Macromolecular Anticancer Therapeutics

L. Harivardhan Reddy is Head of Nanovectors group at Sanofi-aventis, France. He completed Ph.D. in Pharmaceutics and Drug delivery in 2005 from The M.S. University of Baroda, India. He has worked for 4 years in two popular pharmaceutical companies (Sun Pharmaceutical Industries Ltd., and Aristo Pharmaceuticals Ltd.) in India, on drug delivery applications. He worked for 3 years (2005-2008) with anticancer drug delivery specialist Prof. Patrick Couvreur in CNRS lab at Université Paris-Sud, Chatenay-Malabry, France. He is an inventor of 3 patents belonging to macromolecular therapeutics and drug delivery. He has published, as an author and co-author, more than 60 publications in various reputed journals. He is also a reviewer for more than 15 journals of the fields of biomacromolecules, drug delivery, cancer therapy, and pharmacology. He is a member of The European Association for Cancer Research. His principal research interests are supramolecular lipidic prodrug nanomedicines and nanotherapeutics for cancer. Patrick Couvreur is a Full Professor of Pharmacy at the University Paris-Sud, France, and holder of the chair of "Innovation Technologique" (2009-2010) at the prestigious ‘Collège de France’. He is a member of the Academy of Technologies (France), of the Academy of Pharmacy (France) and corresponding member of the Royal Academy of Medicine (Belgium). Prof. Patrick COUVREUR’s contributions in the field of drug delivery and targeting are highly recognized and respected around the world. Patrick COUVREUR performed a pioneer work together with Peter SPEISER, and demonstrated for the first time in 1977 that nanoparticles may be used as intracellular carriers for compounds which don’t diffuse spontaneously into cells. Patrick COUVREUR’s research is primarily on polymer-based and metallic-based nanomedicines, surface engineered nanosystems, and also focuses on lipid-based nanocarriers. He has publishedas an author and co-author, 341 publications, 109 review articles and book chapters, 6 books as editor, 50 patents, and 193 invited and plenary lectures at national and international congresses. He has received Pharmaceutical Sciences World Congress Award (2004), the "Marie-Maurice Janot Lecture" (2008) and above all the prestigious "Host Madsen Medal" (2007) in honour of his outstanding research achievements. He is a Field Editor of "Pharmaceutical Research", European Editor of the "Journal of Nanoparticles Research", and is a reviewer of more than 15 high reputed journals in the fields of Drug delivery, cancer research, macromolecules, physical chemistry etc. He is acting or acted as Board of Governors of the Controlled Release Society (CRS), Board of APGI, Expert Member of the Board of Pharmaceutical Sciences, International Pharmaceutical Federation (FIP). His exceptional research has led to two start-up companies BIOALLIANCE and MEDSQUAL dealing with novel therapeutics, in France.

• Chapter 1. Classification of anticancer drugs based on therapeutic targetsEnrique Espinosa, César Gómez RaposoSectionContents  Abstract1Introduction2Drugs directed against tumour dna2.1Drugs directly affecting DNA helix: alkylators2.2Inhibitors of DNA-related proteins2.2.1Topoisomerases inhibitors2.2.2Antimetabolites2.2.3Histone related enzymes2.2.4Inhibitors of transcription factors2.3Specific genes3Drugs directed against tumour RNA4Drugs directed against proteins in the tumour cell4.1Receptors in the tumour membrane4.2Intracellular pathways in tumour cells4.3Tubulin5Drugs acting on the endothelium5.1Inhibition of pro-angiogenic factors5.2Inhibition of vascular receptors5.3Inside