Drug Delivery in Cancer - technologies, markets and companies

SUMMARY

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 108

• Introduction 108
• Routes of drug delivery in cancer 108
• Intravenous delivery systems for cancer therapy 109
• Oral delivery of anticancer agents 110
• Oral UFT 110
• 5-FU combined with eniluracil 111
• Oral paclitaxel 112
• Oral fluoropyrimidines 112
• Oral satraplatin 113
• Oral PXD101 113
• ARRY-142886 113
• High dose pulse administration of calcitrol 113
• Transdermal drug delivery 113
• Delivery of the photosensitizer drug δ-amino levulinic acid 114
• Transdermal delivery of the methotrexate 114
• Transdermal delivery of peptide cancer vaccines 114
• Intradermal delivery of cancer vaccines by adenoviral vectors 115
• Pulmonary delivery of anticancer agents 115
• Regional intra-arterial delivery of chemotherapy 115
• Gas embolotherapy of tumors 116
• Drug delivery to lymph nodes 116
• Intraperitoneal macrophages as drug delivery vehicle 117
• Challenges of cancer drug delivery 117
• Tumor blood vessel pore barrier to drug delivery 117
• Improvement of drug transport in tumors 117
• Delivery of anticancer drugs to nuclear targets 118
• Innovative formulations for drug delivery in cancer 119
• Cancer targeting with polymeric drugs 119
• Linking anticancer drugs to polyglutamate 120
• Bacterial ghosts as drug delivery systems for anticancer drugs 120
• Microparticles as therapeutic delivery systems in cancer 121
• Subcutaneous injection of microspheres carrying anticancer drugs 121
• Intravascular delivery systems using microparticles 122
• Tumor embolization with drug-eluting beads 122
• Tumor embolization with radioactive microparticles 123
• Microparticles heated by magnetic field 123
• Magnetic targeted microparticle technology 123
• Release of drugs from micelles by ultrasound 123
• Release of drugs from biSphere by ultrasound 124
• Release of drugs from microcapsules by laser 124
• Chemoembolization 125
• Anticancer drugs bound to carbon particles 125
• Anticancer drugs bound to protein microspheres 125
• Nanoerythrosomes 125
• Micronized droplets of olive oil 125
• Nanobiotechnology-based drug delivery for cancer 126
• Nanoparticle formulations for drug delivery in cancer 127
• Anticancer drug particles incorporated in liposomes 127
• Bacterial nanoparticles for encapsulation and chemotherapy delivery 128
• Encapsulating drugs in hydrogel nanoparticles 129
• Exosomes 129
• Folate-linked nanoparticles 130
• Lipid based nanocarriers 130
• Micelles for drug delivery in cancer 130
• Nanoparticle formulations of paclitaxel 132
• Nanoparticles containing albumin and antisense oligonucleotides 132
• Non-aggregating nanoparticles 132
• Pegylated nanoliposomal formulation 133
• Perfluorocarbon nanoparticles 133
• Protosphere nanoparticle technology 133
• Nanoparticles for targeted delivery of drugs into the cancer cells 134
• Antiangiogenic therapy using nanoparticles 135
• Carbon magnetic nanoparticles for targeted drug delivery in cancer 136
• Carbon nanotubes for targeted drug delivery to cancer cells 136
• Fullerenes for enhancing tumor targeting by antibodies 136
• Gold nanoparticles for drug delivery in cancer 137
• Iron oxide magnetic nanoparticle formulation for drug delivery 138
• Lipoprotein nanoparticles targeted to cancer-associated receptors 138
• Magnetic nanoparticles for remote-controlled drug delivery to tumors 138
• Nanocell for targeted drug delivery to tumor 139
• Nanodroplets for site-specific cancer treatment 140
• Phage nanoparticles as antibody-drug conjugates 140
• Polymer nanoparticles for targeted drug delivery in cancer 140
• Polymersomes for targeted cancer drug delivery 140
• Targeted drug delivery with nanoparticle-aptamer bioconjugates 141
• Dendrimers for anticancer drug delivery 142
