Despite aggressive multimodality therapy combining surgery, radiation, and/or chemotherapy, mesothelioma is a nearly universally fatal cancer with the majority of patients succumbing to symptoms of local recurrence. To date, there is no effective cure for this disease and there is no way to prevent local recurrence. Consequently, new drug delivery approaches, biomaterials, and mechanisms to deliver pharmacologically active agents are needed. Ionic Pharmaceuticals is developing a novel nanoparticle-based drug delivery system for localizing intraperitoneally administered chemotherapy directly to the site of established disease that remains following surgical resection procedures, resulting in increased tumor-tissue drug concentrations and, subsequently, reduced recurrence and improved patient survival. Recent data demonstrate that, in a murine model of established, human, intraperitoneal (IP) mesothelioma, treatment with paclitaxel-loaded expansile nanoparticles (Pax-eNPs) significantly (p<0.05 ANOVA) improves survival compared to treatment with the standard clinical formulation of paclitaxel solubilized in Cremophor/ethanol (Pax-C/E) (median survival 90 days vs. 51 days;complete clinical responses 66% vs. 16%). The superior performance of Pax-eNPs compared to Pax-C/E is attributed to: 1) tumor specific localization of eNPs;and, subsequently, 2) significantly higher (250- fold) tumor tissue concentrations of paclitaxel when administered as Pax-eNPs as compared to Pax-C/E. Three critical steps towards commercialization of this technology and the use of this drug delivery system in the clinic are addressed in this proposal: synthetic scale-up, biodistribution, and preclinical testing Thus, the specific aims of this proposal are:
Aim 1 : Perform large-scale synthesis of eNP monomer (~500 g) and paclitaxel-loaded-eNPs (2 L);and, optimize batch-to-batch reproducibility with establishment of release specifications and analytics.
Aim 2 : Determine the biodistribution of C14-labeled-eNPs (IP and plasma-time course, tissue distribution, routes and rates of excretion following IP injection in rats).
Aim 3 : Submit a proposal to the Nanotechnology Characterization Laboratory (NCL) for further pre- clinical testing of the paclitaxel-loaded-eNPs. At the completion of these Phase I aims, we will be positioned to submit a Phase II SBIR for GMP synthesis of Pax-eNPs and pre-clinical PK, safety, and toxicology studies. We have discussed this project with the NCL (see letter) and will collaborate and coordinate our activities with them to ensure an efficient and rigorous development and commercialization of this drug delivery technology.
New drug delivery approaches are needed to improve the therapeutic window of many current anti-cancer agents. One example where new approaches can have a significant impact is in the prevention of recurrent mesothelioma following surgical resection-which carries a universally fatal diagnosis. This SBIR Phase I proposal furthers the development of a new expansile nanoparticle drug delivery system for localized delivery of paclitaxel to intraperitoneal mesothelioma tumors by manufacturing it on a large scale and determining its biodistribution.