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Drug Delivery in Cancer - technologies, markets and companies

Notes

Drug delivery strategies vary according to the type and location of cancer. This report will provide an in-depth analysis of innovative cancer therapies as well as methods of delivery.

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

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

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

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

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

The market value of drug delivery technologies and the anticancer drugs are difficult to separate. Cancer market estimates from 2013-2023 are given according to organs involved and the types of cancer as well as according to technologies. Distribution of the into major regions is also described.

Profiles of 227 companies involved in developing innovative cancer therapies and methods of delivery are presented along with their 260 collaborations. The bibliography contains over 650 publications that are cited in the report.The report is supplemented with 67 tables and 10 figures.

Table of Contents

Part - I: Technologies & Markets

0. Executive Summary

1. Introduction to cancer therapy

  • Molecular biology of cancer
    • The genesis of cancer
      • Normal cell cycle and growth
      • Oncogenes
      • Tumor Suppressor Genes
      • Role of microRNAs in cancer
      • Role of Bub 1 gene in cell division
      • Mechanism of DNA damage in Fanconi anemia leading to leukemia
      • Accumulation of random mutations
      • Chromosomal instability
      • Aneuploidy
      • Telomeres and cancer
      • DNA methylation and cancer
      • Anticancer treatments based on RNA regulation of genes
    • Hallmarks of cancer
    • Self-sufficiency of tumor proliferation
    • Apoptosis
      • Therapeutic implications of apoptosis in cancer
      • Autophagy
    • Tumor angiogenesis
    • Oxidative stress and cancer
    • Acquisition of a potential for unlimited replication
    • Invasion and metastases
      • Tumor suppressor genes and metastases
  • Cancer biomarkers
    • Molecular imaging of cancer
  • Cancer genomics
    • Gene expression profiling in cancer
  • Cancer proteomics
  • Limitations of genomics and proteomics for understanding cancer
  • Cancer microenvironment
  • Epidemiology of cancer
  • Current management of cancer
    • Chemotherapy
      • Limitations of cancer chemotherapy
    • Radiotherapy
      • Brachytherapy
    • Surgery
  • Basics of drug delivery in cancer
    • Role of mechanical forces in tumor growth and delivery of therapy
  • Methods of assessing drug delivery in cancer
    • Positron emission tomography (PET)
  • Historical landmarks in cancer drug delivery

