Drug Delivery in Cancer - Technologies, Markets and Companies

NEW YORK, Nov. 30, 2011 /PRNewswire/ -- Reportlinker.com announces that a new market research report is available in its catalogue:

Drug Delivery in Cancer - technologies, markets and companies

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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 2010-2020 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 212 companies involved in developing innovative cancer therapies and methods of delivery are presented along with their 241 collaborations. The bibliography contains over 600 publications that are cited in the report.The report is supplemented with 58 tables and 8 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

Mechanism of DNA damage in Fanconi anemia leading to leukemia 23

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 26

Self-sufficiency of tumor proliferation 26

Apoptosis 27

Therapeutic implications of apoptosis in cancer 27

Autophagy 29

Tumor angiogenesis 29

Acquisition of a potential for unlimited replication 31

Invasion and metastases 31

Tumor suppressor genes and metastases 32

Cancer biomarkers 32

Molecular imaging of cancer 32

Cancer genomics 33

Gene expression profiling in cancer 33

Cancer proteomics 33

Limitations of genomics and proteomics for understanding cancer 34

Cancer microenvironment 34

Epidemiology of cancer 35

Current management of cancer 35

Chemotherapy 36

Limitations of cancer chemotherapy 36

Radiotherapy 36

Brachytherapy 37

Surgery 37

Basics of drug delivery in cancer 37

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

Galectin-3 as a target for inhibiting angiogenesis 43

Inhibitors of endothelial proliferation 43

Inducers of apoptosis of endothelial cells of tumor vessels 44

Lodamin 44

Matrix metalloproteinase inhibitors 44

Monoclonal antibodies with vasculostatic properties 45

PPAR? agonists 46

Rapalogues as antiangiogenic agents 47

VEGF Trap 47

Agents that decrease the permeability of tumor blood vessels 47

Antiangiogenic agents in clinical trials 48

Combination of antiangiogenic with cytotoxic therapy 48

Bacterial anticancer agents 48

Tumor-targeted bacteria 49

Genetically modified Salmonella typhimurium as anticancer agent 50

TAPET (Tumor Amplified Protein Expression Therapy) 50

Bacterial protein for targeted delivery of liposomal cancer drugs 50

Killed but metabolically active (KBMA) bacteria 51

Bacterial toxins targeted to tumors 51

Immunotoxins 51

Escherichia Coli toxins 51

Engineered anthrax toxin 52

Recombinant fusion toxins 52

Type III secretion systems 54

Induction of apoptosis in cancer by bacterial proteins 54

Induction of immune response by bacteriolytic therapy 54

Innovations in cell therapy for cancer 55

Stem cell transplantation for cancer 56

Cancer drug/gene delivery by mesenchymal stem cells 56

Cancer immunotherapy 56

Cytokines 57

Cancer vaccines 57

5T4 as a target for cancer immunotherapy 58

Anti-telomerase vaccine 59

Antigen-specific cancer vaccines 59

Carcinoembryonic antigen-based vaccines 60

Dendritic cells for cancer vaccination 60

Hybrid cell vaccination 62

Adoptive cell therapy 63

Tumor cell vaccines 64

Vaccines that simultaneously target different cancer antigens 65

Concluding remarks about cancer vaccines 66

Chemoimmunotherapy 66

Cancer Vaccine Consortium 66

Innovative methods of radiation delivery 66

Image-guided ultrasound technology for delivery of radiation 67

Respiratory gating technology for radiation therapy 67

Positron therapy 67

Boron neutron capture therapy 68

Application of drug delivery systems to BNCP 68

Use of nanotechnology to enhance BNCT 68

Skeletal Targeted Radiotherapy 69

Irreversible electroporation 69

Methods to overcome multidrug resistance (MDR) 70