the endothelium6Drugs directed against extracellular matrix6.1Matrix metalloproteinases inhibitors6.2Anti-integrin therapy6.3Copper chelators6.4L1-CAM protein6.5Thrombospondin and others7Immunotherapy7.1Antibody-based immunotherapy of cancer7.1.1Unconjugated monoclonal antibodies7.1.2Conjugated monoclonal antibodies7.1.3Monoclonal antibodies as immunogens 7.2Cytokines in cancer immunotherapy7.3Cancer vaccines7.3.1Peptide vaccines7.3.2Dendritic cell-based cancer vaccines7.3.3Cellular vaccines7.3.4DNA vaccines 7.3.5Heat shock protein vaccines 7.4Adoptive TCell transfer for cancer immunotherapy7.5Natural killer cell-based immunotherapy7.6Regulatory cells and cancer immunotherapy7.7Toll-like receptors8Drugs acting on potentially metastatic sites and glands9Conclusion  References  Figure legends  Tables Chapter 2. Signal transduction pathways as therapeutic targets in cancer therapyMichele Milella, Ludovica Ciuffreda, Emilio BriaSectionContents  Abstract1Introduction2Protein tyrosine kinases (TK) as therapeutic targets2.1RTK as therapeutic targets: the paradigm of EGFR mutations in NSCLC3Cytoplasmic signaling intermediates3.1The Ras/Raf/MAPK pathway3.2The PI3K/AKT/mTOR pathway3.3Signaling crosstalk4Oncogenic addiction4.1Oncogenic shock4.2Oncogene amnesia5Open issues in the clinical development of signal transduction-targeted anticancer agents5.1The role of ‘early phases’: are phase II studies still necessary?5.2Phase II randomized studies: a new tale with targeted agents5.3Targeted agents: moving into phase III Chapter 3. HPMA-anticancer drug conjugatesRihova B, Hovorka O, Kovar L, Kovar M, Mrkvan T, Sirova M, Ulbrich KSectionContents  Abstract1.Introduction2.Synthesis and structure of N-(2-hydroxypropyl)methacrylamide copolymer-drug conjugates2.1Synthesis of linear polymer-drug conjugates2.2Polymer conjugates with biologically activeproteins2.3Polymer systems designed for targeted drug delivery2.3.1Passively targeted HPMA copolymer-drug conjugates2.3.1.1Branched and grafted high-molecular-weight HPMA copolymer conjugates 2.3.1.2Self-assembled and micellar structures2.3.2Actively targeted HPMA copolymer-drug conjugates2.3.2.1Antibody-targeted HPMA copolymer conjugates2.3.2.2Lectin -targeted HPMA copolymer conjugates2.3.2.3Oligopeptide-targeted HPMA copolymer conjugates2.3.2.4HPMA copolymer conjugates targeted with other low-molecular weight moieties3.Immunogenicity of HPMA-based conjugates3.1The humoral response against HPMA3.2The cellular response to HPMA3.3Complement activation3.4The chronic treatment3.5The decreased immunogenicity of proteins bound to HPMA3.6Decrease of side toxicity of HPMA-copolymer carrier bound drugs4.HPMA copolymer–doxorubicin conjugates with pH-controlled activation4.1Linear Dox-HPMAHYD conjugates4.2Branched and grafted Dox-HPMAHYD conjugates4.3Micellar Dox-HPMAHYD conjugates4.4Antibody-targeted Dox-HPMAHYD conjugates4.5Immunomodulatory properties of Dox-HPMAHYD conjugates5.HPMA copolymer doxorubicin conjugates with amide bond between the drug and carrier5.1Dox-HPMAAM (PK1)5.2Dox-HPMAAM conjugate containing human immunoglobulin (HuIg)5.2.1Preclinical evaluation of Dox-HPMAAM-HuIg 5.2.2Pilot clinical study with Dox-HPMAAM-HuIg5.3HPMA-based polymer prodrugs in clinicaltrials6.Specific targeting of HPMA copolymer-bound drug conjugates to cancer cells6.1Targeting to asialoglycoprotein receptor6.2Targeting using lectins 6.3Targeting using antibodies6.4Targeting to transferrin receptor6.5Targeting using synthetic peptides7.Intracellular destiny of polymeric conjugates based on HPMA7.1Lysosomotropic delivery of the polymeric drugs7.2Intracellular destiny of polymeric drugs7.3Effect of