This Phase I proposal details the rationale and the research plan for the synthesis and characterization of targeted, backbone degradable, long-circulating polymer conjugates containing two anticancer drugs per macromolecule. The polymeric carrier will be composed of alternating N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer segments (blocks) and enzymatically degradable oligopeptide sequences. Each construct will contain multiple copies of two anticancer drugs (paclitaxel and gemcitabine) and of Fab'fragment of the OV-TL16 antibody (complementary to OA-3 antigen expressed on the majority of human ovarian carcinomas). The combination of FDA approved anticancer drugs, paclitaxel and gemcitabine, is one of novel combinations evaluated in the clinics. Attachment of both drugs to the Fab'fragment-targeted, long-circulating (high molecular weight) backbone degradable HPMA copolymer carrier will result in enhanced and simultaneous delivery of both drugs to cancer cells. The combination of active targeting, due to biorecognition of the Fab'fragments, and of passive targeting, due to the EPR (enhanced permeability and retention) effect, will result in augmented efficacy and minimal adverse effects, thus improving the usefulness of cancer therapy.
The specific aims of the proposal are three-fold: A) Design, synthesis, and characterization of Fab'fragment- targeted HPMA copolymer-paclitaxel/gemcitabine conjugates;optimization of the structure based on feedback from biological evaluation. B) Evaluation of the conjugates on human ovarian cancer cells in vitro: internalization and subcellular fate, stability and enzymatically catalyzed drug release, and cytotoxicity. C) Therapeutic efficacy of polymer-drug conjugates on a human ovarian carcinoma xenograft model in nude mice. By completion of the Phase I studies TheraTarget will have established the feasibility of synthesis and characterization of the HPMA copolymer-drug conjugates, evaluated their activity in vitro and in vivo, and selected the leading conjugate for Phase II evaluation. The ultimate goal of the project is the development of an effective and marketable polymer drug delivery system capable of significantly improving the survival time of ovarian cancer patients.

Public Health Relevance

This Phase I proposal details the rationale and the research plan for the synthesis and characterization of backbone degradable, long-circulating polymer conjugates containing two anticancer drugs per macromolecule. The simultaneous delivery of two drugs to ovarian cancer cells will result in enhanced efficacy and minimal adverse effects, thus improving the usefulness of cancer therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Business Technology Transfer (STTR) Grants - Phase I (R41)
Project #
1R41CA156933-01A1
Application #
8124344
Study Section
Special Emphasis Panel (ZRG1-IMST-D (13))
Program Officer
Kurtz, Andrew J
Project Start
2011-09-26
Project End
2013-02-28
Budget Start
2011-09-26
Budget End
2013-02-28
Support Year
1
Fiscal Year
2011
Total Cost
$148,304
Indirect Cost
Name
Theratarget
Department
Type
DUNS #
828787379
City
Salt Lake City
State
UT
Country
United States
Zip Code
84108
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Zhang, Rui; Yang, Jiyuan; Sima, Monika et al. (2014) Sequential combination therapy of ovarian cancer with degradable N-(2-hydroxypropyl)methacrylamide copolymer paclitaxel and gemcitabine conjugates. Proc Natl Acad Sci U S A 111:12181-6
Zhang, Rui; Luo, Kui; Yang, Jiyuan et al. (2013) Synthesis and evaluation of a backbone biodegradable multiblock HPMA copolymer nanocarrier for the systemic delivery of paclitaxel. J Control Release 166:66-74
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
Larson, Nate; Yang, Jiyuan; Ray, Abhijit et al. (2013) Biodegradable multiblock poly(N-2-hydroxypropyl)methacrylamide gemcitabine and paclitaxel conjugates for ovarian cancer cell combination treatment. Int J Pharm 454:435-43

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