P-glycoprotein-mediated MDR 70

MDR-associated protein gene 70

Strategies for overcoming MDR 71

Blocking the action of P-glycoprotein 71

Combination of targeted drugs with different specificities 71

Enzyme Catalyzed Therapeutic Activation 72

Inhibition of DNA repair 72

Iron chelators that overcomes resistance to chemotherapeutics 72

Liposome formulation of drugs 73

Modification of the chemical structure of the anticancer drug 73

Managing resistance to antiapoptotic action of anticancer agents 73

Modulation of SPARC expression 74

Nitric oxide inducers 74

Proton pump inhibitors 74

Repression of Prohibitin1 in drug-resistant cancer cells 74

Targeted cancer therapies 75

Targeting cellular pathways 75

Targeting antigens in virus-associated cancer 75

Targeting HAAH for cancer therapy 76

Targeting the IGF-I receptor 76

Targeting Mcl-1 protein 76

Targeting mitochondrial membranes 76

Targeting tumor lymphatics 78

Targeting tyrosine kinase receptors 78

Inhibitors of bcr-abl tyrosine kinase 79

Inhibition of multiple tyrosine kinases 79

Inhibitors of ErbB tyrosine kinase 79

Targeting the Hedgehog signaling pathway 80

Targeting caspase-8 80

Targeting oncogenes 81

Targeting miRNA for cancer therapeutics 82

Targeting the transferrin receptor-mediated endocytosis pathway 82

Targeted anticancer therapies based on the Rad51 promoter 82

Targeting cancer stem cells 82

Targeting glycolytic pathway in cancer 83

Targeting glycoproteins 84

Tagging cancer with modified sugars 84

Anticancer agents based on glycobiology 84

Targeting cell surface glycoproteins 84

Biofusion for targeted cancer therapy 85

Enhancing the effects of radiation and chemotherapy 85

Sensitizing agents for chemotherapy 86

Tesmilifene for chemosensitization 86

CoFactor to enhance the efficacy of chemotherapy 86

Enzyme-enhanced chemotherapy 86

Sensitizing agents for radiotherapy 87

IPdR 87

Manipulation of tumor oxygenation 87

Hypoxia-based methods to enhance chemotherapy and radiotherapy 88

Hyperbaric oxygen and radiation 88

HIF-1 antagonists to enhance radiotherapy 89

Nonsteroidal antiinflammatory drugs enhance tumor radiosensitivity 89

ONCONASE as radiosensitivity enhancer 89

Hyperthermia and chemotherapy/radiation therapy 89

Techniques for hyperthermia 90

Trimodality therapy: radiation, chemotherapy, and hyperthermia 90

Photodynamic therapy 91

Novel anticancer agents 93

Anti-EphA2 antibodies 93

Antioxidants 93

Brostallicin 93

Agents disrupting folate metabolism 94

Pemetrexed 94

Cell cycle inhibitors 94

Cytotoxic ribonucleases 95

DNA hypomethylating agents 95

Histone-based cancer therapy 95

Histone deacetylase inhibitors 95

Modulation of p300/CBP histone acetyltransferase activity 96

Simulation of endogenous histone for anticancer therapy 96

HSP90 inhibitors 97

Ion channel blockers 97

IOT-101 97

Endovion 98

LPAAT-beta inhibitors 98

Modulation of pyruvate kinase M2 98

P13-kinase inhibitors 98

PARP inhibitors 99

Targeted destruction of BRCA2 deficient tumors by PARP inhibitors 99

Prodrugs 100

Enzyme-activated prodrugs 100

Ascorbic acid as a prodrug for cancer 100

Prolarix 101

Protein kinase G activation 101

Proteasome inhibitors 101

Recombinant human insulin-like growth factor binding protein-3 102

Second generation nucleosides 102

Targeting topoisomerase IB 103

Telomerase inhibitors 103

Therapeutic strategies based on the P53 pathway 104

Therapeutic strategies based on molecular mechanisms 104

Checkpoint activation as a strategy against cancer 104

Deletion-specific targeting for cancer therapy 105

In vivo models for molecularly anticancer drugs 105

Repair-blocking drugs for enhancing effect of chemotherapy 106

Targeting mTOR signaling defects 106