2. Innovative treatments for cancer

  • Introduction
  • Selective estrogen receptor modulators
  • Antiangiogenic strategies for cancer
    • Development of antiangiogenic therapies
    • Classification of antiangiogenic agents
    • Examples of antiangiogenic agents
      • ACE-041
      • Angiopoietin-2 as a target
      • Chemotherapy at lower than maximum tolerated dose
      • Galectin-3 as a target for inhibiting angiogenesis
      • Inhibitors of endothelial proliferation
      • Inducers of apoptosis of endothelial cells of tumor vessels
      • Lodamin
      • Matrix metalloproteinase inhibitors
      • Monoclonal antibodies with vasculostatic properties
      • PPARα agonists
      • Rapalogues as antiangiogenic agents
      • VEGF Trap
    • Agents that decrease the permeability of tumor blood vessels
    • Antiangiogenic agents in clinical trials
    • Antiangiogenic therapy resistance
    • Combination of antiangiogenic with cytotoxic therapy
  • Bacterial anticancer agents
    • Tumor-targeted bacteria
      • Live bacteria for delivering radioactive anticancer agents
      • Genetically modified bacteria as anticancer agents
      • TAPET (Tumor Amplified Protein Expression Therapy)
      • Bacterial protein for targeted delivery of liposomal cancer drugs
    • Killed but metabolically active (KBMA) bacteria
    • Bacterial toxins targeted to tumors
      • Immunotoxins
      • Escherichia Coli toxins
      • Engineered anthrax toxin
      • Recombinant fusion toxins
    • Type III secretion systems
    • Induction of apoptosis in cancer by bacterial proteins
    • Induction of immune response by bacteriolytic therapy
  • Innovations in cell therapy for cancer
    • Stem cell transplantation for cancer
    • Cancer drug/gene delivery by mesenchymal stem cells
  • Cancer immunotherapy
    • Cytokines
    • Cancer vaccines
      • 5T4 as a target for cancer immunotherapy
      • Adoptive cell therapy
      • Antigen-specific cancer vaccines
      • Carcinoembryonic antigen-based vaccines
      • Carbohydrate-based cancer vaccines
      • Dendritic cells for cancer vaccination
      • Hybrid cell vaccination
      • SMART vaccines
      • Tumor cell vaccines
      • Vaccines that simultaneously target different cancer antigens
      • Vaccines based on multiple tumor-associated peptides
    • Cancer Vaccine Consortium
    • Chemoimmunotherapy
    • Concluding remarks about cancer vaccines
    • Targeted delivery of peptides to tumor-associated macrophages
    • Targeting cancer stem cells
  • Innovative methods of radiation delivery
    • Image-guided ultrasound technology for delivery of radiation
    • Respiratory gating technology for radiation therapy
    • Positron therapy
    • Boron neutron capture therapy
      • Application of drug delivery systems to BNCP
      • Use of nanotechnology to enhance BNCT
  • Ion channels and transporters in cancer
  • Irreversible electroporation
  • Methods to overcome multidrug resistance (MDR)
    • Mechanism of MDR
      • MDR-associated protein gene
      • P-glycoprotein-mediated MDR
    • Strategies for overcoming MDR
      • Blocking the action of P-glycoprotein
      • Combination of targeted drugs with different specificities
      • Enzyme Catalyzed Therapeutic Activation
      • Inhibition of DNA repair
      • Iron chelators that overcomes resistance to chemotherapeutics
      • Liposome formulation of anticancer drugs
      • Modification of the chemical structure of the anticancer drug
      • Managing resistance to antiapoptotic action of anticancer agents
      • Modulation of SPARC expression
      • Nitric oxide inducers
      • Proton pump inhibitors
      • Repression of Prohibitin1 in drug-resistant cancer cells
  • Targeted cancer therapies
    • Targeting cellular pathways
    • Targeting antigens in virus-associated cancer
    • Targeting the IGF-I receptor
    • Targeting Mcl-1 protein
    • Targeting mitochondrial membranes
    • Targeting tumor lymphatics
    • Targeting tyrosine kinase receptors
      • Inhibitors of bcr-abl tyrosine kinase
      • Inhibition of multiple tyrosine kinases
      • Inhibitors of ErbB tyrosine kinase
    • Targeting the Hedgehog signaling pathway
    • Targeting caspase-8
    • Targeting metallodrugs to tumor cells
    • Targeting oncogenes
    • Targeting miRNA for cancer therapeutics
    • Targeting the transferrin receptor-mediated endocytosis pathway
    • Targeted anticancer therapies based on the Rad51 promoter
    • Targeting cancer stem cells
    • Targeting glycolytic pathway in cancer
    • Targeting glycoproteins
      • Tagging cancer with modified sugars
      • Anticancer agents based on glycobiology
      • Targeting cell surface glycoproteins
      • Biofusion for targeted cancer therapy
  • Enhancing the effects of radiation and chemotherapy
    • Sensitizing agents for chemotherapy
      • Tesmilifene for chemosensitization
      • CoFactor to enhance the efficacy of chemotherapy
      • Enzyme-enhanced chemotherapy
    • Sensitizing agents for radiotherapy
      • IPdR
      • Ultrasound for enhancing response to radiation
    • Manipulation of tumor oxygenation
      • Hypoxia-based methods to enhance chemotherapy and radiotherapy
      • Hyperbaric oxygen and radiation
      • HIF-1 antagonists to enhance radiotherapy
      • Nonsteroidal antiinflammatory drugs enhance tumor radiosensitivity
      • ONCONASE as radiosensitivity enhancer
    • Hyperthermia and chemotherapy/radiation therapy
      • Techniques for hyperthermia
      • Trimodality therapy: radiation, chemotherapy, and hyperthermia
    • Photodynamic therapy
  • Novel anticancer agents
    • Anti-EphA2 antibodies
    • Antioxidants
    • Brostallicin
    • Agents disrupting folate metabolism
      • Pemetrexed
    • Cell cycle inhibitors
    • Cytotoxic ribonucleases
    • DNA hypomethylating agents
    • Histone-based cancer therapy
      • Histone deacetylase inhibitors
      • Modulation of p300/CBP histone acetyltransferase activity
      • Simulation of endogenous histone for anticancer therapy
    • HSP90 inhibitors
    • Ion channel blockers
      • IOT-101
      • Endovion
    • LPAAT-beta inhibitors
    • Modulation of pyruvate kinase M2
    • P13-kinase inhibitors
    • PARP inhibitors
      • Targeted destruction of BRCA2 deficient tumors by PARP inhibitors
    • Prodrugs
      • Enzyme-activated prodrugs
      • Ascorbic acid as a prodrug for cancer
      • Prolarix
    • Protein kinase G activation
    • Proteasome inhibitors
    • Recombinant human insulin-like growth factor binding protein-3
    • Second generation nucleosides
    • Targeting topoisomerase IB
    • Telomerase inhibitors
    • Therapeutic strategies based on the P53 pathway
    • Therapeutic strategies based on molecular mechanisms
      • Checkpoint activation as a strategy against cancer
      • Deletion-specific targeting for cancer therapy
      • In vivo models for molecularly anticancer drugs
      • Repair-blocking drugs for enhancing effect of chemotherapy
      • Targeting mTOR signaling defects
    • Combining novel anticancer approaches
  • Personalized therapy of cancer
    • Challenges of cancer classification
    • Design of future cancer therapies
    • Personalized drug development in oncology
      • Role of molecular imaging
      • Role of molecular imaging in targeted cancer therapy
      • Screening for personalized anticancer drugs
      • Targeting pathways for personalized cancer therapy

