Drug Delivery in Cancer

Part I: Technologies & Markets

By
Prof. K. K. Jain
MD, FRACS, FFPM

Jain PharmaBiotech
Basel, Switzerland

July 2012

A Jain PharmaBiotech Report

AUTHOR'S

BIOGRAPHY

Professor K. K. Jain is a neurologist/neurosurgeon by training and has been working in

the biotechnology/biopharmaceuticals industry for several years. He received graduate
training in both Europe and USA, has held academic positions in several countries and is
a Fellow of the Faculty of Pharmaceutical Medicine of the Royal College of Physicians of
UK. Currently he is a consultant at Jain PharmaBiotech. Prof. Jain is the author of 440
publications including 21 books (4 as editor) and 50 special reports, which have covered
important areas in biotechnology, gene therapy and biopharmaceuticals.
His other recent books include "Handbook of Nanomedicine" (Springer/Humana 2008,
Chinese edition, Peking University Press 2011, 2nd ed Springer 2012), Textbook of
Personalized Medicine (Springer 2009), "Handbook of Biomarkers" (Springer 2010),
Application of Biotechnology in Cardiovascular Therapeutics (Springer, 2011), and
Application of Biotechnology in Neurology (Springer, 2012, in preparation).

ABOUT

THIS

REPORT

The original report on Drug Delivery in Cancer by the author was published by Decision
Resources Inc in 2000 as an enlargement of the chapter on this topic in his report on
Drug Delivery Technologies (1998), which was also published by Decision Resources. The
second edition was published at Jain PharmaBiotech in 2003 and has been constantly
updated and rewritten since then.

July 2012 (first edition published in 2000)

Copyright 2012 by
Jain PharmaBiotech
Blsiring 7
CH-4057 Basel
Switzerland
Tel & Fax:
Email:
Web site:

+4161-6924461
info@pharmabiotech.ch
http://pharmabiotech.ch/

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted
in any form or by any means, electronic, mechanical, photocopying, or otherwise without the prior written
permission of the Publisher. This report may not be lent, resold or otherwise traded in any manner without the
consent of the Publisher. While all reasonable steps have been taken to ensure the accuracy of the information
presented, the Publisher cannot accept responsibility for inadvertent errors or omissions.

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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 ................................................................................ 42
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 ............................................................................. 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 bacteria as anticancer agents .......................................................... 49
TAPET (Tumor Amplified Protein Expression Therapy) ...................................................... 50

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Bacterial protein for targeted delivery of liposomal cancer drugs ....................................... 51

Killed but metabolically active (KBMA) bacteria .................................................................... 51
Bacterial toxins targeted to tumors .................................................................................... 51
Immunotoxins ............................................................................................................ 51
Escherichia Coli toxins ................................................................................................. 52
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 ......................................................... 55
Innovations in cell therapy for cancer................................................................................ 55
Stem cell transplantation for cancer ................................................................................... 56
Cancer drug/gene delivery by mesenchymal stem cells ......................................................... 56
Cancer immunotherapy ...................................................................................................... 57
Cytokines ........................................................................................................................ 57
Cancer vaccines ............................................................................................................... 57
5T4 as a target for cancer immunotherapy ..................................................................... 59
Anti-telomerase vaccine ............................................................................................... 59
Antigen-specific cancer vaccines ................................................................................... 59
Carcinoembryonic antigen-based vaccines ...................................................................... 60
Dendritic cells for cancer vaccination ............................................................................. 61
Hybrid cell vaccination ................................................................................................. 62
Adoptive cell therapy ................................................................................................... 63
Tumor cell vaccines ..................................................................................................... 65
Vaccines that simultaneously target different cancer antigens ........................................... 66
Concluding remarks about cancer vaccines .......................................................................... 66
Chemoimmunotherapy ..................................................................................................... 66
Cancer Vaccine Consortium ............................................................................................... 67
Innovative methods of radiation delivery .......................................................................... 67
Image-guided ultrasound technology for delivery of radiation ................................................ 67
Respiratory gating technology for radiation therapy.............................................................. 67
Positron therapy .............................................................................................................. 68
Boron neutron capture therapy .......................................................................................... 68
Application of drug delivery systems to BNCP ................................................................. 68
Use of nanotechnology to enhance BNCT........................................................................ 69
Skeletal Targeted Radiotherapy ......................................................................................... 69
Irreversible electroporation ............................................................................................... 70
Methods to overcome multidrug resistance (MDR) ............................................................ 70
P-glycoprotein-mediated MDR............................................................................................ 71
MDR-associated protein gene ............................................................................................ 71
Strategies for overcoming MDR .......................................................................................... 71
Blocking the action of P-glycoprotein ............................................................................. 71
Combination of targeted drugs with different specificities ................................................. 72
Enzyme Catalyzed Therapeutic Activation ....................................................................... 72
Inhibition of DNA repair ............................................................................................... 72
Iron chelators that overcomes resistance to chemotherapeutics ........................................ 73
Liposome formulation of drugs ...................................................................................... 73
Modification of the chemical structure of the anticancer drug ............................................ 73
Managing resistance to antiapoptotic action of anticancer agents ...................................... 74
Modulation of SPARC expression ................................................................................... 74
Nitric oxide inducers .................................................................................................... 74
Proton pump inhibitors ................................................................................................ 74
Repression of Prohibitin1 in drug-resistant cancer cells .................................................... 75
Targeted cancer therapies ................................................................................................. 75
Targeting cellular pathways ............................................................................................... 75
Targeting antigens in virus-associated cancer ...................................................................... 76
Targeting HAAH for cancer therapy .................................................................................... 76
Targeting the IGF-I receptor.............................................................................................. 76
Targeting Mcl-1 protein ..................................................................................................... 77
Targeting mitochondrial membranes................................................................................... 77
Targeting tumor lymphatics ............................................................................................... 78
Targeting tyrosine kinase receptors .................................................................................... 79
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 ......................................................................................................... 81
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

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Targeting cancer stem cells ............................................................................................... 83

