Improving delivery of paclitaxel to ovarian cancer via expansile nanoparticles

Ionic Pharmaceuticals, Watertown MA

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Abstract

ABSTRACT A primary challenge in ovarian cancer is preventing tumor recurrence in patients following a resection / debulking procedure (5-year survival rate <45%). Intraperitoneal (IP) administration of chemotherapy (most notably paclitaxel) can 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 in sub- therapeutic levels within the tumor tissue. The proposed research uses a novel, patented technology, the expansile nanoparticle (eNP), to target the primary observable cause of patient relapse (locally recurrent IP tumor) and address these challenges. eNPs decrease toxicity and increased efficacy via: a) unique Materials- Based Targeting, which leads to preferential uptake 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. Preliminary data demonstrate that, following IP administration, paclitaxel- loaded-eNPs (PTX-eNPs): 1) accumulate in both microscopic (<1 mm) and large (0.5 cm ? 1 cm) IP tumors via Materials-based Targeting without the need for targeting ligands?this characteristic is hypothesized to result from: 1a) the rapid metabolism of cancer cells vs. healthy cells; and, 1b) swelling of the eNPs within tumor cells which disrupts endosomal / autophagosomal turnover and leads to intracellular accumulation of eNPs; 2) exhibit greater in vitro cytotoxicity than Taxol against multi-drug resistant patient samples?this is hypothesized to result from the formation of an intracellular ?drug depot? upon eNP internalization that overcomes cellular evacuation of drug; 3) deliver 10- to 1000-fold higher intratumoral concentrations of paclitaxel than Taxol over a seven day period following injection; and, 4) reduce the amount of recurrent ovarian tumor by 3-fold (v. Taxol) and more than double survival (v. Taxol) in a multiple-dose treatment of IP mesothelioma model (similarly diffuse/widespread disease presentation in the peritoneum). A key Go/No-Go decision regarding the commercialization of this technology is addressed herein, via: 1) determination of the PTX-eNP maximum tolerated dose (MTD) and identification of target organs and toxicity (which may differ from Taxol due to the pharmacokinetics and distribution of the carrier; i.e., eNPs); and, 2) definitive and robust evaluation of PTX-eNPs v. Taxol to determine the value of further preclinical development of this technology. Thus, the aims are: Aim 1) Determine the MTD of PTX-eNPs, the target organs and characteristic toxicity when administered IP; and, Aim 2) Determine the maximum efficacy of PTX-eNPs in treating ovarian cancer.