a doxorubicin derivative 7,8-dehydro-9,10-desacetyldoxorubicinone (D*) in the detection of fluorescence7.4The cleavability of conjugates 7.5Apoptosis, necrosis and cell signalling8.Immunomodulatory properties of HPMA copolymer-bound doxorubicin Chapter 4. Poly-L-Glutamic acid anti-cancer drug conjugatesJack W. Singer, Marc McKennon, Gabriella Pezzoni, Stefano di Giovine, Mara Cassin, Paola de Feudis, Cecilia Allievi, Patrizia Angiuli, Marco Natangelo, Enrico Vezzali, and Stefano FazioniSectionContents  Abstract1.Introduction2.CT-2103 (Paclitaxel Poliglumex)2.1Chemistry and Manufacturing2.1.1.Technical Issues in the synthesis of CT-21032.1.2.Synthetic strategy2.1.3.Synthesis Optimization2.1.4.Formulation of CT-21032.1.5.Development of analytic methods and characterization of CT-21032.1.6.Setting molecular weight and loading limits, the four corners approach2.2.Preclinical Pharmacology2.2.1.Pharmacokinetics2.2.2.Tissue distribution in rats and dogs2.2.3.Tissue distribution in comparison with paclitaxel in tumor bearing mice: 2.2.4.Mass balance in rat2.2.5.Toxicology studies2.3.Cellular pharmacology 2.3.1.Cellular Metabolism2.3.2.The role of the macrophage 2.3.3.Preclinical efficacy 2.3.4.In vivo efficacy studies in combination with radiation2.3.5.The effect of estradiol on CT-21032.4.Preclinical Summary 2.5.Clinical studies2.5.1.Phase I Studies: Determination of a safe and effective dose 2.5.2.Phase II Studies2.6.Use of CT-2103 as a radiosensitizer2.7.Phase III Programs2.7.1Non-small cell lung cancer (NSCLC)2.7.2.Ovarian Cancer3.CT-2106 (poly-L-glutamic acid gly-camptothecin)3.1.Design and Synthesis3.2.Overview of preclinical studies3.3.Phase I Clinical Studies  Chapter 5. Polysaccharide-based anticancer prodrugsPaolo Caliceti, Stefano Salmaso and Sara Bersani SectionContents  Abstract1.Introduction2.Chitin and Chitosan 2.1Mitomycin C2.1.1Insoluble Suc-Chitosan-MMC derivatives2.1.2Soluble MMC-Suc-Chitosan derivatives2.1.3Lactosyl-Suc-Chitosan-MMC derivatives2.2Epirubcin2.3Doxorubicin2.41-ß -D-arabinofuranosylcytosine2.55-fluorouracil2.6Tyr-Ile-Gly-Ser-Arg2.7DNA3.Hyaluronic Acid3.1Paclitaxel3.2Doxorubicin3.3Butyric acid3.4All-Trans RetinoicAcid4.Dextran4.1Doxorubicin4.2Daunomycin4.3 Adriamycin4.4Mitomycin C4.5Paclitaxel4.61-ß-D-arabinofuranosylcytosine4.7Cisplatin4.8Camptothecin4.9Methylprednisolone and Tacrolimus4.10Radionuclides4.11Proteins5.Arabinogalactan6.Pullulan7.Cyclodextrins   Chapter 6. PEG-anticancer drugsFrancesca Cateni, Marina Zacchigna SectionContents  Abstract1Introduction1.1Drug delivery using permanent PEGylation1.2Non permanently bonded PEG-drugs: PEG prodrugs2PEG-anticancer prodrugs2.1PEG-Paclitaxel2.2PEG-Camptothecin2.3PEG-Doxorubicin2.4PEG-Daunorubucin2.5PEG-Epirubicin2.6PEG-Ara-C2.7PEG-Gemcitabine2.8PEG-Platinum drugs2.9PEG-Methotrexate Chapter 7. Poly(ethylene glycol)-protein, peptide and enzyme conjugatesF.M.Veronese, G. Pasut, S.Drioli and G.M.BonoraSectionContents  Abstract1Introduction2PEG-proteins and peptides 2.1Antibodies and antibody fragments 2.2Granulocyte colony-stimulating factor 2.3Interferons2.4Thrombopoietin or megakaryocyte growth and development factor 2.5Anti-cancer peptides 3PEG-enzymes 3.1Arginase3.2Argininedeiminase3.3Asparaginase3.4Methioninase3.5Glutaminase3.6Uricase3.7Other anti-cancer enzymes   Chapter 8. Lipid-based anticancer prodrugsL. Harivardhan Reddy and Patrick CouvreurS. No.Contents1Introduction2Lipids applied in cancer treatment2.1Non-fatty acids2.1.1Cardiolipin2.1.2Ceramide2.2Fatty acids2.2.1Essential fatty acids (EFAs)2.2.2Omega-3 fatty acids2.2.3Conjugated Linoleic acids2.2.4Olive oil constituent2.2.4.1Oleic acid2.2.4.2Elaidic