• Application of dendrimers in boron neutron capture therapy 142
• Application of dendrimers in photodynamic therapy 143
• Dendrimer-based synthetic vector for targeted cancer gene therapy 143
• Devices for nanotechnology-based cancer therapy 144
• Convection-enhanced delivery with nanoliposomal CPT-11 144
• Nanocomposite devices 144
• Nanoengineered silicon for brachytherapy 145
• Nanoparticles combined with physical agents for tumor ablation 145
• Carbon nanotubes for laser-induced cancer destruction 145
• Nanoparticles and thermal ablation 145
• Nanoparticles combined with ultrasound radiation of tumors 146
• Nanoparticles as adjuncts to photodynamic therapy of cancer 146
• Nanoparticles for boron neutron capture therapy 147
• RNA nanotechnology for delivery of cancer therapeutics 147
• Nanocarriers for simultaneous delivery of multiple anticancer agents 148
• Combination of diagnostics and therapeutics for cancer 148
• Biomimetic nanoparticles targeted to tumors 148
• Dendrimer nanoparticles for targeting and imaging tumors 148
• Gold nanorods for diagnosis plus photothermal therapy of cancer 149
• Magnetic nanoparticles for imaging as well as therapy of cancer 149
• pHLIP nanotechnology for detection and targeted therapy of cancer 150
• Radiolabeled carbon nanotubes for tumor imaging and targeting 150
• Targeted therapy with magnetic nanomaterials guided by antibodies 150
• Ultrasonic tumor imaging and targeted chemotherapy by nanobubbles 150
• Polyethylene glycol technology 151
• Enzon's PEG technology 151
• Debiopharm's PEG biconjugate drug delivery platform 152
• Nektar PEGylation 152
• PEG Intron 152
• Single-chain antibody-binding protein technology 153
• Liposomes for anticancer drug delivery 153
• Antibody-targeted liposomes for cancer therapy 154
• AlZA's Stealth liposomes 154
• Boron-containing liposomes 155
• DepoFoam technology 155
• Hyperthermia and liposomal drug delivery 155
• Liposomal doxorubicin formulation with N-octanoyl-glucosylceramide 156
• Liposome-nucleic acid complexes for anticancer drug delivery 156
• Non-pegilated liposomal doxorubicin 156
• Tumor-selective targeted drug delivery via folate-PEG liposomes 156
• Ultrasound-mediated anticancer drug release from liposomes 157
• Companies developing liposome-based anticancer drugs 157
• Emulsion formulations of anticancer drugs 158
• Albumin-based drug carriers 158
• Anticancer drugs that bind to tumors 159
• Monoclonal antibodies 159
• Murine monoclonal antibodies 159
• Humanized MAbs 159
• Actions and uses of monoclonal antibodies in cancer 160
• Targeted antibody-based cancer therapy 160
• Antibody cytokine fusion proteins 160
• Antibody J591 for targeted delivery of anticancer therapy 161
• Anti-Thomsen-Friedenreich antigen MAb 161
• Combining MAbs with anti-CD55 antibody 161
• MAbs targeted to alpha fetaprotein receptor 162
• MAbs targeted to tumor blood vessels 162
• MAbs targeted to HAAH 162
• MAbs for immune activation 162
• Delivery of cancer therapy with MAbs 163
• Antibody-directed enzyme prodrug therapy 164
• Chemically programmed antibodies 164
• Combining diagnostics with therapeutics based on MAbs 165
• Radiolabeled antibodies 165
• Clinical development of MAbs for treatment of cancer 166
• Advantages and limitations of MAbs for cancer therapy 171
• Monoclonal T cell receptors 172
• Radiolabeled somatostatin receptor antagonists 172
• Strategies for drug delivery in cancer 172
• Direct introduction of anticancer drugs into the tumor 174
• Injection into the tumor 174
• Antineoplastic drug implants into tumors 174
• Tumor necrosis therapy 175
• Injection into the arterial blood supply of cancer 175
• Electrochemotherapy 177
• Pressure-induced filtration of drugs across vessels to the tumor 177
• Improving drug transport to tumors 177
• Carbohydrate-enhanced chemotherapy 177