Targeting glycolytic pathway in cancer ................................................................................ 83
Targeting glycoproteins .................................................................................................... 84
Tagging cancer with modified sugars ............................................................................. 84
Anticancer agents based on glycobiology........................................................................ 85
Targeting cell surface glycoproteins ............................................................................... 85
Biofusion for targeted cancer therapy ............................................................................ 85
Enhancing the effects of radiation and chemotherapy ....................................................... 86
Sensitizing agents for chemotherapy .................................................................................. 86
Tesmilifene for chemosensitization ................................................................................ 86
CoFactor to enhance the efficacy of chemotherapy .......................................................... 86
Enzyme-enhanced chemotherapy .................................................................................. 87
Sensitizing agents for radiotherapy .................................................................................... 87
IPdR .......................................................................................................................... 87
Manipulation of tumor oxygenation .................................................................................... 88
Hypoxia-based methods to enhance chemotherapy and radiotherapy ................................ 88
Hyperbaric oxygen and radiation ................................................................................... 89
HIF-1 antagonists to enhance radiotherapy .................................................................... 89
Nonsteroidal antiinflammatory drugs enhance tumor radiosensitivity ................................. 89
ONCONASE as radiosensitivity enhancer ........................................................................ 89
Hyperthermia and chemotherapy/radiation therapy .............................................................. 90
Techniques for hyperthermia ........................................................................................ 90
Trimodality therapy: radiation, chemotherapy, and hyperthermia...................................... 90
Photodynamic therapy ...................................................................................................... 91
Novel anticancer agents..................................................................................................... 93
Anti-EphA2 antibodies ...................................................................................................... 93
Antioxidants .................................................................................................................... 94
Brostallicin ...................................................................................................................... 94
Agents disrupting folate metabolism ................................................................................... 94
Pemetrexed ................................................................................................................ 94
Cell cycle inhibitors .......................................................................................................... 95
Cytotoxic ribonucleases .................................................................................................... 95
DNA hypomethylating agents ............................................................................................ 95
Histone-based cancer therapy ........................................................................................... 96
Histone deacetylase inhibitors....................................................................................... 96
Modulation of p300/CBP histone acetyltransferase activity................................................ 97
Simulation of endogenous histone for anticancer therapy ................................................. 97
HSP90 inhibitors .............................................................................................................. 97
Ion channel blockers ........................................................................................................ 98
IOT-101 ..................................................................................................................... 98
Endovion .................................................................................................................... 98
LPAAT-beta inhibitors ....................................................................................................... 98
Modulation of pyruvate kinase M2 ...................................................................................... 99
P13-kinase inhibitors ........................................................................................................ 99
PARP inhibitors ................................................................................................................ 99
Targeted destruction of BRCA2 deficient tumors by PARP inhibitors ................................. 100
Prodrugs ....................................................................................................................... 101
Enzyme-activated prodrugs ........................................................................................ 101
Ascorbic acid as a prodrug for cancer........................................................................... 101
Prolarix .................................................................................................................... 101
Protein kinase G activation .............................................................................................. 101
Proteasome inhibitors ..................................................................................................... 102
Recombinant human insulin-like growth factor binding protein-3 .......................................... 102
Second generation nucleosides ........................................................................................ 103
Targeting topoisomerase IB............................................................................................. 103
Telomerase inhibitors ..................................................................................................... 104
Therapeutic strategies based on the P53 pathway .............................................................. 104
Therapeutic strategies based on molecular mechanisms ...................................................... 105
Checkpoint activation as a strategy against cancer ........................................................ 105
Deletion-specific targeting for cancer therapy ............................................................... 105
In vivo models for molecularly anticancer drugs ............................................................ 106
Repair-blocking drugs for enhancing effect of chemotherapy .......................................... 106
Targeting mTOR signaling defects ............................................................................... 107
Combining novel anticancer approaches ............................................................................ 107
Personalized therapy of cancer ........................................................................................ 108
Challenges of cancer classification .................................................................................... 110
Design of future cancer therapies ..................................................................................... 110
Personalized drug development in oncology....................................................................... 111
Role of molecular imaging .......................................................................................... 111
Role of molecular imaging in targeted cancer therapy .................................................... 112
Screening for personalized anticancer drugs ................................................................. 113

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Targeting pathways for personalized cancer therapy ...................................................... 113

3. Drug delivery systems for cancer........................................................ 115

Introduction..................................................................................................................... 115
Routes of drug delivery in cancer..................................................................................... 115
Intravenous delivery systems for cancer therapy ............................................................... 116
Intravenous versus oral ascorbate for treatment of cancer ............................................. 117
Subcutaneous injection of anticancer agents ..................................................................... 117
Oral delivery of anticancer agents .................................................................................... 117
Oral UFT .................................................................................................................. 118
5-FU combined with eniluracil ..................................................................................... 118
Oral paclitaxel .......................................................................................................... 119
Oral fluoropyrimidines ............................................................................................... 119
Oral satraplatin ......................................................................................................... 120
Oral PXD101 ............................................................................................................. 120
ARRY-142886 ........................................................................................................... 121
High dose pulse administration of calcitrol .................................................................... 121
Oral gefitinib vs intravenous docetaxel ......................................................................... 121
Transdermal drug delivery .............................................................................................. 121
Delivery of the photosensitizer drug -amino levulinic acid ............................................. 122
Transdermal delivery of the methotrexate .................................................................... 122
Transdermal nitroglycerine for prostate cancer ............................................................. 122
Transdermal delivery of peptide cancer vaccines ........................................................... 123
Intradermal delivery of cancer vaccines by adenoviral vectors ........................................ 123
Pulmonary delivery of anticancer agents ........................................................................... 123
Regional intra-arterial delivery of chemotherapy ................................................................ 124
Gas embolotherapy of tumors .......................................................................................... 124
Drug delivery to lymph nodes .......................................................................................... 125
Intraperitoneal macrophages as drug delivery vehicle ......................................................... 125
Challenges of cancer drug delivery ................................................................................... 125
Tumor blood vessel pore barrier to drug delivery ............................................................... 125
Improvement of drug transport in tumors ......................................................................... 126
Delivery of anticancer drugs to nuclear targets .................................................................. 126
Innovative formulations for drug delivery in cancer ........................................................ 127
Cancer targeting with polymeric drugs .............................................................................. 127
Linking anticancer drugs to polyglutamate.................................................................... 128
Improving delivery of protein-polymer anticancer drugs ................................................. 128
Macromolecules as delivery systems for taxanes ................................................................ 129
Polyamine conjugates as anticancer agents ....................................................................... 129
Bacterial ghosts as drug delivery systems for anticancer drugs ............................................ 129
Microparticles as therapeutic delivery systems in cancer ..................................................... 130
Subcutaneous injection of microspheres carrying anticancer drugs .................................. 130
Intravascular delivery systems using microparticles....................................................... 131
Tumor embolization with drug-eluting beads ................................................................ 131
Tumor embolization with radioactive microparticles ....................................................... 131
Microparticles heated by magnetic field ........................................................................ 132
Magnetic targeted microparticle technology .................................................................. 132
Release of drugs from micelles by ultrasound ............................................................... 132
Release of drugs from biSphere by ultrasound .............................................................. 133
Release of drugs from microcapsules by laser ............................................................... 133
Chemoembolization ................................................................................................... 133
Anticancer drugs bound to carbon particles .................................................................. 134
Anticancer drugs bound to protein microspheres ........................................................... 134
Nanoerythrosomes .................................................................................................... 134
Micronized droplets of olive oil .................................................................................... 134
Nanobiotechnology-based drug delivery for cancer ......................................................... 135
Nanoparticle formulations for drug delivery in cancer ......................................................... 136
Anticancer drug particles incorporated in liposomes ....................................................... 136
Encapsulating drugs in hydrogel nanoparticles .............................................................. 138
Exosomes ................................................................................................................ 138
Folate-linked nanoparticles ......................................................................................... 139
Lipid based nanocarriers ............................................................................................ 139
Micelles for drug delivery in cancer .............................................................................. 139
Minicells for targeted delivery of nanoscale anticancer therapeutics ................................. 141
Nanobombs for cancer .................................................................................................... 141
Nanodiamonds for local delivery of chemotherapy at site of cancer ................................. 142
Nanoparticle formulation for enhancing anticancer efficacy of cisplatin ............................. 142
Nanoparticle formulations of paclitaxel ......................................................................... 142
Nanoparticles containing albumin and antisense oligonucleotides .................................... 143
Non-aggregating nanoparticles ................................................................................... 143
Pegylated nanoliposomal formulation ........................................................................... 143