Combining novel anticancer approaches 106

Personalized therapy of cancer 107

Challenges of cancer classification 109

Design of future cancer therapies 110

Personalized drug development in oncology 110

Role of molecular imaging 110

Role of molecular imaging in targeted cancer therapy 111

Screening for personalized anticancer drugs 112

Targeting pathways for personalized cancer therapy 112

3. Drug delivery systems for cancer 113

Introduction 113

Routes of drug delivery in cancer 113

Intravenous delivery systems for cancer therapy 114

Intravenous versus oral ascorbate for treatment of cancer 115

Subcutaneous injection of anticancer agents 115

Oral delivery of anticancer agents 115

Oral UFT 116

5-FU combined with eniluracil 116

Oral paclitaxel 117

Oral fluoropyrimidines 117

Oral satraplatin 118

Oral PXD101 118

ARRY-142886 119

High dose pulse administration of calcitrol 119

Oral gefitinib vs intravenous docetaxel 119

Transdermal drug delivery 119

Delivery of the photosensitizer drug ?-amino levulinic acid 120

Transdermal delivery of the methotrexate 120

Transdermal nitroglycerine for prostate cancer 120

Transdermal delivery of peptide cancer vaccines 121

Intradermal delivery of cancer vaccines by adenoviral vectors 121

Pulmonary delivery of anticancer agents 121

Regional intra-arterial delivery of chemotherapy 122

Gas embolotherapy of tumors 122

Drug delivery to lymph nodes 123

Intraperitoneal macrophages as drug delivery vehicle 123

Challenges of cancer drug delivery 123

Tumor blood vessel pore barrier to drug delivery 123

Improvement of drug transport in tumors 124

Delivery of anticancer drugs to nuclear targets 124

Innovative formulations for drug delivery in cancer 125

Cancer targeting with polymeric drugs 125

Linking anticancer drugs to polyglutamate 126

Improving delivery of protein-polymer anticancer drugs 126

Macromolecules as delivery systems for taxanes 127

Polyamine conjugates as anticancer agents 127

Bacterial ghosts as drug delivery systems for anticancer drugs 127

Microparticles as therapeutic delivery systems in cancer 128

Subcutaneous injection of microspheres carrying anticancer drugs 128

Intravascular delivery systems using microparticles 129

Tumor embolization with drug-eluting beads 129

Tumor embolization with radioactive microparticles 129

Microparticles heated by magnetic field 130

Magnetic targeted microparticle technology 130

Release of drugs from micelles by ultrasound 130

Release of drugs from biSphere by ultrasound 131

Release of drugs from microcapsules by laser 131

Chemoembolization 131

Anticancer drugs bound to carbon particles 132

Anticancer drugs bound to protein microspheres 132

Nanoerythrosomes 132

Micronized droplets of olive oil 132

Nanobiotechnology-based drug delivery for cancer 133

Nanoparticle formulations for drug delivery in cancer 134

Anticancer drug particles incorporated in liposomes 134

Encapsulating drugs in hydrogel nanoparticles 136

Exosomes 136

Folate-linked nanoparticles 137

Lipid based nanocarriers 137

Micelles for drug delivery in cancer 137

Minicells for targeted delivery of nanoscale anticancer therapeutics 139

Nanobombs for cancer 139

Nanodiamonds for local delivery of chemotherapy at site of cancer 140

Nanoparticle formulation for enhancing anticancer efficacy of cisplatin 140

Nanoparticle formulations of paclitaxel 140

Nanoparticles containing albumin and antisense oligonucleotides 141

Non-aggregating nanoparticles 141

Pegylated nanoliposomal formulation 141

Perfluorocarbon nanoparticles 142

Polypeptide-doxorubicin conjugated nanoparticles 142

Protosphere nanoparticle technology 142

Nanoparticles for targeted delivery of drugs into the cancer cells 143

Antiangiogenic therapy using nanoparticles 144

