table 6 3: Estimated number of cancer patients in major markets 2007-2017 311
• Table 6 4: Worldwide values for therapies of selected cancers from 2007 to 2017 313
• Table 6 5: Geographical distribution of cancer markets 2007-2017 314
• Table 6 6: Market values of cancer drug delivery technologies from 2007-2017 314

Figures

• Figure 1 1: An overview of some key steps in tumor angiogenesis 29
• Figure 2 1: Schematic role of T-helper cells in immune response to cancer 58
• Figure 3 1: Cyclacel' s Penetratin Transport System for delivery of drugs to targets 120
• Figure 3 2: Micelle for drug delivery in cancer 132
• Figure 3 3: Mechanism of action of Targaceutical drugs 181
• Figure 3 4: ALZA' s DUROS implant 193
• Figure 6 1: Unmet needs in cancer drug delivery 318