3. Drug delivery systems for cancer

  • Introduction
  • Routes of drug delivery in cancer
    • Intravenous delivery systems for cancer therapy
      • Intravenous versus oral ascorbate for treatment of cancer
    • Subcutaneous injection of anticancer agents
    • Oral delivery of anticancer agents
      • Oral UFT
      • 5-FU combined with eniluracil
      • Oral paclitaxel
      • Oral fluoropyrimidines
      • Oral satraplatin
      • Oral PXD101
      • ARRY-142886
      • High dose pulse administration of calcitrol
      • Oral gefitinib vs intravenous docetaxel
    • Transdermal drug delivery
      • Delivery of the photosensitizer drug delta;-amino levulinic acid
      • Nanoemulsion-based delivery of caffeine for skin cancer
      • Transdermal delivery of methotrexate
      • Transdermal nitroglycerine for prostate cancer
      • Transdermal delivery of peptide cancer vaccines
      • Intradermal delivery of cancer vaccines by adenoviral vectors
    • Pulmonary delivery of anticancer agents
    • Regional intra-arterial delivery of chemotherapy
    • Gas embolotherapy of tumors
    • Drug delivery to lymph nodes
    • Intraperitoneal macrophages as drug delivery vehicle
    • Challenges of cancer drug delivery
    • Tumor blood vessel pore barrier to drug delivery
    • Improvement of drug transport in tumors
    • Delivery of anticancer drugs to nuclear targets
  • Innovative formulations for drug delivery in cancer
    • Cancer targeting with polymeric drugs
      • Linking anticancer drugs to polyglutamate
      • Improving delivery of protein-polymer anticancer drugs
    • Macromolecules as delivery systems for taxanes
    • Polyamine conjugates as anticancer agents
    • Bacterial vectors as drug delivery systems for anticancer drugs
    • Microparticles as therapeutic delivery systems in cancer
      • Subcutaneous injection of microspheres carrying anticancer drugs
      • Intravascular delivery systems using microparticles
      • Tumor embolization with drug-eluting beads
      • Tumor embolization with radioactive microparticles
      • Microparticles heated by magnetic field
      • Magnetic targeted microparticle technology
      • Release of drugs from biSphere by ultrasound
      • Release of drugs from micelles by ultrasound
      • Release of drugs from microcapsules by laser
      • Chemoembolization
      • Anticancer drugs bound to carbon particles
      • Anticancer drugs bound to protein microspheres
      • Nanoerythrosomes
      • Micronized droplets of olive oil
  • Nanobiotechnology-based drug delivery for cancer
    • Nanoparticle formulations for drug delivery in cancer
      • Anticancer drug particles incorporated in liposomes
      • Doxorubicin nanocarriers
      • Encapsulating drugs in hydrogel nanoparticles
      • Exosomes
      • Folate-linked nanoparticles
      • Lipid based nanocarriers
      • Micelles for drug delivery in cancer
      • Minicells for targeted delivery of nanoscale anticancer therapeutics
      • Nanobombs for cancer
      • Nanodiamonds for local delivery of chemotherapy at site of cancer
      • Nanoparticle formulation for enhancing anticancer efficacy of cisplatin
      • Nanoparticle formulations of paclitaxel
      • Nanoparticles containing albumin and antisense oligonucleotides
      • Non-aggregating nanoparticles
      • Pegylated nanoliposomal formulation
      • Perfluorocarbon nanoparticles
      • Protosphere nanoparticle technology
    • Nanoparticles-based targeted delivery of drugs for cancer
      • Antiangiogenic therapy using nanoparticles
      • Carbon magnetic nanoparticles for targeted drug delivery in cancer
      • Carbon nanotubes for targeted drug delivery to cancer cells
      • DNA aptamer-micelle for targeted drug delivery in cancer
      • Fullerenes for enhancing tumor targeting by antibodies
      • Gold nanoparticles for targeted drug delivery in cancer
      • Iron oxide magnetic nanoparticle formulation for drug delivery
      • Lipoprotein nanoparticles targeted to cancer-associated receptors
      • Magnetic nanoparticles for remote-controlled drug delivery to tumors
      • Nanobees for targeted delivery of cytolytic peptide melittin
      • Nanocell for targeted drug delivery to tumor
      • Nanodroplets for site-specific cancer treatment
      • Nanoparticle-mediated targeted delivery of peptides into tumors
      • Nanoparticle-mediated targeting of MAPK signaling pathway
      • Nanoparticles for targeted delivery of concurrent chemoradiation
      • Nanostructured hyaluronic acid for targeted drug delivery in cancer
      • Nanoparticles as antibody-drug conjugates
      • Nanoparticle-coated peptides for tumor targeting
      • Nanoparticle-mediated delivery of multiple anticancer agents
      • Polymer nanoparticles for targeted drug delivery in cancer
      • Polymersomes for targeted cancer drug delivery
      • Targeted drug delivery with nanoparticle-aptamer bioconjugates
      • Targeted nanoparticles delivery of cisplatin to mitochondrial genome
      • Time-delayed, dual-drug nanoparticle delivery system for cancer
    • Dendrimers for anticancer drug delivery
      • Application of dendrimers in boron neutron capture therapy
      • Application of dendrimers in photodynamic therapy
      • Dendrimer-based synthetic vector for targeted cancer gene therapy
    • Devices for nanotechnology-based cancer therapy
      • Convection-enhanced delivery with nanoliposomal CPT-11
      • Nanocomposite devices
      • Nanoengineered silicon for brachytherapy
      • Nanosensors for targeted drug delivery in cancer
    • Nanoparticles combined with physical agents for tumor ablation
      • Carbon nanotubes for laser-induced cancer destruction
      • Nanoparticles and thermal ablation
      • Nanoparticles combined with ultrasound radiation of tumors
      • Nanoparticles as adjuncts to photodynamic therapy of cancer
      • Nanoparticles for boron neutron capture therapy
    • RNA nanotechnology for delivery of cancer therapeutics
    • Nanocarriers for simultaneous delivery of multiple anticancer agents
    • Multistage nanoparticle delivery system for penetration into tumor tissue
    • Combination of diagnostics and therapeutics for cancer
      • Biomimetic nanoparticles targeted to tumors
      • Dendrimer nanoparticles for targeting and imaging tumors
      • Gold nanoparticle plus bombesin for imaging and therapy of cancer
      • Gold nanorods for diagnosis plus photothermal therapy of cancer
      • Magnetic nanoparticles for imaging as well as therapy of cancer
      • Nanobialys for combining MRI with delivery of anticancer agents
      • pHLIP nanotechnology for detection and targeted therapy of cancer
      • Polymer nanobubbles for targeted and controlled drug delivery
      • Biomimetic nanoparticles targeted to tumors
      • Dendrimer nanoparticles for targeting and imaging tumors
      • Gold nanoparticle plus bombesin for imaging and therapy of cancer
      • Gold nanorods for diagnosis plus photothermal therapy of cancer