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Perfluorocarbon nanoparticles ..................................................................................... 144

Polypeptide-doxorubicin conjugated nanoparticles ......................................................... 144
Protosphere nanoparticle technology ........................................................................... 144
Nanoparticles for targeted delivery of drugs into the cancer cells ......................................... 145
Antiangiogenic therapy using nanoparticles .................................................................. 146
Carbon magnetic nanoparticles for targeted drug delivery in cancer ................................ 146
Carbon nanotubes for targeted drug delivery to cancer cells ........................................... 147
DNA aptamer-micelle for targeted drug delivery in cancer .............................................. 147
Fullerenes for enhancing tumor targeting by antibodies ................................................. 147
Gold nanoparticles for targeted drug delivery in cancer .................................................. 148
Iron oxide magnetic nanoparticle formulation for drug delivery ....................................... 149
Lipoprotein nanoparticles targeted to cancer-associated receptors................................... 149
Magnetic nanoparticles for remote-controlled drug delivery to tumors.............................. 150
Nanobees for targeted delivery of cytolytic peptide melittin ............................................ 150
Nanocell for targeted drug delivery to tumor ................................................................ 151
Nanodroplets for site-specific cancer treatment ............................................................. 151
Nanoparticle-mediated targeted delivery of peptides into tumors .................................... 152
Nanoparticle-mediated targeting of MAPK signaling pathway .......................................... 152
Nanoparticles for targeted delivery of concurrent chemoradiation .................................... 152
Nanostructured hyaluronic acid for targeted drug delivery in cancer ................................ 153
Nanoparticles as antibody-drug conjugates .................................................................. 153
Nanoparticle-coated peptides for tumor targeting .......................................................... 153
Polymer nanoparticles for targeted drug delivery in cancer ............................................. 153
Polymersomes for targeted cancer drug delivery ........................................................... 154
Targeted drug delivery with nanoparticle-aptamer bioconjugates .................................... 154
Dendrimers for anticancer drug delivery ........................................................................... 155
Application of dendrimers in boron neutron capture therapy ........................................... 156
Application of dendrimers in photodynamic therapy ....................................................... 156
Dendrimer-based synthetic vector for targeted cancer gene therapy................................ 157
Devices for nanotechnology-based cancer therapy ............................................................. 157
Convection-enhanced delivery with nanoliposomal CPT-11 ............................................. 157
Nanocomposite devices .............................................................................................. 157
Nanoengineered silicon for brachytherapy .................................................................... 158
Nanosensors for targeted drug delivery in cancer .......................................................... 158
Nanoparticles combined with physical agents for tumor ablation .......................................... 158
Carbon nanotubes for laser-induced cancer destruction.................................................. 159
Nanoparticles and thermal ablation ............................................................................. 159
Nanoparticles combined with ultrasound radiation of tumors........................................... 160
Nanoparticles as adjuncts to photodynamic therapy of cancer......................................... 160
Nanoparticles for boron neutron capture therapy........................................................... 161
RNA nanotechnology for delivery of cancer therapeutics ..................................................... 161
Nanocarriers for simultaneous delivery of multiple anticancer agents .................................... 162
Multistage nanoparticle delivery system for penetration into tumor tissue ............................. 162
Combination of diagnostics and therapeutics for cancer ...................................................... 162
Biomimetic nanoparticles targeted to tumors ................................................................ 162
Dendrimer nanoparticles for targeting and imaging tumors ............................................ 162
Gold nanoparticle plus bombesin for imaging and therapy of cancer ................................ 163
Gold nanorods for diagnosis plus photothermal therapy of cancer ................................... 163
Magnetic nanoparticles for imaging as well as therapy of cancer ..................................... 164
Nanobialys for combining MRI with delivery of anticancer agents .................................... 164
pHLIP nanotechnology for detection and targeted therapy of cancer ................................ 164
Radiolabeled carbon nanotubes for tumor imaging and targeting..................................... 165
Targeted therapy with magnetic nanomaterials guided by antibodies ............................... 165
Ultrasonic tumor imaging and targeted chemotherapy by nanobubbles ............................ 165
Future prospects of nanobiotechnology and targeted cancer therapy ............................... 166
Polyethylene glycol technology ........................................................................................ 166
Enzon's PEG technology .................................................................................................. 166
Debiopharm's PEG biconjugate drug delivery platform ........................................................ 167
Nektar PEGylation .......................................................................................................... 167
PEG Intron .................................................................................................................... 167
Single-chain antibody-binding protein technology ........................................................... 168
Vesicular systems for drug delivery in cancer .................................................................. 168
Liposomes for anticancer drug delivery ........................................................................... 169
Antibody-targeted liposomes for cancer therapy ................................................................ 169
AlZAs Stealth liposomes ................................................................................................. 170
Boron-containing liposomes............................................................................................. 170
DepoFoam technology .................................................................................................... 170
Hyperthermia and liposomal drug delivery ........................................................................ 171
Liposomal doxorubicin formulation with N-octanoyl-glucosylceramide ................................... 171
Liposome-nucleic acid complexes for anticancer drug delivery ............................................. 171
Non-pegilated liposomal doxorubicin ................................................................................ 172