Carbon magnetic nanoparticles for targeted drug delivery in cancer 144

Carbon nanotubes for targeted drug delivery to cancer cells 145

DNA aptamer-micelle for targeted drug delivery in cancer 145

Fullerenes for enhancing tumor targeting by antibodies 145

Gold nanoparticles for targeted drug delivery in cancer 146

Iron oxide magnetic nanoparticle formulation for drug delivery 147

Lipoprotein nanoparticles targeted to cancer-associated receptors 147

Magnetic nanoparticles for remote-controlled drug delivery to tumors 148

Nanobees for targeted delivery of cytolytic peptide melittin 148

Nanocell for targeted drug delivery to tumor 149

Nanodroplets for site-specific cancer treatment 149

Nanoparticle-mediated targeted delivery of peptides into tumors 150

Nanoparticle-mediated targeting of MAPK signaling pathway 150

Nanoparticles for targeted delivery of concurrent chemoradiation 150

Nanostructured hyaluronic acid for targeted drug delivery in cancer 151

Nanoparticles as antibody-drug conjugates 151

Nanoparticle-coated peptides for tumor targeting 151

Polymer nanoparticles for targeted drug delivery in cancer 151

Polymersomes for targeted cancer drug delivery 152

Targeted drug delivery with nanoparticle-aptamer bioconjugates 152

Dendrimers for anticancer drug delivery 153

Application of dendrimers in boron neutron capture therapy 154

Application of dendrimers in photodynamic therapy 154

Dendrimer-based synthetic vector for targeted cancer gene therapy 155

Devices for nanotechnology-based cancer therapy 155

Convection-enhanced delivery with nanoliposomal CPT-11 155

Nanocomposite devices 155

Nanoengineered silicon for brachytherapy 156

Nanosensors for targeted drug delivery in cancer 156

Nanoparticles combined with physical agents for tumor ablation 156

Carbon nanotubes for laser-induced cancer destruction 157

Nanoparticles and thermal ablation 157

Nanoparticles combined with ultrasound radiation of tumors 158

Nanoparticles as adjuncts to photodynamic therapy of cancer 158

Nanoparticles for boron neutron capture therapy 159

RNA nanotechnology for delivery of cancer therapeutics 159

Nanocarriers for simultaneous delivery of multiple anticancer agents 160

Multistage nanoparticle delivery system for penetration into tumor tissue 160

Combination of diagnostics and therapeutics for cancer 160

Biomimetic nanoparticles targeted to tumors 160

Dendrimer nanoparticles for targeting and imaging tumors 160

Gold nanoparticle plus bombesin for imaging and therapy of cancer 161

Gold nanorods for diagnosis plus photothermal therapy of cancer 161

Magnetic nanoparticles for imaging as well as therapy of cancer 162

Nanobialys for combining MRI with delivery of anticancer agents 162

pHLIP nanotechnology for detection and targeted therapy of cancer 162

Radiolabeled carbon nanotubes for tumor imaging and targeting 163

Targeted therapy with magnetic nanomaterials guided by antibodies 163

Ultrasonic tumor imaging and targeted chemotherapy by nanobubbles 163

Future prospects of nanobiotechnology and targeted cancer therapy 164

Polyethylene glycol technology 164

Enzon's PEG technology 164

Debiopharm's PEG biconjugate drug delivery platform 165

Nektar PEGylation 165

PEG Intron 165

Single-chain antibody-binding protein technology 166

Vesicular systems for drug delivery in cancer 166

Liposomes for anticancer drug delivery 167

Antibody-targeted liposomes for cancer therapy 167

AlZA's Stealth liposomes 168

Boron-containing liposomes 168

DepoFoam technology 168

Hyperthermia and liposomal drug delivery 169

Liposomal doxorubicin formulation with N-octanoyl-glucosylceramide 169

Liposome-nucleic acid complexes for anticancer drug delivery 169

Non-pegilated liposomal doxorubicin 170

