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-(2- 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.
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.
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