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Tumor-selective targeted drug delivery via folate-PEG liposomes ......................................... 172

Ultrasound-mediated anticancer drug release from liposomes .............................................. 172
Companies developing liposome-based anticancer drugs ..................................................... 172
Pharmacosomes for controlled anticancer drug delivery.................................................. 173
Emulsion formulations of anticancer drugs ...................................................................... 174
Albumin-based drug carriers............................................................................................ 175
Anticancer drugs that bind to tumors .............................................................................. 175
Monoclonal antibodies ..................................................................................................... 175
Murine monoclonal antibodies .......................................................................................... 175
Humanized MAbs ........................................................................................................... 176
Actions and uses of monoclonal antibodies in cancer .......................................................... 176
Targeted antibody-based cancer therapy .......................................................................... 177
Antibodycytokine fusion proteins ............................................................................... 177
Antibody J591 for targeted delivery of anticancer therapy .............................................. 177
Anti-Thomsen-Friedenreich antigen MAb ...................................................................... 177
Combining MAbs with anti-CD55 antibody .................................................................... 178
MAbs targeted to alpha fetaprotein receptor ................................................................. 178
MAbs targeted to tumor blood vessels ......................................................................... 178
MAbs targeted to HAAH ............................................................................................. 178
Velociximab .............................................................................................................. 179
MAbs for immune activation ............................................................................................ 179
Delivery of cancer therapy with MAbs ............................................................................... 179
Antibody-directed enzyme prodrug therapy ....................................................................... 180
Chemically programmed antibodies .................................................................................. 181
Combining diagnostics with therapeutics based on MAbs ..................................................... 181
Radiolabeled antibodies for detection and targeted therapy of cancer ................................... 181
Clinical development of MAbs for treatment of cancer ......................................................... 183
Advantages and limitations of MAbs for cancer therapy ....................................................... 186
Antibody drug conjugates ............................................................................................... 188
Monoclonal T cell receptors.............................................................................................. 189
Radioactive materials for diagnosis and targeted therapy of cancer ................................ 189
Pretargeted radioimmunotherapy of cancer ....................................................................... 189
Radiolabeled somatostatin receptor antagonists ................................................................. 189
Theophylline enhances radioiodide uptake by cancer .......................................................... 190
Strategies for drug delivery in cancer .............................................................................. 190
Direct introduction of anticancer drugs into the tumor ........................................................ 191
Injection into the tumor ............................................................................................. 191
Antineoplastic drug implants into tumors ..................................................................... 192
Tumor necrosis therapy ............................................................................................. 192
Injection into the arterial blood supply of cancer ........................................................... 193
Electrochemotherapy ................................................................................................. 194
Pressure-induced filtration of drugs across vessels to the tumor...................................... 195
Improving drug transport to tumors ................................................................................. 195
Carbohydrate-enhanced chemotherapy ........................................................................ 195
Dextrans as macromolecular anticancer drug carriers .................................................... 195
In situ production of anticancer agents in tumors .......................................................... 196
Targeted drug delivery in cancer ...................................................................................... 196
Affibody molecules for targeted anticancer therapy ....................................................... 197
Fatty acids as targeting vectors .................................................................................. 197
Genetic targeting of the kinase activity in cancer cells ................................................... 198
Heat-activated targeted drug delivery .......................................................................... 198
Novel transporters to target photosensitizers to cancer cell nuclei ................................... 199
Photodynamic therapy of cancer ................................................................................. 199
Radionuclides delivered with receptor targeting technology ............................................ 200
Targeting ligands specific for cancer cells ..................................................................... 200
Targeting abnormal DNA in cancer cells ....................................................................... 201
Targeting using a bispecific antibody ........................................................................... 201
Targeted chemotherapy using transporters .................................................................. 201
Targeted generation of intracellular reactive oxygen species ........................................... 202
Targeted delivery to receptors found in tumors ............................................................. 202
Targeted delivery by tumor-activated prodrug therapy .................................................. 202
Targeting glutathione S-transferase............................................................................. 204
Targeting tumors by exploiting leaky blood vessels ....................................................... 204
Targeted drug delivery of anticancer agents with controlled activation ............................. 205
Targeted delivery of anticancer agents with ReCODE technology .................................. 205
Transmembrane Carrier Systems ................................................................................ 205
Transferrin-oligomers as targeting carriers in anticancer drug delivery ............................. 206
Tumor targeting with peptides .................................................................................... 206
Ultrasound and microbubbles for targeted anticancer drug delivery ................................. 206
Ultrasound for targeted delivery of chemotherapeutics................................................... 207
Vitamin B12 and folate for targeting cancer chemotherapy ............................................. 208

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Cell-based drug delivery in cancer .................................................................................... 209