Tumor-selective targeted drug delivery via folate-PEG liposomes 170

Ultrasound-mediated anticancer drug release from liposomes 170

Companies developing liposome-based anticancer drugs 170

Pharmacosomes for controlled anticancer drug delivery 171

Emulsion formulations of anticancer drugs 172

Albumin-based drug carriers 173

Anticancer drugs that bind to tumors 173

Monoclonal antibodies 173

Murine monoclonal antibodies 173

Humanized MAbs 174

Actions and uses of monoclonal antibodies in cancer 174

Targeted antibody-based cancer therapy 175

Antibody–cytokine fusion proteins 175

Antibody J591 for targeted delivery of anticancer therapy 175

Anti-Thomsen-Friedenreich antigen MAb 175

Combining MAbs with anti-CD55 antibody 176

MAbs targeted to alpha fetaprotein receptor 176

MAbs targeted to tumor blood vessels 176

MAbs targeted to HAAH 176

MAbs for immune activation 177

Delivery of cancer therapy with MAbs 177

Antibody-directed enzyme prodrug therapy 178

Chemically programmed antibodies 178

Combining diagnostics with therapeutics based on MAbs 179

Radiolabeled antibodies 179

Clinical development of MAbs for treatment of cancer 181

Advantages and limitations of MAbs for cancer therapy 184

Antibody drug conjugates 186

Monoclonal T cell receptors 187

Radioactive materials for diagnosis and targeted therapy of cancer 187

Pretargeted radioimmunotherapy of cancer 187

Radiolabeled somatostatin receptor antagonists 187

Theophylline enhances radioiodide uptake by cancer 188

Strategies for drug delivery in cancer 188

Direct introduction of anticancer drugs into the tumor 189

Injection into the tumor 189

Antineoplastic drug implants into tumors 190

Tumor necrosis therapy 190

Injection into the arterial blood supply of cancer 191

Electrochemotherapy 192

Pressure-induced filtration of drugs across vessels to the tumor 193

Improving drug transport to tumors 193

Carbohydrate-enhanced chemotherapy 193

Dextrans as macromolecular anticancer drug carriers 193

In situ production of anticancer agents in tumors 194

Targeted drug delivery in cancer 194

Affibody molecules for targeted anticancer therapy 195

Fatty acids as targeting vectors 195

Genetic targeting of the kinase activity in cancer cells 196

Heat-activated targeted drug delivery 196

Novel transporters to target photosensitizers to cancer cell nuclei 197

Photodynamic therapy of cancer 197

Radionuclides delivered with receptor targeting technology 198

Targeting ligands specific for cancer cells 198

Targeting abnormal DNA in cancer cells 199

Targeting using a bispecific antibody 199

Targeted chemotherapy using transporters 199

Targeted generation of intracellular reactive oxygen species 200

Targeted delivery to receptors found in tumors 200

Targeted delivery by tumor-activated prodrug therapy 200

Targeting glutathione S-transferase 202

Targeting tumors by exploiting leaky blood vessels 202

Targeted drug delivery of anticancer agents with controlled activation 203

Targeted delivery of anticancer agents with ReCODE™ technology 203

Transmembrane Carrier Systems 203

Transferrin-oligomers as targeting carriers in anticancer drug delivery 204

Tumor targeting with peptides 204

Ultrasound and microbubbles for targeted anticancer drug delivery 204

Ultrasound for targeted delivery of chemotherapeutics 205

Vitamin B12 and folate for targeting cancer chemotherapy 206

Cell-based drug delivery in cancer 207

Red blood cells as vehicles for drug delivery 207

Cells as vehicles for gene delivery 208

Drug delivery in relation to circadian rhythms 208

Implants for systemic delivery of anticancer drugs 208

Drug-eluting polymer implants 209

Angiogenesis and drug delivery to tumors 209

Antiangiogenesis strategies 210

Targeting tumor endothelial cells 210