      • Magnetic nanoparticles for imaging as well as therapy of cancer
      • Nanobialys for combining MRI with delivery of anticancer agents
      • pHLIP nanotechnology for detection and targeted therapy of cancer
      • Polymer nanobubbles for targeted and controlled drug delivery
      • Radiolabeled carbon nanotubes for tumor imaging and targeting
      • Targeted therapy with magnetic nanomaterials guided by antibodies
      • Ultrasonic tumor imaging and targeted chemotherapy by nanobubbles
      • Future prospects of nanobiotechnology and targeted cancer therapy
  • Polyethylene glycol technology
    • Enzon's PEG technology
    • Debiopharm's PEG biconjugate drug delivery platform
    • Nektar PEGylation
    • PEG Intron
  • Single-chain antibody-binding protein technology
  • Vesicular systems for drug delivery in cancer
  • Liposomes for anticancer drug delivery
    • Antibody-targeted liposomes for cancer therapy
    • ALZA's Stealth liposomes
    • Boron-containing liposomes
    • DepoFoam technology
    • Hyperthermia and liposomal drug delivery
    • Liposomal doxorubicin formulation with N-octanoyl-glucosylceramide
    • Liposome-nucleic acid complexes for anticancer drug delivery
    • Non-pegilated liposomal doxorubicin
    • Tumor-selective targeted drug delivery via folate-PEG liposomes
    • Ultrasound-mediated anticancer drug release from liposomes
    • Companies developing liposome-based anticancer drugs
  • Pharmacosomes for controlled anticancer drug delivery
  • Emulsion formulations of anticancer drugs
  • Albumin-based drug carriers
  • Anticancer drugs that bind to tumors
  • Monoclonal antibodies
    • Murine MAbs
    • Humanized MAbs
    • Actions and uses of monoclonal antibodies in cancer
    • Targeted antibody-based cancer therapy
      • Antibody-cytokine fusion proteins
      • Antibody J591 for targeted delivery of anticancer therapy
      • Anti-Thomsen-Friedenreich antigen MAb
      • Combining MAbs with anti-CD55 antibody
      • MAbs targeted to alpha fetaprotein receptor
      • MAbs targeted to tumor blood vessels
      • Velociximab
    • MAbs for immune activation
    • Delivery of cancer therapy with MAbs
    • Antibody-directed enzyme prodrug therapy
    • Chemically programmed antibodies
    • Combining diagnostics with therapeutics based on MAbs
    • Radiolabeled antibodies for detection and targeted therapy of cancer
    • Other innovations for administration of antibodies
      • Bispecific antibodies
      • Trifunctional antibodies
      • Tetravalent bispecific antibodies
      • Immunotoxins
      • Immunoliposomes
      • Combined use of MAbs and cytokines
      • huHMFG1-huDNase I
      • MAbs that selectively target cancer
    • NanoMAbs for targeting cancer
    • Advantages and limitations of MAbs for cancer therapy
    • Antibody-drug conjugates
      • Kadcyla
      • Adcetris
    • Current status and future trends in antibody-based cancer drugs
  • Monoclonal T cell receptor technology
  • Radioactive materials for diagnosis and targeted therapy of cancer
    • Pretargeted radioimmunotherapy of cancer
    • Radiolabeled somatostatin receptor antagonists
    • Theophylline enhances radioiodide uptake by cancer
  • Strategies for drug delivery in cancer
    • Direct introduction of anticancer drugs into the tumor
      • Injection into the tumor
      • Antineoplastic drug implants into tumors
      • Tumor necrosis therapy
      • Injection into the arterial blood supply of cancer
      • Electrochemotherapy
      • Pressure-induced filtration of drugs across vessels to the tumor
    • Improving drug transport to tumors
      • Carbohydrate-enhanced chemotherapy
      • Dextrans as macromolecular anticancer drug carriers
      • In situ production of anticancer agents in tumors
    • Strategies for increasing drug penetration into solid cancers
    • Selective destruction of cancer cells
      • Sphingolipids
      • Hyperbaric oxygen
      • Targeting response to transformation-induced oxidative stress
      • Targeting enzymes to prevent proliferation of cancer cells
    • Targeted drug delivery in cancer
      • Affibody molecules for targeted anticancer therapy
      • Fatty acids as targeting vectors
      • Genetic targeting of the kinase activity in cancer cells
      • Heat-activated targeted drug delivery
      • Novel transporters to target photosensitizers to cancer cell nuclei
      • Photodynamic therapy of cancer
      • Radionuclides delivered with receptor targeting technology
      • Targeting ligands specific for cancer cells
      • Targeting abnormal DNA in cancer cells
      • Targeted delivery by tumor-activated prodrug therapy
      • Targeting glutathione S-transferase
      • Targeting tumors by exploiting leaky blood vessels
      • Targeted drug delivery of anticancer agents with controlled activation
      • Targeted delivery of anticancer agents with ReCODE™ technology
      • Transmembrane Carrier Systems
      • Transferrin-oligomers as targeting carriers in anticancer drug delivery
      • Tumor targeting with peptides
      • Ultrasound and microbubbles for targeted anticancer drug delivery
      • Ultrasound for targeted delivery of chemotherapeutics
      • Vitamin B12 and folate for targeting cancer chemotherapy
    • Cell-based drug delivery in cancer
      • Red blood cells as vehicles for drug delivery
      • Cells as vehicles for gene delivery
    • Drug delivery in relation to circadian rhythms
    • Implants for systemic delivery of anticancer drugs
      • Drug-eluting polymer implants
    • Angiogenesis and drug delivery to tumors
    • Antiangiogenesis strategies
      • Targeting tumor endothelial cells
      • Methods for overcoming limitations of antiangiogenesis approaches
    • Vascular targeting agents
      • Alpha-emitting antibodies for vascular targeting
      • Angiolytic therapy
      • Anti-phosphatidylserine antibodies as VTA
      • Vadimezan
      • Cadherin inhibitors
      • Fosbretabulin tromethamine
      • Drugs to induce clotting in tumor vessels
      • Selective permeation of the anticancer agent into the tumor
      • Targeted delivery of tissue factor
      • Vascular targeting agents versus antiangiogenesis agents
      • ZD6126
    • Delivery of proteins and peptides for cancer therapy
      • CELLECTRA™ electroporation device
      • Emisphere's Eligen™ system
      • Diatos Peptide Vector intra-cellular/intra-nuclear delivery technology
      • Lytic peptides and cancer
      • Modification of proteins and peptides with polymers
      • Peptide-based targeting of cancer biomarkers for drug delivery
      • Peptide-cytokine complexes as vascular targeting agents
      • Peptide-polymer conjugates with radionuclides
      • Transduction of proteins in vivo
      • Tumor targeting by stable toxin (ST) peptides
    • Image-guided personalized drug delivery in cancer
    • A computational approach to integration of drug delivery methods for cancer

