Ovarian cancer is the leading cause of death from gynecological malignancies in the United States. The NIH panel on ovarian cancer concluded that """"""""innovative approaches for the treatment of advanced primary as well as recurrent cancer must be identified and studied."""""""" Clinical data indicate that the therapeutic use of water-soluble polymer-anticancer drug conjugates appears to be a novel and successful strategy for cancer treatment. The data obtained by the research team to date clearly demonstrated the advantages of macromolecular therapeutics when compared to low molecular weight drugs: increased efficacy, increased maximum tolerated dose, decreased non-specific toxicity, targetability, activity toward mutlidrug resistant cells, increased solubility, enhanced accumulation in solid tumors, enhanced apoptosis induction, and activation of different signaling pathways. Targeted and nontargeted combination chemotherapy and photodynamic therapy (PDT) using macromolecular therapies showed tumor cures that could not be obtained with either chemotherapy of PDT alone. The main aim of the proposed research is to design new, effective macromolecular therapeutics for the treatment of cancer. Water soluble polymeric carriers, based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers will be used. Geldanamycin (GA), 2,5-bis(6-hydroxymethyl-2-thienyl)furan (SOS thiphene), and mesochlorin e6 (Mce6) will be used as anticancer drugs. Novel synthetic pathways will be designed to permit the synthesis of long-circulating conjugates and of targeted conjugates containing antibody fragments and bispecific antibody fragment constructs. Both approaches will further enhance the preferential tumor accumulation of macromolecular therapeutics. The relationship between the detailed structure of the conjugates, namely content of drug, molecular weight distribution, content and specificity of targeting moieties, and the mechanism of action will be evaluated in vitro and in vivo. Based on the detailed analysis of alterations in gene expression profiles, new molecular targets specific to macromolecular therapeutics will be identified. Second-generation conjugates will be designed to match the identified targets, evaluated and optimized. A lead compound will be selected from the second-generation conjugates and its detailed preclinical evaluation will be performed in year five.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA051578-11
Application #
6633026
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Stone, Helen B
Project Start
1992-09-04
Project End
2006-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
11
Fiscal Year
2003
Total Cost
$249,000
Indirect Cost
Name
University of Utah
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Yang, Jiyuan; Kope?ek, Jind?ich (2016) Design of smart HPMA copolymer-based nanomedicines. J Control Release 240:9-23
Yang, Jiyuan; Kope?ek, Jind?ich (2015) POLYMERIC BIOMATERIALS AND NANOMEDICINES. J Drug Deliv Sci Technol 30:318-330
Duangjai, Acharaporn; Luo, Kui; Zhou, Yan et al. (2014) Combination cytotoxicity of backbone degradable HPMA copolymer gemcitabine and platinum conjugates toward human ovarian carcinoma cells. Eur J Pharm Biopharm 87:187-96
Yang, Jiyuan; Kope?ek, Jind?ich (2014) Macromolecular therapeutics. J Control Release 190:288-303
Pan, Huaizhong; Sima, Monika; Yang, Jiyuan et al. (2013) Synthesis of long-circulating, backbone degradable HPMA copolymer-doxorubicin conjugates and evaluation of molecular-weight-dependent antitumor efficacy. Macromol Biosci 13:155-60
Kope?ek, Jind?ich (2013) Polymer-drug conjugates: origins, progress to date and future directions. Adv Drug Deliv Rev 65:49-59
Zhou, Yan; Kope?ek, Jind?ich (2013) Biological rationale for the design of polymeric anti-cancer nanomedicines. J Drug Target 21:1-26
Fowers, Kirk D; Kope?ek, Jind?ich (2012) Targeting of multidrug-resistant human ovarian carcinoma cells with anti-P-glycoprotein antibody conjugates. Macromol Biosci 12:502-14
Pan, Huaizhong; Yang, Jiyuan; Kopeckova, Pavla et al. (2011) Backbone degradable multiblock N-(2-hydroxypropyl)methacrylamide copolymer conjugates via reversible addition-fragmentation chain transfer polymerization and thiol-ene coupling reaction. Biomacromolecules 12:247-52
Yang, Jiyuan; Luo, Kui; Pan, Huaizhong et al. (2011) Synthesis of Biodegradable Multiblock Copolymers by Click Coupling of RAFT-Generated HeterotelechelicPolyHPMA Conjugates. React Funct Polym 71:294-302

Showing the most recent 10 out of 82 publications