Red blood cells as vehicles for drug delivery ................................................................. 209
Cells as vehicles for gene delivery ............................................................................... 210
Drug delivery in relation to circadian rhythms .................................................................... 210
Implants for systemic delivery of anticancer drugs ............................................................. 210
Drug-eluting polymer implants.................................................................................... 211
Angiogenesis and drug delivery to tumors ......................................................................... 211
Antiangiogenesis strategies ............................................................................................. 212
Targeting tumor endothelial cells ................................................................................ 212
Methods for overcoming limitations of antiangiogenesis approaches ................................ 213
Vascular targeting agents ............................................................................................... 213
Alpha-emitting antibodies for vascular targeting ........................................................... 214
Angiolytic therapy ..................................................................................................... 214
Anti-phosphatidylserine antibodies as VTA.................................................................... 214
ASA404 ................................................................................................................... 215
Cadherin inhibitors .................................................................................................... 215
Combretastatin A4 Prodrug ........................................................................................ 216
Drugs to induce clotting in tumor vessels ..................................................................... 216
Selective permeation of the anticancer agent into the tumor .......................................... 217
Targeted delivery of tissue factor ................................................................................ 217
Vascular targeting agents versus antiangiogenesis agents .............................................. 218
ZD6126 ................................................................................................................... 218
Delivery of proteins and peptides for cancer therapy .......................................................... 219
CELLECTRA electroporation device ............................................................................ 220
Emisphere's eligen system....................................................................................... 220
Diatos Peptide Vector intra-cellular/intra-nuclear delivery technology .............................. 220
Lytic peptides and cancer ........................................................................................... 221
Modification of proteins and peptides with polymers ...................................................... 221
Peptide-based targeting of cancer biomarkers for drug delivery ...................................... 221
Peptide-cytokine complexes as vascular targeting agents ............................................... 222
Peptide-polymer conjugates with radionuclides ............................................................. 222
Transduction of proteins in vivo .................................................................................. 223
Tumor targeting by stable toxin (ST) peptides .............................................................. 223
Image-guided personalized drug delivery in cancer ............................................................ 223
A computational approach to integration of drug delivery methods for cancer ........................ 224

4. Delivery of Biological Therapies for Cancer ......................................... 225

Introduction..................................................................................................................... 225
Antisense therapy ............................................................................................................ 225
Basics of antisense approaches ........................................................................................ 225
Antisense cancer therapy ................................................................................................ 225
Mechanisms of anticancer effect of antisense oligonucleotides ............................................. 226
Selected antisense drugs in development for cancer ........................................................... 226
Antisense targeted to ribonucleotide reductase ............................................................. 226
Immune modulatory oligonucleotide ............................................................................ 227
Ribozyme therapy .......................................................................................................... 227
Antisense drug delivery issues ......................................................................................... 228
Strategies to overcome delivery problems of antisense oligonucleotides ................................ 228
Antisense delivery in microspheres .............................................................................. 228
Delivery of antisense using nanoparticles ..................................................................... 229
Delivery across the blood-brain barrier ........................................................................ 229
Delivery of ribozymes ................................................................................................ 230
Iontophoretic delivery of oligonucleotides ..................................................................... 230
Liposomes-mediated oligonucleotide delivery................................................................ 230
Neugene antisense drugs......................................................................................... 230
Oral delivery of oligonucleotides.................................................................................. 231
Peptide nucleic acid delivery ....................................................................................... 231
Receptor-mediated endocytosis .................................................................................. 231
Delivery of ribozymes ................................................................................................ 232
Combination of antisense and electrochemotherapy ........................................................... 232
Aptamers for combined diagnosis and therapeutics of cancer............................................... 233
Antisense compounds in clinical trials ............................................................................... 233
RNA interference ............................................................................................................. 234
Basics of RNAi ............................................................................................................... 234
Comparison of antisense and RNAi ................................................................................... 234
RNAi applications in oncology .......................................................................................... 235
siRNA-based cancer immunotherapy ................................................................................ 236
Delivery of siRNA in cancer ............................................................................................. 236
Delivery of siRNA by nanoparticles .............................................................................. 237
Delivery of siRNA by nanosize liposomes ...................................................................... 237
Lipid nanoparticles for delivery of anticancer siRNAs ...................................................... 238

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Polymer nanoparticles for targeted delivery of anticancer siRNA ...................................... 238

Companies developing cancer therapies based on antisense and RNAi .................................. 239
DNA interference ............................................................................................................. 240
Cancer gene therapy ........................................................................................................ 240
Basics of gene therapy ................................................................................................... 240
Strategies for cancer gene therapy ................................................................................... 241
Gene transfer techniques as applied to cancer gene therapy ................................................ 242
Viral vectors ............................................................................................................. 242
Nonviral vectors ........................................................................................................ 243
A polymer approach to gene therapy for cancer ............................................................ 243
Direct gene delivery to the tumor..................................................................................... 244
Injection into tumor .................................................................................................. 244
Reversible electroporation .......................................................................................... 245
Hematopoietic gene transfer............................................................................................ 246
Genetic modification of human hematopoietic stem cells ................................................ 246
Gene-based strategies for immunotherapy of cancer (immunogene therapy) ......................... 247
Cytokine gene therapy ............................................................................................... 248
Monoclonal antibody gene transfer ................................................................................... 251
Transfer and expression of intracellular adhesion-1 molecules ............................................. 251
Other gene-based techniques of immunotherapy of cancer .................................................. 251
Fas (Apo-1) .............................................................................................................. 251
Chemokines ............................................................................................................. 252
Major Histocompatibility Complex (MHC) Class I ........................................................... 252
IGF (Insulin-Like Growth Factor) ................................................................................. 252
Inhibition of immunosuppressive function ......................................................................... 252
microRNA gene therapy .................................................................................................. 253
Delivery of toxic genes to tumor cells for eradication (molecular chemotherapy) .................... 253
Gene-directed enzyme prodrug therapy ....................................................................... 253
Combination of gene therapy with radiotherapy ................................................................. 254
Multipronged therapy of cancer with microencapsulated cells............................................... 255
Correction of genetic defects in cancer cells (mutation compensation) .................................. 255
Targeted gene therapy for cancer .................................................................................... 256
Transcriptional targeting for cancer gene therapy .......................................................... 256
Targeted epidermal growth factor-mediated DNA delivery .............................................. 256
Gene-based targeted drug delivery to tumors ............................................................... 256
Targeting gene expression to hypoxic tumor cells.......................................................... 257
Targeting gene expression by progression-elevated gene-3 promoter .............................. 257
Targeted delivery of retroviral particles hitchhiking on T cells ......................................... 258
Targeting tumors with genetically modified T cells ......................................................... 258
Targeting tumors by genetically engineered stem cells................................................... 258
Tumor-targeted gene therapy by receptor-mediated endocytosis .................................... 259
Targeted site-specific delivery of anticancer genes by nanoparticles ................................ 259
Immunolipoplex for delivery of p53 gene ..................................................................... 260
Combination of electrogene and electrochemotherapy ................................................... 260
Virus-mediated oncolysis ................................................................................................ 260
Targeted cancer treatments based on oncolytic viruses .................................................. 260
Oncolytic gene therapy .............................................................................................. 261
Cytokine-induced killer cells for delivery of an oncolytic virus ......................................... 261
Facilitating oncolysis by targeting innate antiviral response by HDIs ................................ 262
Oncolytic HSV ........................................................................................................... 262
Oncolytic adenoviruses .............................................................................................. 262
Oncolytic Coxsackie virus A21..................................................................................... 264
Oncolytic vesicular stomatitis virus .............................................................................. 264
Oncolytic measles virus.............................................................................................. 265
Oncolytic paramyxovirus ............................................................................................ 265
Oncolytic reovirus ..................................................................................................... 265
Oncolytic vaccinia virus .............................................................................................. 266
Cancer terminator virus ............................................................................................. 266
Monitoring of viral-mediated oncolysis by PET ............................................................... 267
Companies developing oncolytic viruses ....................................................................... 267
Antiangiogenic therapy for cancer .................................................................................... 267
Apoptotic approach to improve cancer gene therapy ........................................................... 268
Bacteria as novel anticancer gene vectors ......................................................................... 269
Concluding remarks on cancer gene therapy ..................................................................... 269
Cancer gene therapy companies ...................................................................................... 270
Cell therapy for cancer ..................................................................................................... 272
Cellular immunotherapy for cancer ................................................................................... 273
Treatments for cancer by ex vivo mobilization of immune cells ............................................ 273
Granulocytes as anticancer agents ................................................................................... 274
Neutrophil granulocytes in antibody-based immunotherapy of cancer ................................... 274
Use of hematopoietic stem cells for targeted cancer therapy ............................................... 275