4. Delivery of Biological Therapies for Cancer

  • Introduction
  • Antisense therapy
    • Basics of antisense approaches
    • Antisense cancer therapy
    • Mechanisms of anticancer effect of antisense oligonucleotides
    • Selected antisense drugs in development for cancer
      • Antisense targeted to ribonucleotide reductase
      • Immune modulatory oligonucleotide
    • Ribozyme therapy
    • Spiegelmers
    • Antisense drug delivery issues
    • Strategies to overcome delivery problems of antisense oligonucleotides
      • Antisense delivery in microspheres
      • Delivery of antisense using nanoparticles
      • Delivery across the blood-brain barrier
      • Delivery of ribozymes
      • Iontophoretic delivery of oligonucleotides
      • Liposomes-mediated oligonucleotide delivery
      • Neugene™ antisense drugs
      • Oral delivery of oligonucleotides
      • Peptide nucleic acid delivery
      • Receptor-mediated endocytosis
      • Delivery of ribozymes
    • Combination of antisense and electrochemotherapy
    • Aptamers for combined diagnosis and therapeutics of cancer
    • Antisense compounds in clinical trials
  • RNA interference
    • Basics of RNAi
    • Comparison of antisense and RNAi
    • RNAi applications in oncology
    • siRNA-based cancer immunotherapy
    • Delivery of siRNA in cancer
      • Delivery of siRNA by nanoparticles
      • Delivery of siRNA by nanosize liposomes
      • Lipid nanoparticles for delivery of anticancer siRNAs
      • Polymer nanoparticles for targeted delivery of anticancer siRNA
    • Companies developing cancer therapies based on antisense and RNAi
  • DNA interference
  • Cancer gene therapy
    • Basics of gene therapy
    • Strategies for cancer gene therapy
    • Gene transfer techniques as applied to cancer gene therapy
      • Viral vectors
      • Nonviral vectors
      • A polymer approach to gene therapy for cancer
    • Direct gene delivery to the tumor
      • Injection into tumor
      • Reversible electroporation
    • Hematopoietic gene transfer
      • Genetic modification of human hematopoietic stem cells
    • Gene-based strategies for immunotherapy of cancer (immunogene therapy)
      • Cytokine gene therapy
    • Monoclonal antibody gene transfer
    • Transfer and expression of intracellular adhesion-1 molecules
    • Other gene-based techniques of immunotherapy of cancer
      • Fas (Apo-1)
      • Chemokines
      • Major Histocompatibility Complex (MHC) Class I
      • IGF (Insulin-Like Growth Factor)
    • Inhibition of immunosuppressive function
    • microRNA gene therapy
    • Delivery of toxic genes to tumor cells for eradication (molecular chemotherapy)
      • Gene-directed enzyme prodrug therapy
    • Combination of gene therapy with radiotherapy
    • Multipronged therapy of cancer with microencapsulated cells
    • Correction of genetic defects in cancer cells (mutation compensation)
    • Targeted gene therapy for cancer
      • Transcriptional targeting for cancer gene therapy
      • Targeted epidermal growth factor-mediated DNA delivery
      • Gene-based targeted drug delivery to tumors
      • Targeting gene expression to hypoxic tumor cells
      • Targeting gene expression by progression-elevated gene-3 promoter
      • Targeted delivery of retroviral particles hitchhiking on T cells
      • Targeting tumors with genetically modified T cells
      • Targeting tumors by genetically engineered stem cells
      • Tumor-targeted gene therapy by receptor-mediated endocytosis
      • Targeted site-specific delivery of anticancer genes by nanoparticles
      • Immunolipoplex for delivery of p53 gene
      • Combination of electrogene and electrochemotherapy
    • Virus-mediated oncolysis
      • Targeted cancer treatments based on oncolytic viruses
      • Oncolytic gene therapy
      • Cytokine-induced killer cells for delivery of an oncolytic virus
      • Facilitating oncolysis by targeting innate antiviral response by HDIs
      • Oncolytic HSV
      • Oncolytic adenoviruses
      • Oncolytic Coxsackie virus A21
      • Oncolytic vesicular stomatitis virus
      • Oncolytic measles virus
      • Oncolytic paramyxovirus
      • Oncolytic reovirus
      • Oncolytic vaccinia virus
      • Cancer terminator virus
      • Monitoring of viral-mediated oncolysis by PET
      • Companies developing oncolytic viruses
    • Antiangiogenic therapy for cancer
    • Apoptotic approach to improve cancer gene therapy
    • Bacteria as novel anticancer gene vectors
    • Concluding remarks on cancer gene therapy
    • Cancer gene therapy companies
  • Cell therapy for cancer
    • Cellular immunotherapy for cancer
    • Treatments for cancer by ex vivo mobilization of immune cells
    • Granulocytes as anticancer agents
    • Neutrophil granulocytes in antibody-based immunotherapy of cancer
    • Use of hematopoietic stem cells for targeted cancer therapy
  • Cancer vaccines
    • Cell-based cancer vaccines
      • Autologous tumor cell vaccines
      • Vaccines that simultaneously target different cancer antigens
      • Delivery systems for cell-based cancer vaccines
      • Intra-lymph node injections of cancer vaccine antigens
    • Nucleic acid-based cancer vaccines
      • DNA cancer vaccines
      • Antiangiogenic DNA cancer vaccine
      • Methods of delivery of DNA vaccines
      • RNA vaccines
    • Viral vector-based cancer vaccines
    • Companies involved in nucleic acid-based vaccines
    • Genetically modified cancer cells vaccines
      • GVAX cancer vaccines
      • Genetically modified dendritic cells
    • Multipeptide-based cancer vaccines

