A primary challenge in the treatment of peritoneal malignancies, such as intraperitoneal mesothelioma and ovarian cancer, is preventing tumor recurrence in patients following the surgical removal of tumor (5-year survival <15% and <45%, respectively). Intraperitoneal administration of chemotherapy (e.g., paclitaxel) has been shown clinically to improve patient outcomes and prevent local tumor recurrence (the principal deterrent to long-term survival). However, despite these modest improvements, there are significant limitations to this therapy. For example, the current clinical formulation of paclitaxel (i.e., Taxol) is: A) limited due to toxic side effects resulting from absorption across the entire surface of the peritoneal cavity with no mechanism for tumor specificity; and, B) rapidly cleared from the peritoneal cavity (<10% remaining after 6 hours) resulting quickly in sub-therapeutic drug levels within the tumor tissue. The proposed project develops a novel, patented, technology, the expansile nanoparticle (eNP), designed to address these challenges and to target the primary observable cause of patient relapse (locally recurrent peritoneal tumors). eNPs decrease toxicity and increase efficacy via: a) unique Materials-Based Targeting, which leads to preferential and prolonged accumulation in tumors; and, b) triggered drug release following particle swelling, which occurs in response to exposure to lowered pH (5-6.5) found in the tumor microenvironment or in the endosomes of tumor cells. The results of our Phase I SBIR project include: 1) a radiolabeled biodistribution study demonstrating up to 65% of the injected dose of paclitaxel-loaded-eNPs (PTX-eNPs) accumulates in tumors via Materials-based Targeting, without the need for targeting ligands, and localization persists for up to 2 weeks; 2) PTX-eNPs deliver 10- to 100-fold higher intratumoral concentrations of paclitaxel than Taxol over a seven day period following injection; 3) PTX-eNPs reduce the amount of recurrent ovarian tumor by 3-fold (v. Taxol) and more than double survival (v. Taxol) in an orthotopic, multiple-dose, treatment of intraperitoneal mesothelioma model; and, 4) successful PTX-eNP production on the liter scale. This proposal addresses four activities on the critical path to obtaining an active IND application to evaluate PTX-eNPs in a Phase I clinical trial, including:
Aim 1) Transfer of production processes and analytical methods for the eNP polymer to Norac Pharma (a contract manufacturing organization; CMO) followed by optimization of a scalable method and production of 1-2 kg of eNP polymer material;
Aim 2) Transfer of production processes for the PTX-eNP to Particle Sciences (CMO) followed by optimization of a large-scale manufacturing method, production of PTX-eNPs for use in Aim 3 & 4 in vivo studies, development of analytics and stability testing;
Aim 3) Perform a dose-escalation to determine the NOAEL and toxicity testing under current Good Laboratory Practices (cGLP) in rats; and, Aim 4) Perform a dose-escalation study of combined PTX-eNP and cisplatin in rats.
Intraperitoneal administration of chemotherapy (e.g., paclitaxel) is a promising means of preventing local tumor recurrence in patients with mesothelioma or ovarian cancer. However, new drug delivery technologies are needed to overcome the limitations of current treatments (e.g., ineffective mechanisms for tumor targeting; rapid drug clearance from the peritoneal cavity and tumor tissue; and, dose-limiting toxicities). This SBIR Phase II proposal furthers the development of a paclitaxel-loaded, nanoparticle-based drug delivery system that employs a novel Materials-Based Targeting strategy to meet this need; the results from this work will forward our understanding of the manufacturing, toxicity and in vivo performance of these nanomaterials.