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Cancer vaccines ............................................................................................................... 275

Cell-based cancer vaccines .............................................................................................. 275
Autologous tumor cell vaccines ................................................................................... 275
Vaccines that simultaneously target different cancer antigens ......................................... 276
Delivery systems for cell-based cancer vaccines ............................................................ 277
Nucleic acid-based cancer vaccines .................................................................................. 277
DNA cancer vaccines ................................................................................................. 277
Antiangiogenic DNA cancer vaccine ............................................................................. 278
Methods of delivery of DNA vaccines............................................................................ 278
RNA vaccines ............................................................................................................ 279
Viral vector-based cancer vaccines ................................................................................... 279
Companies involved in nucleic acid-based vaccines ............................................................ 280
Genetically modified cancer cells vaccines ......................................................................... 281
GVAX cancer vaccines ................................................................................................ 281
Genetically modified dendritic cells .............................................................................. 281
Multipeptide-based cancer vaccines .................................................................................. 282

5. Delivery strategies according to cancer type and location .................. 283

Introduction..................................................................................................................... 283
Bladder cancer ................................................................................................................. 283
Intravesical drug delivery ................................................................................................ 283
Intravesical agents combined with systemic chemotherapy ................................................. 283
Targeted anticancer therapy for bladder cancer ................................................................. 284
Prodrug EOquin for bladder cancer ................................................................................... 284
Antisense treatment of bladder cancer .............................................................................. 285
Gene therapy for bladder cancer ...................................................................................... 285
Brain tumors .................................................................................................................... 286
Methods for evaluation of anticancer drug penetration into brain tumor ................................ 286
Innovative methods of drug delivery for glioblastoma multiforme ......................................... 286
Delivery of anticancer drugs across the blood-brain barrier ................................................. 287
Anticancer agents with increased penetration of BBB ..................................................... 287
BBB disruption .......................................................................................................... 288
Nanoparticle-based targeted delivery of chemotherapy across the BBB ............................ 289
Tyrosine kinase inhibitor increases topotecan penetration into CNS ................................. 290
Bypassing the BBB by alternative methods of drug delivery ................................................. 290
Intranasal perillyl alcohol ........................................................................................... 290
Intraarterial chemotherapy......................................................................................... 291
Enhancing tumor permeability to chemotherapy ................................................................ 291
Local delivery of chemotherapeutic agents into the tumor ................................................... 292
Carmustine biodegradable polymer implants................................................................. 292
Fibrin glue implants containing anticancer drugs. .......................................................... 293
Biodegradable microspheres containing 5-FU ................................................................ 293
Magnetically controlled microspheres ........................................................................... 293
Convection-enhanced delivery ......................................................................................... 293
CED for receptor-directed cytotoxin therapy ................................................................. 293
CED of topotecan ...................................................................................................... 294
CED of a modified diphtheria toxin conjugated to transferrin .......................................... 294
CED of nanoliposomal CPT-11 ..................................................................................... 295
CED for delivery 131I-chTNT-1/B MAb ........................................................................... 295
Anticancer drug formulations for targeted delivery to brain tumors ...................................... 295
Lipid-coated microbubbles as a delivery vehicle for taxol ................................................ 295
Liposomes for drug delivery to brain tumors ................................................................. 295
MAbs targeted to brain tumors ................................................................................... 296
Multiple targeted drugs for brain tumors ...................................................................... 296
Nanoparticles for targeted drug delivery in glioblastoma multiforme ................................ 297
Targeted antiangiogenic/apoptotic/cytotoxic therapies ................................................... 298
Introduction of the chemotherapeutic agent into the CSF pathways ...................................... 299
Intraventricular chemotherapy for meningeal cancer ..................................................... 299
Intrathecal chemotherapy .......................................................................................... 300
Interstitial delivery of dexamethasone for reduction of peritumor edema............................... 300
Combination of chemotherapy with radiotherapy................................................................ 300
Photodynamic therapy for chemosensitization of brain tumors ............................................. 300
Nanoparticles for photodynamic therapy of brain tumors ................................................ 301
Innovative delivery of radiotherapy to brain tumors ........................................................... 301
GliaSite Radiation Therapy System .............................................................................. 301
Boron neutron capture therapy for brain tumors ........................................................... 301
Cell therapy for glioblastoma multiforme ........................................................................... 302
Mesenchymal stem cells to deliver treatment for gliomas ............................................... 302
Gene therapy for glioblastoma multiforme. ........................................................................ 302
Antiangiogenic gene therapy ...................................................................................... 303
Anticancer drug delivery by genetically engineered MSCs ............................................... 304

