Patients with advanced pancreatic cancer have a bleak prognosis, with a median survival time of less than 6 months. These patients usually present with multiple solid tumors in the peritoneal cavity;systemic intravenous (iv) therapy with various chemotherapeutic agents produce an overall response rate of <10% with little survival advantage. Intraperitoneal (ip) therapy has been used to deliver high drug concentrations to tumors located in the peritoneal cavity. The utility and efficacy of ip therapy are limited by two problems. First, drug penetration into a tumor is usually restricted to the periphery. Second, ip therapy is associated with infection due to prolonged use of indwelling catheter and with local toxicity (i.e., abdominal pain) due to the high local drug concentrations. During the Phase I SBIR grant, we developed a two-component, biocompatible, biodegradable, controlled-release polymeric paclitaxel-loaded microparticles. The first component releases a small fraction of the dose to induce apoptosis, reduce the tumor cell density, disrupt the tumor structure and expand the interstitial space, and thereby facilitates the penetration of drug/particles into tumors. The second component provides sustained drug delivery and thereby eliminates the use of indwelling ip catheter and reducing the potential local toxicity. The two drug release rates also enabled the control of both rapidly and slowly growing tumors. In addition, the particle size and surface properties were selected to enhance the particle retention in the peritoneal cavity and the particle localization on the surface of tumor nodules. This proprietary product is referred to as tumor-priming microparticles (TPM). Our completed studies showed TPM localized on tumor surface, penetrated and resided in tumor matrix. TPM also produced significant survival benefits (3 times longer survival compared to untreated controls) in both early and late stage diseases (indicated by carcinomatosis or ascites formation) in mice bearing the rapidly growing human pancreatic Hs766T xenograft tumors and the slowly growing human ovarian SKOV3 xenograft tumors. The overall goal of the present Phase II SBIR application is to continue the development of TPM, including obtaining an IND from FDA. The three aims are to (a) establish specifications for scale-up GMP products;(b) file IND with FDA;(c) develop a clinical development strategy.
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