Methods for overcoming limitations of antiangiogenesis approaches 211

Vascular targeting agents 211

Alpha-emitting antibodies for vascular targeting 212

Angiolytic therapy 212

Anti-phosphatidylserine antibodies as VTA 212

ASA404 213

Cadherin inhibitors 213

Combretastatin A4 Prodrug 214

Drugs to induce clotting in tumor vessels 214

Selective permeation of the anticancer agent into the tumor 215

Targeted delivery of tissue factor 215

Vascular targeting agents versus antiangiogenesis agents 216

ZD6126 216

Delivery of proteins and peptides for cancer therapy 217

CELLECTRA™ electroporation device 218

Emisphere's eligen™ system 218

Diatos Peptide Vector intra-cellular/intra-nuclear delivery technology 218

Lytic peptides and cancer 219

Modification of proteins and peptides with polymers 219

Peptide-based targeting of cancer biomarkers for drug delivery 219

Peptide-cytokine complexes as vascular targeting agents 220

Peptide-polymer conjugates with radionuclides 220

Transduction of proteins in vivo 221

Tumor targeting by stable toxin (ST) peptides 221

Image-guided personalized drug delivery in cancer 221

A computational approach to integration of drug delivery methods for cancer 222

4. Delivery of Biological Therapies for Cancer 223

Introduction 223

Antisense therapy 223

Basics of antisense approaches 223

Antisense cancer therapy 223

Mechanisms of anticancer effect of antisense oligonucleotides 224

Selected antisense drugs in development for cancer 224

Antisense targeted to ribonucleotide reductase 224

Immune modulatory oligonucleotide 225

Ribozyme therapy 225

Antisense drug delivery issues 226

Strategies to overcome delivery problems of antisense oligonucleotides 226

Antisense delivery in microspheres 226

Delivery of antisense using nanoparticles 227

Delivery across the blood-brain barrier 227

Delivery of ribozymes 228

Iontophoretic delivery of oligonucleotides 228

Liposomes-mediated oligonucleotide delivery 228

Neugene? antisense drugs 228

Oral delivery of oligonucleotides 229

Peptide nucleic acid delivery 229

Receptor-mediated endocytosis 229

Delivery of ribozymes 230

Combination of antisense and electrochemotherapy 230

Aptamers for combined diagnosis and therapeutics of cancer 231

Antisense compounds in clinical trials 231

RNA interference 232

Basics of RNAi 232

Comparison of antisense and RNAi 232

RNAi applications in oncology 233

siRNA-based cancer immunotherapy 234

Delivery of siRNA in cancer 234

Delivery of siRNA by nanoparticles 235

Delivery of siRNA by nanosize liposomes 235

Lipid nanoparticles for delivery of anticancer siRNAs 236

Polymer nanoparticles for targeted delivery of anticancer siRNA 236

Companies developing cancer therapies based on antisense and RNAi 237

DNA interference 238

Cancer gene therapy 238

Basics of gene therapy 238

Strategies for cancer gene therapy 239

Gene transfer techniques as applied to cancer gene therapy 240

Viral vectors 240

Nonviral vectors 241

A polymer approach to gene therapy for cancer 241

Direct gene delivery to the tumor 242

Injection into tumor 242

Reversible electroporation 243

Hematopoietic gene transfer 244

Genetic modification of human hematopoietic stem cells 244

Gene-based strategies for immunotherapy of cancer (immunogene therapy) 245

Cytokine gene therapy 245

Monoclonal antibody gene transfer 249

Transfer and expression of intracellular adhesion-1 molecules 249

Other gene-based techniques of immunotherapy of cancer 249

Fas (Apo-1) 249

Chemokines 249

Major Histocompatibility Complex (MHC) Class I 250

IGF (Insulin-Like Growth Factor) 250

Inhibition of immunosuppressive function 250

microRNA gene therapy 251

Delivery of toxic genes to tumor cells for eradication (molecular chemotherapy) 251