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Gene transfer to brain tumor across the BBB by nanobiotechnology ................................ 304
Intravenous gene delivery with nanoparticles into brain tumors ...................................... 304
Ligand-directed delivery of dsRNA molecules targeted to EGFR ....................................... 305
Neural stem cells for drug/gene delivery to brain tumors ............................................... 305
Peptides targeted to glial tumor cells ........................................................................... 306
RNAi gene therapy of brain cancer .............................................................................. 306
Single-chain antibody-targeted adenoviral vectors ........................................................ 307
Targeting normal brain cells with an AAV vector encoding interferon- ............................. 307
Treatment of medulloblastoma by suppressing genes in Shh pathway.............................. 307
Virus-mediated oncolytic therapy of brain cancer .......................................................... 308
Vaccination for glioblastoma multiforme ............................................................................ 310
Breast Cancer .................................................................................................................. 310
Therapies for breast cancer involving innovative methods of drug delivery ............................ 311
Injectable biodegradable polymer delivery system for local chemotherapy ............................ 311
MammoSite brachytherapy .............................................................................................. 312
Monoclonal antibodies targeted to HER2 receptor ............................................................... 312
Breast cancer vaccines ................................................................................................... 312
HER-2 DNA AutoVac vaccine .................................................................................... 313
Recombinant adenoviral ErbB-2/neu vaccine ................................................................ 313
Gene vaccine for breast cancer ................................................................................... 314
NeuVax .................................................................................................................... 315
Gene therapy for breast cancer ........................................................................................ 315
Antisense therapy for breast cancer ................................................................................. 315
Inhibitors of growth factors FGF2 and VEGF for breast cancer .............................................. 316
Targeted multi-drug delivery approach to breast cancer ...................................................... 316
Cancer of the cervix and the uterus ................................................................................. 316
Gene therapy for cervical cancer ...................................................................................... 317
Delivery of chemoradiation therapy .................................................................................. 317
Cervical cancer vaccines ................................................................................................. 317
Colorectal cancer ............................................................................................................. 317
Perifosine ...................................................................................................................... 318
Oxaliplatin long-circuting liposomes.................................................................................. 318
Cancer of the liver............................................................................................................ 318
Hepatocellular carcinoma ................................................................................................ 318
Treatment of liver metastases ......................................................................................... 320
Leukemia ......................................................................................................................... 320
Clofarabine ............................................................................................................... 320
Malignant melanoma ........................................................................................................ 321
Targeted therapies for melanoma..................................................................................... 321
Immunotherapy for malignant melanoma.......................................................................... 322
Gene therapy for malignant melanoma ............................................................................. 322
Neuroblastoma ................................................................................................................ 324
Genetically modified NSCs for treatment of neuroblastoma ................................................. 324
Non-Hodgkin's lymphoma ................................................................................................ 325
Pixantrone .................................................................................................................... 325
Non-small cell lung cancer ............................................................................................... 325
Aerosol delivery of anticancer agents for lung cancer .......................................................... 326
Aerosol gene delivery for lung cancer ............................................................................... 327
Complex nanoscale pulmonary delivery of drugs for resistant lung cancer ............................. 327
Intratumoral administration of anticancer drugs through a bronchoscope .............................. 328
Ovarian cancer ................................................................................................................. 328
Innovative drug delivery for ovarian cancer ....................................................................... 328
Intraperitoneal delivery .................................................................................................. 329
Dendritic cell vaccination for ovarian cancer ...................................................................... 329
Gene Therapy for ovarian cancer ..................................................................................... 330
Pancreatic cancer ............................................................................................................ 330
Targeted chemotherapy for pancreatic cancer.................................................................... 331
Local anticancer drug delivery for pancreatic cancer ........................................................... 331
Vaccine for pancreatic cancer .......................................................................................... 331
Gene therapy for pancreatic cancer .................................................................................. 331
Adenovirus-mediated transfer of vasostatin gene .......................................................... 332
Rexin-G for targeted gene delivery in pancreatic cancer .............................................. 332
Targeted Expression of BikDD gene ............................................................................. 332
Prostate cancer ................................................................................................................ 333
PACLIMER Microspheres .................................................................................................. 333
PRX302 ........................................................................................................................ 334
Brachytherapy for cancer of prostate ................................................................................ 334
Capridine-beta ............................................................................................................... 334
LHRH for prostate cancer ................................................................................................ 335
LHRH analogs ........................................................................................................... 335
Histrelin implant ....................................................................................................... 335

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Immunomodulatory drugs ............................................................................................... 335

MAbs for prostate cancer ................................................................................................ 335
Targeted therapies for prostate cancer ............................................................................. 336
Delivery of cisplatin to prostate cancer by nanoparticles................................................. 336
Delivery of siRNAs to prostate cancer with aptamer-siRNA chimeras ................................ 336
Delivery of siRNA for prostate cancer with metastases ................................................... 337
PSA-activated protoxin that kills prostate cancer ........................................................... 337
Targeted drug delivery with nanoparticle-aptamer bioconjugates .................................... 337
Targeted delivery of a nanoparticulate platinum prodrug ................................................ 338
Targeting oncogene MDM2 in prostate cancer ............................................................... 338
Vascular targeting of prostate cancer ........................................................................... 338
Gene therapy for cancer of prostate ................................................................................. 339
Experimental studies ................................................................................................. 339
Nanoparticule-based gene therapy for prostate cancer ................................................... 339
Tumor suppressor gene therapy in prostate cancer ....................................................... 339
Vaccines for prostate cancer ....................................................................................... 340
Clinical trials of gene therapy for prostate cancer .......................................................... 340
Combined approaches ............................................................................................... 341
Combined autovaccination and hyperthermia ................................................................ 342

