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

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 2R42CA156933-02A1
Agency Tracking Number: R42CA156933
Amount: $995,235.00
Phase: Phase II
Program: STTR
Solicitation Topic Code: NCI
Solicitation Number: PA13-235
Timeline
Solicitation Year: 2014
Award Year: 2014
Award Start Date (Proposal Award Date): 2014-09-04
Award End Date (Contract End Date): 2016-08-31
Small Business Information
615 Arapeen Drive, Suite 302-Y, Salt Lake City, UT, 84108-1289
DUNS: 828787379
HUBZone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 JINDRICH KOPECEK
 (801) 581-4532
 jindrich.kopecek@m.cc.utah.edu
Business Contact
 DARWIN CHENEY
Phone: (801) 587-1514
Email: dcheney@theratarget.com
Research Institution
 UNIVERSITY OF UTAH
 75 SOUTH 2000 EAST
SALT LAKE CITY, UT, 84112-8930
 Nonprofit college or university
Abstract
DESCRIPTION provided by applicant The purpose of this Phase II STTR project is to develop a polymeric system for the combination delivery of two antineoplastic agents gemcitabine and paclitaxel Based on the successful results of the STTR Phase I award this Phase II proposal details the rationale and research plan for the synthesis and evaluation of in vivo efficacy of two novel macromolecular therapeutics with diverse and complementary mode of action for the treatment of ovarian carcinoma Their design is based on new innovative long circulating backbone degradable N hydroxypropyl methacrylamide HPMA copolymer drug conjugates The polymeric carrier will be composed of alternating HPMA copolymer segments blocks and enzymatically degradable oligopeptide sequences Each construct will contain multiple copies of either gemcitabine or paclitaxel The drugs are attached to the backbone via a lysosomally degradable spacer that will allow intracellular release and bioactivity The choice of drugs bodes well for the success of the project Gemcitabine is a synthetic nucleoside analog of cytidine Its triphosphate metabolite is incorporated into DNA thereby stopping cell division Gemcitabine has demonstrated activity in several ovarian cancer models and has been approved by FDA for combination therapy of ovarian cancer Paclitaxel is a mitotic inhibitor which acts by stabilizing microtubules thereby inhibiting their breakdown during cellular division It is currently indicated as first line and subsequent therapy for the treatment of advanced stages of ovarian cancer The long circulating time of the new innovative backbone degradable carriers will result in augmented tumor accumulation due to the EPR enhanced permeability and retention effect In addition the combination of two polymer drug conjugates with diverse mechanisms of action will result in enhanced efficacy of ovarian cancer treatment and minimal adverse effects The specific aims of the proposal are three fold a To scale up of the synthesis and to characterize backbone degradable HPMA copolymer drug gemcitabine and paclitaxel conjugates containing enzymatically degradable sequences in the backbone and in side chains b To establish the maximum tolerated dose MTD as well as the acute toxicity of the conjugates and their combination in vivo and c To evaluate the biodistribution clearance anticancer efficacy and dose escalation studies of the conjugates in vivo The ultimate goal of this project is to develop an effective and marketable drug combination with a novel drug delivery system for the treatment of ovarian cancer where the drugs are localized at the site of the tumor adverse effects of chemotherapy are minimized and efficacy maximized PUBLIC HEALTH RELEVANCE This Phase II proposal extends a successful Phase I project and further details the rationale and the research plan for the synthesis and characterization of backbone degradable long circulating polymer conjugates with anticancer drugs gemcitabine and paclitaxel The combination of two polymer drug conjugates with diverse mechanisms of action will result in enhanced efficacy of ovarian cancer treatment and minimal adverse effects

* Information listed above is at the time of submission. *

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