2003 WHRG Grant Program

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Polymeric Delivery of a Camptothecin Analogue for the Treatment of Ovarian Cancer
Simin Hassannejad Tabasi
School of Pharmacy, University of Maryland, Baltimore

Ovarian cancer is the fifth leading cause of death among women and the second most common gynecologic malignancy, accounting for approximately 14,000 deaths annually in the United States. Conventional chemotherapy has insufficient impact on long-term survival with severe adverse effects. This has led investigators to develop new strategies for the treatment of the disease. Irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy-camptothecin or CPT-11), is a camptothecin derivative undergoing clinical trials for the treatment of ovarian cancer. These trials have so far demonstrated significant antitumor activity of this drug in ovarian cancer cell lines as well as human tumors. CPT-11 is metabolized to 100-1000 fold more active compound, 7-ethyl-10-hydroxycamptothecin (SN-38), by carboxylesterases (CE). However, the systemic toxicity of this drug limits its clinical application. Such toxicities cause pain and suffering of women undergoing treatment. One way to circumvent this problem is to use water-soluble polymers as drug carriers for the selective targeting of anticancer chemotherapeutics to the tumor cells. While these systems have shown success, limited penetration of the macromolecular delivery systems into the heterogenous solid tumor mass results in incomplete access of the conjugates to all cancer cells, therefore incomplete therapy and tumor regression. One way to overcome this problem is to use a recently developed technique namely polymer-directed enzyme prodrug therapy (PDEPT) approach. Using this technique our aim is to target both SN38 and CE to the ovarian tumor cells. Based on the PDEPT approach, first, a water-soluble polymer conjugated to SN-38 with an ester bond is administered. These conjugates will be localized around the tumor by a phenomenon called enahnced permeability and retention effect. In the second step, CE is conjugated to a water-soluble polymer and is directed to the tumor by the same mechanism. The enzyme-polymer conjugate cleaves the bond between the polymer and the anticancer drug and releases the free drug directly at the tumor site. To achieve this, the site of attachment of the drug to the polymer, and the molecular weight of the polymer need to be optimized for a desirable release profile. The Specific Aims of this proposal are to 1) synthesize and characterize a series of water-soluble polymer-SN38 conjugates with varying molecular weights and attachment sites (end chains vs. side chains) and, 2) evaluate the influence of the molecular weight and site of attachment of the drug on drug release in the presence of CE. Once developed, these systems can be used for the localized delivery of other enzyme/chemotherapeutic combinations resulting in less adverse effects and improvement of health of women with ovarian cancer and other malignancies.