Apoptosis Inducing to Enhance Tumor Targeting

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DESCRIPTION (provided by applicant): Management of patients with metastatic pancreatic and ovarian cancer faces unmet needs. These patients usually present with multiple solid tumors and malignant ascites in the peritoneal cavity that are not adequately managed by systemic intravenous (iv) therapy. Intraperitoneal (ip) therapy can deliver high drug concentrations to tumors located in the peritoneal cavity, but is generally not effective against distant extra-abdominal metastases. These deficiencies can be overcome by combining ip and iv treatments. In fact, such combinations have demonstrated a survival advantage in advanced ovarian cancer patients. IP treatment has not been tested in pancreatic cancer. The utility and efficacy of ip therapy are limited by two problems. First, drug penetration into a tumor is usually restricted to the tumor periphery. Second, ip therapy is associated with infection due to prolonged use of indwelling catheters and abdominal pain due to the high local drug concentrations. The objective of this application is to develop drug delivery formulations that can overcome these two problems. We have demonstrated that tissue structure and composition are the major determinants of drug penetration in solid tumors, and that high tumor cell density is a major penetration barrier. We further showed that disruption of tumor structure and reduction of tumor cell density, by using drugs that induce apoptosis, resulted in greater and more even penetration of drug (administered after apoptosis has occurred) in solid tumors. This occurs for drug administered iv, or regionally in the peritumoral space. Hence, we hypothesize that drug delivery to tumors located in the peritoneal cavity can be enhanced by using a combination of two formulations, one that rapidly releases a sufficient fraction of the dose to induce apoptosis and one that slowly releases the remaining dose to provide sustained drug delivery over several months and thereby eliminates the use of indwelling ip catheters and reduces the local toxicity. These formulations can be given ip, will manage the peritoneal tumors, and, at the same time, will enhance the tumor delivery of the iv administered drug. In our preliminary studies, we found that paclitaxel was active against ovarian and pancreatic tumor cells, and have developed paclitaxel-loaded (poly(lactide-co-glycolide)) microspheres that showed greater tumor penetration and retention, and superior antitumor activity in mice bearing peritoneal human xenograft tumors, as compared to the commercial paclitaxel/Cremophor formulation. The two aims of this phase I application are to (a) develop paclitaxel-loaded, biodegradable controlled-release polymeric microspheres, and (b) determine the tumor targeting advantage and antitumor activity of ip paclitaxel microspheres.