• Dextrans as macromolecular anticancer drug carriers 178
• In situ production of anticancer agents in tumors 178
• Targeted drug delivery in cancer 178
• Affibody molecules for targeted anticancer therapy 180
• Fatty acids as targeting vectors 180
• Genetic targeting of the kinase activity in cancer cells 180
• Heat-activated targeted drug delivery 181
• Novel transporters to target photosensitizers to cancer cell nuclei 181
• Photodynamic therapy of cancer 182
• Radionuclides delivered with receptor targeting technology 182
• Targeting ligands specific for cancer cells 183
• Targeting abnormal DNA in cancer cells 183
• Targeting using a bispecific antibody 183
• Targeted chemotherapy using transporters 184
• Targeted generation of intracellular reactive oxygen species 184
• Targeted cytotoxic peptides 184
• Targeted delivery to receptors found in tumors 185
• Targeted delivery by tumor-activated prodrug therapy 185
• Targeting glutathione S-transferase 187
• Targeting tumors by exploiting leaky blood vessels 187
• Transmembrane Carrier Systems 188
• Transferrin-oligomers as targeting carriers in anticancer drug delivery 188
• Ultrasound and microbubbles for targeted anticancer drug delivery 188
• Ultrasound for targeted delivery of chemotherapeutics 189
• Vitamin B12 and folate for targeting cancer chemotherapy 189
• Drug delivery in relation to circadian rhythms 191
• Implants for systemic delivery of anticancer drugs 191
• Drug-eluting polymer implants 192
• Angiogenesis and drug delivery to tumors 192
• Antiangiogenesis strategies 192
• Targeting tumor endothelial cells 193
• Methods for overcoming limitations of antiangiogenesis approaches 193
• Vascular targeting agents 194
• Alpha-emitting antibodies for vascular targeting 195
• Angiolytic therapy 195
• Anti-phosphatidylserine antibodies as VTA 195
• AS1404 196
• Cadherin inhibitors 196
• Combretastatin A4 Prodrug 197
• Drugs to induce clotting in tumor vessels 197
• Selective permeation of the anticancer agent into the tumor 197
• Targeted delivery of tissue factor 198
• Vascular targeting agents versus antiangiogenesis agents 199
• ZD6126 199
• Delivery of proteins and peptides for cancer therapy 200
• CELLECTRA"! electroporation device 200
• Emisphere's eligen"! system 201
• Diatos Peptide Vector intra-cellular/intra-nuclear delivery technology 201
• Lytic peptides and cancer 201
• Modification of proteins and peptides with polymers 202
• Peptide-based targeting of cancer biomarkers for drug delivery 202
• Peptide-cytokine complexes as vascular targeting agents 203
• Peptide-polymer conjugates with radionuclides 203
• Transduction of proteins in vivo 204
• Tumor targeting by stable toxin (ST) peptides 204
• Cell-based cancer vaccines 204
• Autologous tumor cell vaccines 204
• Vaccines that simultaneously target different cancer antigens 205
• Delivery systems for cancer vaccines 205
• A computational approach to integration of drug delivery methods for cancer 206

4. Antisense, RNAi and Gene Therapy for Cancer 207

• Basics of antisense therapy 207
• Antisense cancer therapy 207
• Mechanisms of anticancer effect of antisense oligonucleotides 208
• Selected antisense drugs in development for cancer 208
• Antisense targeted to ribonucleotide reductase 208
• Targeting C-myb with LR3001 209
• Immune modulatory oligonucleotide 209
• Ribozyme therapy 209
• Antisense drug delivery issues 210
• Strategies to overcome delivery problems of antisense oligonucleotides 210
• Oral delivery of oligonucleotides 210
• Iontophoretic delivery of oligonucleotides 211
• Delivery across the blood-brain barrier 211
• Receptor-mediated endocytosis 211
• Liposomes-mediated oligonucleotide delivery 212
• Antisense delivery in microspheres 212
• Antisense nanoparticles 212
• Peptide nucleic acid delivery 213
• NeugeneÔ