acid2.2.4.3Squalene2.2.5Miscellaneous fatty acids2.2.5.1Valproic acid2.2.5.2Butyrates3Anticancer lipid prodrugs3.1Antibiotic anticancer drug-lipid conjugates3.1.1Mitomycin C-lipid conjugates3.1.2Doxorubicin-lipid conjugates3.2Antimetabolite anticancer drug-lipid conjugates3.2.1Methotrexate-lipid conjugates3.2.2Nucleoside analogue anticancer drug-lipid conjugates3.2.2.1Ara C-lipid conjugates3.2.2.2Gemcitabine-lipid conjugates3.2.2.3Troxacitabine-lipid conjugates3.3Taxane-lipid conjugates3.4Others: Camptothecin alkaloids-lipid conjugatesChapter 9. Antibody-Cytotoxic Compound Conjugates for OncologyCarol A. Vater and Victor S. GoldmacherSectionContents  Abstract1Introduction2Target selection3Antibody selection4Cytotoxic compounds used in Antibody-Cytotoxic compound Conjugates (ACCs1)5Antibody-cytotoxic compound linker strategies6ACCs in clinical development7Conclusions and future prospects  Chapter 10. Immunoconjugate anticancer therapeuticsSerengulam V. Govindan and David M. GoldenbergSectionContents  Abstract1.Introduction2.mAb forms for conjugates2.1Radionuclide conjugates2.1.1Radionuclides for RAIT2.1.2Therapy of hematological cancers2.1.3Therapy of solid cancers2.1.3.1As an adjuvant 2.1.3.2Combination therapy2.1.3.3Locoregional application 2.1.3.4Pretargeting2.1.4Quo vadis?2.2Antibody-drug conjugates2.2.1Drugs2.2.2Cleavable linker in drug conjugate design2.2.2.1Hydrazone-containing conjugates2.2.2.2Disulfide-containing conjugates2.2.2.3Conjugates with a cleavable-peptide 2.2.2.4Ester linker2.2.3MAb conjugates: Homogeneity and site-specificity 2.3Toxin conjugates 2.3.1Plant and bacterial toxin conjugates2.3.2Ribonuclease conjugates   Conclusions  Chapter 11. Antibody directed enzyme prodrug therapy (ADEPT) for cancerSurinder K Sharma and Kenneth D BagshaweSectionContents  Abstract1.Introduction and Principles2.Antibodies and targets3.Enzymes3.1Mammalian enzymes including human 3.2Non-mammalian enzymes3.3Catalytic Antibodies4.Prodrugs5.Carboxypeptidase G25.1Antibody-Enzyme conjugates5.1.1Pre-Clinical Studies5.1.2Clinical studies5.2Fusion Proteins6.Immunogenicity  Conclusion  Chapter 12. EGFR-directed monoclonal antibodiesRoberto Bianco, Teresa Gelardi, Sonia Garofalo, Roberta Rosa, Giampaolo TortoraSectionContents  Abstract1.EGFR and cancer2.EGFR inhibitors as anticancer therapy3.Anti-EGFR monoclonal antibodies (MAbs)3.1.Cetuximab (IMC-225)3.2. Panitumumab (ABX-EGF)3.3.Matuzumab (EMD72000)3.4.Nimotuzumab (hR3)3.5.Zalutumumab3.6.MDX-4473.7.ch806  Conclusion Chapter 13. The Biology of the HER Family and Her2/neu Directed-AntibodyJennifer K. Litton and Gabriel N. HortobagyiSectionContents  Abstract1.Introduction2.The HER Family3.HER2 and Downstream Signaling Pathways3.1The PI3k/Akt/mammalian target of rapamycin (mTOR) Pathway3.2HER2 and PTEN3.3The Ras/Raf/mitogen-activated protein kinase (MAPK) Pathway3.4HER2 and Endocrine Receptors (ER)3.5HER2 and p274.HER2 Targeted Antibodies4.1Trastuzumab4.1.1Trastuzumab and Metastatic Breast Cancer: single agent trastuzumab4.1.2Dosing of Trastuzumab4.1.3Trastuzumab and Chemotherapy for Metastatic Breast Cancer4.1.4Trastuzumab and Aromatase Inhibitors for Metastatic Breast Cancer4.1.5Trastuzumab and Adjuvant Therapy4.1.6Trastuzumab and Neoadjuvant Chemotherapy4.1.7Treating with Trastuzumab Beyond Progression4.1.8Trastuzumab and Cardiotoxicity4.1.9Mechanisms of Resistance4.2HER and PTEN/PI3k/Akt/mammalian target of rapamycin (mTOR) Pathway4.3Insulin-like growth factor-1 receptor 4.4MUC4 Over-expression4.5HER2 Receptor truncation or mutations5.Novel HER Family-directed antibodies5.1Pertuzumab5.2Trastuzumab-DM15.3HER2 monoclonal antibodies and nanoparticles in development:  Conclusion