Gene-directed enzyme prodrug therapy 251

Combination of gene therapy with radiotherapy 252

Multipronged therapy of cancer with microencapsulated cells 253

Correction of genetic defects in cancer cells (mutation compensation) 253

Targeted gene therapy for cancer 254

Transcriptional targeting for cancer gene therapy 254

Targeted epidermal growth factor-mediated DNA delivery 254

Gene-based targeted drug delivery to tumors 254

Targeting gene expression to hypoxic tumor cells 255

Targeting gene expression by progression-elevated gene-3 promoter 255

Targeted delivery of retroviral particles hitchhiking on T cells 256

Targeting tumors with genetically modified T cells 256

Targeting tumors by genetically engineered stem cells 256

Tumor-targeted gene therapy by receptor-mediated endocytosis 257

Targeted site-specific delivery of anticancer genes by nanoparticles 257

Immunolipoplex for delivery of p53 gene 257

Combination of electrogene and electrochemotherapy 258

Virus-mediated oncolysis 258

Targeted cancer treatments based on oncolytic viruses 258

Oncolytic gene therapy 259

Cytokine-induced killer cells for delivery of an oncolytic virus 259

Facilitating oncolysis by targeting innate antiviral response by HDIs 260

Oncolytic HSV 260

Oncolytic adenoviruses 260

Oncolytic Coxsackie virus A21 262

Oncolytic vesicular stomatitis virus 262

Oncolytic measles virus 263

Oncolytic paramyxovirus 263

Oncolytic reovirus 263

Oncolytic vaccinia virus 264

Cancer terminator virus 264

Monitoring of viral-mediated oncolysis by PET 264

Companies developing oncolytic viruses 265

Antiangiogenic therapy for cancer 265

Apoptotic approach to improve cancer gene therapy 266

Bacteria as novel anticancer gene vectors 267

Concluding remarks on cancer gene therapy 267

Cancer gene therapy companies 268

Cell therapy for cancer 270

Cellular immunotherapy for cancer 271

Treatments for cancer by ex vivo mobilization of immune cells 271

Granulocytes as anticancer agents 272

Neutrophil granulocytes in antibody-based immunotherapy of cancer 272

Use of hematopoietic stem cells for targeted cancer therapy 272

Cancer vaccines 273

Cell-based cancer vaccines 273

Autologous tumor cell vaccines 273

Vaccines that simultaneously target different cancer antigens 274

Delivery systems for cell-based cancer vaccines 275

Nucleic acid-based cancer vaccines 275

DNA cancer vaccines 275

Antiangiogenic DNA cancer vaccine 276

Methods of delivery of DNA vaccines 276

RNA vaccines 277

Viral vector-based cancer vaccines 277

Companies involved in nucleic acid-based vaccines 277

Genetically modified cancer cells vaccines 278

GVAX cancer vaccines 279

Genetically modified dendritic cells 279

Multipeptide-based cancer vaccines 280

5. Delivery strategies according to cancer type and location 281

Introduction 281

Bladder cancer 281

Intravesical drug delivery 281

Intravesical agents combined with systemic chemotherapy 281

Targeted anticancer therapy for bladder cancer 282

Prodrug EOquin for bladder cancer 282

Antisense treatment of bladder cancer 283

Gene therapy for bladder cancer 283

Brain tumors 284

Methods for evaluation of anticancer drug penetration into brain tumor 284

Innovative methods of drug delivery for glioblastoma multiforme 284

Delivery of anticancer drugs across the blood-brain barrier 285

Anticancer agents with increased penetration of BBB 285

BBB disruption 286

Nanoparticle-based targeted delivery of chemotherapy across the BBB 287

Tyrosine kinase inhibitor increases topotecan penetration into CNS 288

Bypassing the BBB by alternative methods of drug delivery 288

Intranasal perillyl alcohol 288

Intraarterial chemotherapy 289

Enhancing tumor permeability to chemotherapy 289

Local delivery of chemotherapeutic agents into the tumor 290

Carmustine biodegradable polymer implants 290

Fibrin glue implants containing anticancer drugs. 291

Biodegradable microspheres containing 5-FU 291

Magnetically controlled microspheres 291

Convection-enhanced delivery 291

CED for receptor-directed cytotoxin therapy 291

CED of topotecan 292

CED of a modified diphtheria toxin conjugated to transferrin 292

CED of nanoliposomal CPT-11 293

CED for delivery 131I-chTNT-1/B MAb 293

Anticancer drug formulations for targeted delivery to brain tumors 293

