Backbone Degradable Polymer-drug Conjugates for the Treatment of Ovarian Cancer

Award Information
Agency:
Department of Health and Human Services
Branch
n/a
Amount:
$148,304.00
Award Year:
2011
Program:
STTR
Phase:
Phase I
Contract:
1R41CA156933-01A1
Agency Tracking Number:
R41CA156933
Solicitation Year:
2011
Solicitation Topic Code:
NCI
Solicitation Number:
PA10-051
Small Business Information
THERATARGET
615 Arapeen Drive, Suite 302-Y, SALT LAKE CITY, UT, 84108-
Hubzone Owned:
N
Minority Owned:
N
Woman Owned:
N
Duns:
828787379
Principal Investigator:
JINDRICH KOPECEK
(801) 581-7211
Jindrich.Kopecek@utah.edu
Business Contact:
DARWIN CHENEY
(801) 587-1514
dcheney@theratarget.com
Research Institution:
UNIVERSITY OF UTAH

UNIVERSITY OF UTAH
75 South 2000 East Room 111
SALT LAKE CITY, UT, 84112-
() -
Nonprofit college or university
Abstract
DESCRIPTION (provided by applicant): 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 biologicalevaluation. 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.

* information listed above is at the time of submission.

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