5. Delivery strategies according to cancer type and location

  • Introduction
  • Bladder cancer
    • Intravesical drug delivery
    • Intravesical agents combined with systemic chemotherapy
    • Targeted anticancer therapy for bladder cancer
    • Prodrug EOquin for bladder cancer
    • Antisense treatment of bladder cancer
    • Gene therapy for bladder cancer
  • Brain tumors
    • Methods for evaluation of anticancer drug penetration into brain tumor
    • Innovative methods of drug delivery for glioblastoma multiforme
    • Delivery of anticancer drugs across the blood-brain barrier
      • Anticancer agents with increased penetration of BBB
      • BBB disruption
      • Nanoparticle-based targeted delivery of chemotherapy across the BBB
      • Tyrosine kinase inhibitor increases topotecan penetration into CNS
    • Bypassing the BBB by alternative methods of drug delivery
      • Intranasal perillyl alcohol
      • Intraarterial chemotherapy
    • Enhancing tumor permeability to chemotherapy
    • Local delivery of chemotherapeutic agents into the tumor
      • Carmustine biodegradable polymer implants
      • Fibrin glue implants containing anticancer drugs
      • Biodegradable microspheres containing 5-FU
      • Magnetically controlled microspheres
    • Convection-enhanced delivery
      • CED for receptor-directed cytotoxin therapy
      • CED of topotecan
      • CED of a modified diphtheria toxin conjugated to transferrin
      • CED of nanoliposomal CPT-11
      • CED for delivery 131I-chTNT-1/B MAb
    • Anticancer drug formulations for targeted delivery to brain tumors
      • Intravenous delivery of anticancer agents bearing transferrin
      • Liposomes for drug delivery to brain tumors
      • MAbs targeted to brain tumors
      • Multiple targeted drugs for brain tumors
      • Nanoparticles for targeted drug delivery in glioblastoma multiforme
      • Targeted antiangiogenic/apoptotic/cytotoxic therapies
    • Introduction of the chemotherapeutic agent into the CSF pathways
      • Intraventricular chemotherapy for meningeal cancer
      • Intrathecal chemotherapy
    • Interstitial delivery of dexamethasone for reduction of peritumor edema
    • Combination of chemotherapy with radiotherapy
    • Photodynamic therapy for chemosensitization of brain tumors
      • Nanoparticles for photodynamic therapy of brain tumors
    • Innovative delivery of radiotherapy to brain tumors
      • GliaSite Radiation Therapy System
      • Boron neutron capture therapy for brain tumors
    • Cell therapy for glioblastoma multiforme
      • Mesenchymal stem cells to deliver treatment for gliomas
      • Stem cell-based therapy targeting EGFR in GBM
    • Gene therapy for glioblastoma multiforme
      • Antiangiogenic gene therapy
      • Anticancer drug delivery by genetically engineered MSCs
      • Gene transfer to brain tumor across the BBB by nanobiotechnology
      • Intravenous gene delivery with nanoparticles into brain tumors
      • Ligand-directed delivery of dsRNA molecules targeted to EGFR
      • Neural stem cells for drug/gene delivery to brain tumors
      • Peptides targeted to glial tumor cells
      • RNAi gene therapy of brain cancer
      • Single-chain antibody-targeted adenoviral vectors
      • Targeting normal brain cells with an AAV vector encoding interferon-β
      • Treatment of medulloblastoma by suppressing genes in Shh pathway
      • Virus-mediated oncolytic therapy of glioblastoma multiforme
    • Vaccination for glioblastoma multiforme
      • Cell-based vaccines for GBM
      • Peptide vaccine to target the cancer survival protein surviving in GBM
  • Breast Cancer
    • Therapies for breast cancer involving innovative methods of drug delivery
    • Injectable biodegradable polymer delivery system for local chemotherapy
    • MammoSite brachytherapy
    • Monoclonal antibodies targeted to HER2 receptor
    • Breast cancer vaccines
      • HER-2 DNA AutoVac™ vaccine
      • Recombinant adenoviral ErbB-2/neu vaccine
      • Gene vaccine for breast cancer
      • NeuVax
    • Gene therapy for breast cancer
    • Antisense therapy for breast cancer
    • Inhibitors of growth factors FGF2 and VEGF for breast cancer
    • Targeted multi-drug delivery approach to breast cancer
  • Cancer of the cervix and the uterus
    • Gene therapy for cervical cancer
    • Delivery of chemoradiation therapy
    • Cervical cancer vaccines