Chapter 14. Anti-Vascular Endothelial Growth Factor Monoclonal AntibodiesErnest S. Han and Bradley J. MonkS. No.Contents  Abstract1.1Angiogenesis and Cancer1.1.1Biologic relevance of vascular endothelial growth factor in tumor angiogenesis1.1.2VEGF family and receptors1.1.3VEGF as a target for cancer therapy1.2VEGF Monoclonal antibodies and clinical experience1.2.1Bevacizumab1.2.1.1Pharmacology1.2.1.2Clinical experience1.2.1.3Side effects1.2.2VEGF Trap1.2.2.1Pharmacology1.2.2.2Clinical experience1.2.3HuMV8331.2.3.1Pharmacology1.2.3.2Clinical experience1.3VEGF receptor monoclonal antibodies1.3.1IMC-1121b1.3.2IMC-18F11.3.3CDP7911.4Monoclonal antibodies to placental growth factor<1.5Current issues emerging from anti-VEGF therapies1.5.1Biologic markers for dosing and efficacy1.5.2Resistance to Anti-VEGF therapy1.6Summary  Chapter 15. Monoclonal Antibody Therapy for Hematologic MalignanciesKenneth A. Foon, Michael Boyiadzis, Samuel A. JacobsSectionContents  Abstract1.Introduction2.Rituximab2.1Follicular Lymphoma2.2Marginal Zone B-Cell Lymphoma2.3Mantle Cell Lymphoma2.4Diffuse Large B-Cell Lymphoma2.5Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma3.90Y Ibritumomab Tiuxetan4.131I tositumomab5.Alemtuzumab6.Gemtuzumab Ozogamicin 7.Ofatumumab8.AME-133v9.Epratuzumab10.CMC-54411.BL2212.Lumiliximab13.Galiximab14.SGN-4015.Bevacizumab16.CP-751,87117.Zanolimumab18.Limtuzumab19.IMC-EB1020.SGN-3021.Chimeric Anti-CD4 Monoclonal Antibody22.TRU-016 23.Milatuzumab24.Ipilimumab  Conclusion Chapter 16. Anticancer oligonucleotidesAnne Laure Ramon and Claude Malvy SectionContents1.Introduction2.Pre-clinical studies2.1Antisense oligonucleotides2.1.1Studies on bcl-2 proto oncogene2.1.2Studies on Raf kinases2.1.3Studies on Ras proteins2.1.4Studies on PKC-a2.2Small interfering RNA2.2.1Studies on bcl-2 proto oncogene2.2.2Studies on Raf kinases2.2.3Studies on Ras proteins and PKC-a2.3Decoys2.4Aptamers2.5Ribozymes2.5.1Studies on bcl-22.5.2Studies on Ras proteins2.5.3Studies on PKC-a2.6Discussion2.6.1Immunostimulation2.6.2Minimal active doses2.6.3Selectivity and off-target effects3.Clinical studies3.1Antisense oligonucleotides3.1.1Clinical trials on Bcl-23.1.2Clinical trials on Raf kinase3.1.3Clinical trials on Ras3.1.4Clinical trials on PKC-a3.2Small interfering RNA3.3Ribozymes3.4Decoys3.5Discussion4.Conclusion  Chapter 17. New molecular therapeutic interventions: the case of breast cancersVéronique Marsaud and Jack-Michel RenoirSectionContents  Abstract1.Introduction2.2. Estrogens, phytoestrogens and xenoestrogens2.1Biosynthesis of estrogens2.2Phytoestrogens and xenoestrogens3.Estrogen receptors 3.1Structure3.2The classical genomic transactivation mechanisms3.3.Non-classical transactivation systems 3.4Nuclear localization and nucleo-cytoplasmic shuttling3.5Estrogen receptors stability4. Estrogen Receptors in Breast cancers4.1Estrogen receptors in the normal mammary gland4.1.1 Estrogen receptor isotypes in breastcancers4.1.2.Classical anti-hormonal treatments4.1.2.1SERDs and SERDs4.1.2.2Aromatase inhibitors4.1.2.3Resistance5.Emergence of innovative strategies for specific targets5.1Apoptosis induction and Cell cycle inhibition5.1.1Apoptosis5.1.2Cdk inhibitors 5.1.3Survivin5.1.4Nuclear factor-k B5.1.5Ubiquitine-proteasome system5.1.6Histone deacetylase inhibitors5.1.7Hsp90 inhibitors5.1.8 p535.1.9Pi3K/Akt pathway5.1.10Farnesyl transferase inhibitors (FTI)5.2Vascular and angiogenesis inhibitors 5.3Monoclonal antibodies and tyrosine kinase inhibitors for EGFR and Erb-B26.Breast cancer and stem cells6. 1.Implication of stem cells in metastasis6.2. Targeting CD44 for breast cancer therapy7.Conclusion and future perspectives