Lipid-coated microbubbles as a delivery vehicle for taxol 293

Liposomes for drug delivery to brain tumors 293

MAbs targeted to brain tumors 294

Multiple targeted drugs for brain tumors 294

Nanoparticles for targeted drug delivery in glioblastoma multiforme 295

Targeted antiangiogenic/apoptotic/cytotoxic therapies 296

Introduction of the chemotherapeutic agent into the CSF pathways 297

Intraventricular chemotherapy for meningeal cancer 297

Intrathecal chemotherapy 297

Interstitial delivery of dexamethasone for reduction of peritumor edema 298

Combination of chemotherapy with radiotherapy 298

Photodynamic therapy for chemosensitization of brain tumors 298

Nanoparticles for photodynamic therapy of brain tumors 299

Innovative delivery of radiotherapy to brain tumors 299

GliaSite Radiation Therapy System 299

Boron neutron capture therapy for brain tumors 299

Cell therapy for glioblastoma multiforme 300

Mesenchymal stem cells to deliver treatment for gliomas 300

Gene therapy for glioblastoma multiforme. 300

Antiangiogenic gene therapy 301

Anticancer drug delivery by genetically engineered MSCs 302

Intravenous gene delivery with nanoparticles into brain tumors 302

Ligand-directed delivery of dsRNA molecules targeted to EGFR 302

Neural stem cells for drug/gene delivery to brain tumors 303

Peptides targeted to glial tumor cells 304

RNAi gene therapy of brain cancer 304

Single-chain antibody-targeted adenoviral vectors 304

Targeting normal brain cells with an AAV vector encoding interferon-? 305

Treatment of medulloblastoma by suppressing genes in Shh pathway 305

Virus-mediated oncolytic therapy of brain cancer 305

Vaccination for glioblastoma multiforme 308

Breast Cancer 308

Therapies for breast cancer involving innovative methods of drug delivery 308

Injectable biodegradable polymer delivery system for local chemotherapy 309

MammoSite brachytherapy 309

Monoclonal antibodies targeted to HER2 receptor 309

Breast cancer vaccines 310

HER-2 DNA AutoVac? vaccine 310

Recombinant adenoviral ErbB-2/neu vaccine 311

Gene vaccine for breast cancer 311

NeuVax 312

Gene therapy for breast cancer 313

Antisense therapy for breast cancer 313

Inhibitors of growth factors FGF2 and VEGF for breast cancer 314

Targeted multi-drug delivery approach to breast cancer 314

Cancer of the cervix and the uterus 314

Gene therapy for cervical cancer 314

Delivery of chemoradiation therapy 314

Cervical cancer vaccines 315

Colorectal cancer 315

Perifosine 315

Oxaliplatin long-circuting liposomes 316

Cancer of the liver 316

Hepatocellular carcinoma 316

Treatment of liver metastases 317

Leukemia 317

Clofarabine 318

Malignant melanoma 318

Targeted therapies for melanoma 319

Immunotherapy for malignant melanoma 319

Gene therapy for malignant melanoma 320

Neuroblastoma 322

Genetically modified NSCs for treatment of neuroblastoma 322

Non-Hodgkin's lymphoma 322

Pixantrone 322

Non-small cell lung cancer 323

Aerosol delivery of anticancer agents for lung cancer 324

Aerosol gene delivery for lung cancer 324

Complex nanoscale pulmonary delivery of drugs for resistant lung cancer 325

Intratumoral administration of anticancer drugs through a bronchoscope 325

Ovarian cancer 325

Innovative drug delivery for ovarian cancer 325

Intraperitoneal delivery 326

Dendritic cell vaccination for ovarian cancer 327

Gene Therapy for ovarian cancer 327

Pancreatic cancer 328

Targeted chemotherapy for pancreatic cancer 328

Local anticancer drug delivery for pancreatic cancer 328

Vaccine for pancreatic cancer 329

Gene therapy for pancreatic cancer 329

Adenovirus-mediated transfer of vasostatin gene 329

Rexin-G? for targeted gene delivery in pancreatic cancer 329

Targeted Expression of BikDD gene 330

Prostate cancer 330

PACLIMER Microspheres 331

PRX302 331

Brachytherapy for cancer of prostate 331

Capridine-beta 332

LHRH for prostate cancer 332

LHRH analogs 332

Histrelin implant 333

Immunomodulatory drugs 333

MAbs for prostate cancer 333

Targeted therapies for prostate cancer 334

Delivery of cisplatin to prostate cancer by nanoparticles 334

Delivery of siRNAs to prostate cancer with aptamer-siRNA chimeras 334

Delivery of siRNA for prostate cancer with metastases 334

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