  • Colorectal cancer
    • Perifosine
    • Oxaliplatin long-circuting liposomes
  • Cancer of the liver
    • Hepatocellular carcinoma
    • Treatment of liver metastases
  • Gastrointestinal cancer
    • Gastrointestinal stromal tumor
  • Hematological malignancies
    • Leukemia
      • Clofarabine
      • Idelalisib for CLL
    • Non-Hodgkin's lymphoma
      • Idelalisib for NHL
      • Pixantrone
  • Malignant melanoma
    • Targeted therapies for melanoma
    • Immunotherapy for malignant melanoma
    • Gene therapy for malignant melanoma
  • Nasopharangeal carcinoma
    • Synergistic effect of gene therapy with 5-FU
  • Neuroblastoma
    • Genetically modified NSCs for treatment of neuroblastoma
  • Non-small cell lung cancer
    • Aerosol delivery of anticancer agents for lung cancer
    • Aerosol gene delivery for lung cancer
    • Complex nanoscale pulmonary delivery of drugs for resistant lung cancer
    • Intratumoral administration of anticancer drugs through a bronchoscope
  • Ovarian cancer
    • Innovative drug delivery for ovarian cancer
    • Intraperitoneal delivery
    • Targeting Notch pathway to overcome resistance to chemotherapy
    • Dendritic cell vaccination for ovarian cancer
    • Gene Therapy for ovarian cancer
  • Pancreatic cancer
    • Delivery of chemotherapy for pancreatic cancer
      • Local drug delivery
      • Targeted chemotherapy for pancreatic cancer
      • Transport properties of pancreatic cancer and gemcitabine delivery
    • Vaccine for pancreatic cancer
    • Gene therapy for pancreatic cancer
      • Correction of altered genes
      • Targeted gene therapy
      • Targeting in pancreatic adenocarcinoma with cell surface antigens
      • Targeted Expression of BikDD gene
      • Viral oncolysis in pancreatic cancer
  • Prostate cancer
    • Alpha emitter radium-223 for targeting bone metastases in cancer
    • Brachytherapy for cancer of prostate
      • Brachytherapy via paravertebral approach lymph node metastases
    • Capridine-beta
    • LHRH for prostate cancer
      • LHRH analogs
      • Histrelin implant
    • Immunomodulatory drugs
    • MAbs for prostate cancer
    • PACLIMER Microspheres
    • PRX302
    • Targeted therapies for prostate cancer
      • Delivery of cisplatin to prostate cancer by nanoparticles
      • Delivery of siRNAs to prostate cancer with aptamer-siRNA chimeras
      • Delivery of siRNA for prostate cancer with metastases
      • Gold nanoparticles targeted to laminin receptor in prostate cancer
      • PSA-activated protoxin that kills prostate cancer
      • Targeted drug delivery with nanoparticle-aptamer bioconjugates
      • Targeted delivery of a nanoparticulate platinum prodrug
      • Targeting oncogene MDM2 in prostate cancer
      • Vascular targeting of prostate cancer
    • Gene therapy for cancer of prostate
      • Experimental studies
      • Nanoparticule-based gene therapy for prostate cancer
      • Tumor suppressor gene therapy in prostate cancer
      • Vaccines for prostate cancer
      • Clinical trials of gene therapy for prostate cancer
    • Viral oncolysis for prostate cancer
    • Combined approaches
    • Combined autovaccination and hyperthermia

6. Cancer drug delivery markets

  • Introduction
    • Global markets for drug delivery
    • Estimation of cancer drug delivery markets
      • Methods used for market estimation
      • Cancer epidemiology
      • Cost of patient care in cancer
  • Market forecasts 2013-2023
    • Cancer drug market
      • Markets for leukemia
      • Markets for brain tumors
      • Geographical distribution of cancer markets
    • Factors affecting future cancer markets
  • Market share according to cancer drug delivery technologies
    • Antiangiogenesis therapies
    • Antineoplastic drug implants for systemic administration
    • Antisense therapy and RNAi
    • Cancer vaccines
    • Gene therapy
    • Liposomes for anticancer drugs
    • Monoclonal antibodies
  • Strategic aspects of cancer drug delivery
  • Unmet needs in cancer drug delivery
  • Future prospects of cancer drug delivery
    • Cancer drug delivery and pharmacogenomics
    • Drug delivery for cancer in the postgenomic era
    • Role of nanobiotechnology in development of cancer drug delivery markets
    • Expansion of cancer drug delivery markets in developing countries
    • Drivers for the development of drug delivery technologies in cancer