6. Cancer drug delivery markets ............................................................. 343

Introduction..................................................................................................................... 343
Global markets for drug delivery ...................................................................................... 343
Estimation of cancer drug delivery markets ....................................................................... 343
Methods used for market estimation ............................................................................ 343
Cancer epidemiology ................................................................................................. 344
Cost of patient care in cancer ..................................................................................... 345
Market forecasts 2011-2021 ............................................................................................ 346
Cancer drug market ....................................................................................................... 346
Markets for leukemia ................................................................................................. 347
Markets for brain tumors ............................................................................................ 347
Geographical distribution of cancer markets ................................................................. 347
Factors affecting future cancer markets ............................................................................ 348
Market share according to cancer drug delivery technologies .......................................... 348
Antiangiogenesis therapies .............................................................................................. 349
Antineoplastic drug implants for systemic administration .................................................... 349
Antisense therapy and RNAi ............................................................................................ 349
Cancer vaccines ............................................................................................................. 350
Gene therapy ................................................................................................................ 350
Liposomes for anticancer drugs........................................................................................ 350
Monoclonal antibodies .................................................................................................... 351
Strategic aspects of cancer drug delivery ........................................................................ 351
Unmet needs in cancer drug delivery ............................................................................... 351
Future prospects of cancer drug delivery ......................................................................... 352
Cancer drug delivery and pharmacogenomics .................................................................... 352
Drug delivery for cancer in the postgenomic era ................................................................ 353
Role of nanobiotechnology in development of cancer drug delivery markets .......................... 353
Expansion of cancer drug delivery markets in developing countries ...................................... 353
Drivers for the development of drug delivery technologies in cancer ..................................... 353

7. References .......................................................................................... 355

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1-1: Estimated new cases of cancer in the US at most involved organs 2011 ......................... 35
1-2: Historical landmarks in drug delivery for cancer ............................................................. 38
2-1: Innovative strategies against cancer ............................................................................. 39
2-2: A classification of antiangiogenic therapies .................................................................... 42
2-3: Antiangiogenic agents in clinical trials ........................................................................... 48
2-4:Approaches to cancer therapy based on bacteria ............................................................. 49
2-5: Cell therapy technologies used for cancer ...................................................................... 55
2-6: Non-nucleic acid cancer vaccines without genetic modification ......................................... 58
2-7: Cellular pathways as targets for anticancer therapies ...................................................... 75
2-8: Examples of anticancer agents that target mitochondrial membranes ............................... 77
2-9: Drugs targeting oncogenes .......................................................................................... 81
2-10: Cancer therapies based on the P53 ........................................................................... 104
2-11: Promise of personalized therapy in cancer ................................................................. 108
2-12: Companies developing personalized therapy for cancer ............................................... 108
3-1: Routes of drug delivery in cancer ............................................................................... 116

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3-2: Systemic intravenous drug delivery systems for chemotherapy of cancer ........................ 116
3-3: Microparticles as therapeutic delivery systems in cancer ............................................... 130
3-4: Classification of nanobiotechnology approaches to drug delivery in cancer ....................... 135
3-5: Approved anticancer drugs using nanocarriers ............................................................. 136
3-6: Clinical trials of anticancer drugs using nanocarriers ..................................................... 136
3-7: Liposome-based anticancer drug delivery .................................................................... 173
3-8: Approved monoclonal antibodies for cancer ................................................................. 176
3-9: Anticancer agents linked to monoclonal antibodies ....................................................... 179
3-10: Monoclonal antibodies in clinical trials for cancer ........................................................ 183
3-11: Antibody drug conjugates in clinical trials for cancer ................................................... 188
3-12: Strategies for drug delivery in cancer ........................................................................ 190
3-13: Implant systems for delivery of anticancer drugs into tumors ....................................... 192
3-14: Systemic delivery of drugs targeted to the tumor ....................................................... 197
3-15: Methods of delivery of antiangiogenesis therapies ....................................................... 212
3-16: Companies developing vascular targeting agents ........................................................ 213
4-1: Mechanisms of anticancer effect of antisense oligonucleotides........................................ 226
4-2: Methods of delivery of oligonucleotides for cancer therapy............................................. 228
4-3: Antisense oligonucleotides in clinical trials for cancer .................................................... 233
4-4: Companies developing antisense and RNAi therapies for cancer ..................................... 239
4-5: Strategies for cancer gene therapy ............................................................................. 241
4-6: Enzyme/prodrug combinations employed in suicide gene therapy ................................... 253
4-7: Mutation compensation strategies used clinically .......................................................... 255
4-8: Companies developing oncolytic viruses ...................................................................... 267
4-9: Companies involved in cancer gene therapy................................................................. 270
4-10: Cell therapy technologies used for cancer .................................................................. 272
4-11: Companies developing nucleic acids/genetically modified cells-based cancer vaccines ..... 280
5-1: Innovative methods of drug delivery for glioblastoma multiforme ................................... 286
5-2: Strategies for gene therapy of malignant brain tumors .................................................. 302
5-3: Therapies for breast cancer involving innovative methods of drug delivery ...................... 311
5-4: Drug delivery for hepatocellular carcinoma .................................................................. 319
5-5: Gene therapy for malignant melanoma ....................................................................... 323
5-6: Targeted treatment of non-small cell lung cancer ......................................................... 326
5-7: Clinical trials of gene therapy in ovarian cancer ............................................................ 330
5-8: Methods of drug delivery in pancreatic cancer .............................................................. 331
5-9: Pharmacological strategies under investigation for cancer of the prostate ........................ 333
5-10: Clinical trials of gene therapy for prostate cancer ....................................................... 341
6-1: Worldwide drug delivery market growth 2011 to 2021 .................................................. 343
6-2: Estimated worldwide prevalence of cancer according to type of cancer ............................ 344
6-3: Estimated number of cancer patients in major markets 2011-2021................................. 345
6-4: Worldwide anticancer drug sales for selected cancers from 2011 to 2021 ........................ 347
6-5: Geographical distribution of cancer markets 2011-2021 ................................................ 348
6-6: Market values of cancer drug delivery technologies from 2011-2021 ............................... 348

Figures
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2-2:
3-1:
3-2:
3-3:
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5-1:
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An overview of some key steps in tumor angiogenesis. .................................................. 30

Targeting tumors with light-emitting engineered bacteria ............................................... 50
Schematic role of T-helper cells in immune response to cancer ....................................... 60
Cyclacel's Penetratin Transport System for delivery of drugs to targets .......................... 127
Micelle for drug delivery in cancer ............................................................................. 140
Mechanism of action of Targaceutical drugs ................................................................ 198
ALZA's DUROS implant ............................................................................................ 211
A concept of targeted drug delivery to GBM across the BBB .......................................... 289
Unmet needs in cancer drug delivery ......................................................................... 352

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