7. References

Tables

  • Table 1-1: Estimated new cases of cancer in the US at most involved organs - 2012
  • Table 1-2: Historical landmarks in drug delivery for cancer
  • Table 2-1: Innovative strategies against cancer
  • Table 2-2: A classification of antiangiogenic therapies
  • Table 2-3: Antiangiogenic agents in clinical trials
  • Table 2-4: Approaches to cancer therapy based on bacteria
  • Table 2-5: Cell therapy technologies used for cancer
  • Table 2-6: Non-nucleic acid cancer vaccines without genetic modification
  • Table 2-7: Third generation boron delivery agents currently under investigation
  • Table 2-8: Cellular pathways as targets for anticancer therapies
  • Table 2-9: Examples of anticancer agents that target mitochondrial membranes
  • Table 2-10: Drugs targeting oncogenes
  • Table 2-11: Companies developing anticancer therapies targeting cancer stem cells
  • Table 2-12: Cancer therapies based on the P53
  • Table 2-13: Promise of personalized therapy in cancer
  • Table 2-14: Companies developing personalized therapy for cancer
  • Table 3-1: Routes of drug delivery in cancer
  • Table 3-2: Systemic intravenous drug delivery systems for chemotherapy of cancer
  • Table 3-3: Approved oral chemotherapy drugs
  • Table 3-4: Microparticles as therapeutic delivery systems in cancer
  • Table 3-5: Classification of nanobiotechnology approaches to drug delivery in cancer
  • Table 3-6: Approved anticancer drugs using nanocarriers
  • Table 3-7: Clinical trials of anticancer drugs using nanocarriers
  • Table 3-8: Marketed preparations for liposome-based anticancer drugs
  • Table 3-9: Clinical trials of liposome-based anticancer drugs
  • Table 3-10: Monoclonal antibodies for cancer approved by the FDA
  • Table 3-11: Anticancer agents linked to monoclonal antibodies
  • Table 3-12: Monoclonal antibodies in clinical trials for cancer
  • Table 3-13: Antibody drug conjugates in clinical trials for cancer
  • Table 3-14: Strategies for drug delivery in cancer
  • Table 3-15: Implant systems for delivery of anticancer drugs into tumors
  • Table 3-16: Methods of delivery of antiangiogenesis therapies
  • Table 3-17: Companies developing vascular targeting agents
  • Table 4-1: Mechanisms of anticancer effect of antisense oligonucleotides
  • Table 4-2: Methods of delivery of oligonucleotides for cancer therapy
  • Table 4-3: Antisense oligonucleotides in clinical trials for cancer
  • Table 4-4: Companies developing antisense and RNAi therapies for cancer
  • Table 4-5: Strategies for cancer gene therapy
  • Table 4-6: Enzyme/prodrug combinations employed in suicide gene therapy
  • Table 4-7: Mutation compensation strategies used clinically
  • Table 4-8: Companies developing oncolytic viruses
  • Table 4-9: Companies involved in cancer gene therapy
  • Table 4-10: Cell therapy technologies used for cancer
  • Table 4-11: Companies developing nucleic acids/genetically modified cells-based cancer vaccines
  • Table 5-1: Innovative methods of drug delivery for glioblastoma multiforme
  • Table 5-2: Strategies for gene therapy of malignant brain tumors
  • Table 5-3: Clinical trials of oncolytic virotherapy against glioblastoma multiforme
  • Table 5-4: Therapies for breast cancer involving innovative methods of drug delivery
  • Table 5-5: Drug delivery for hepatocellular carcinoma
  • Table 5-6: Gene therapy for malignant melanoma
  • Table 5-7: Targeted treatment of non-small cell lung cancer
  • Table 5-8: Clinical trials of gene therapy in ovarian cancer
  • Table 5-9: Methods of drug delivery in pancreatic cancer
  • Table 5-10: Pharmacological strategies under investigation for cancer of the prostate
  • Table 5-11: Clinical trials of gene therapy for prostate cancer
  • Table 6-1: Worldwide drug delivery market growth 2013 to 2023
  • Table 6-2: Worldwide prevalence of cancer according to type of cancer 2013-2023
  • Table 6-3: Estimated number of cancer patients in major markets 2013-2023
  • Table 6-4: Worldwide anticancer drug sales for selected cancers from 2013 to 2023
  • Table 6-5: Geographical distribution of cancer markets 2013-2023
  • Table 6-6: Market values of cancer drug delivery technologies from 2013-2023

Figures

  • Figure 1-1: An overview of some key steps in tumor angiogenesis
  • Figure 2-1: Targeting tumors with light-emitting engineered bacteria
  • Figure 2-2: Schematic role of T helper cells in immune response to cancer
  • Figure 3-1: Cyclacel's Penetratin Transport System for delivery of drugs to targets
  • Figure 3-2: Micelle for drug delivery in cancer
  • Figure 3-3: Mechanism of action of Targaceutical drugs
  • Figure 3-4: VIADUR leuprolide acetdrate using DUROS implant technology
  • Figure 5-1: A concept of targeted drug delivery to GBM across the BBB
  • Figure 6-1: Unmet needs in cancer drug delivery

Part - II: Companies

8. Companies involved in cancer drug delivery

  • Introduction
  • Profiles of companies
  • Collaborations

Tables

  • Table 8-1: Oncology pipeline of GlaxoSmithKline
  • Table 8-2: Roche pipeline of oncology products
  • Table 8-3: Collaborations of companies in cancer drug delivery
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