Improving delivery of paclitaxel to ovarian cancer via expansile nanoparticles

ABSTRACT A primary challenge in ovarian cancer is preventing tumor recurrence in patients following a resection debulking procedure year survival rate andlt 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 andlt remaining after 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 found in the tumor microenvironment or in the endosomes of tumor cells Preliminary data demonstrate that following IP administration paclitaxel loaded eNPs PTX eNPs accumulate in both microscopic andlt mm and large cm cm IP tumors via Materials based Targeting without the need for targeting ligands this characteristic is hypothesized to result from a the rapid metabolism of cancer cells vs healthy cells and b swelling of the eNPs within tumor cells which disrupts endosomal autophagosomal turnover and leads to intracellular accumulation of eNPs 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 deliver to fold higher intratumoral concentrations of paclitaxel than Taxol over a seven day period following injection and reduce the amount of recurrent ovarian tumor by 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 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 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 Determine the MTD of PTX eNPs the target organs and characteristic toxicity when administered IP and Aim Determine the maximum efficacy of PTX eNPs in treating ovarian cancer PROJECT NARRATIVE Intraperitoneal administration of chemotherapy e g paclitaxel is a promising means of preventing local tumor recurrence in patients with ovarian cancer However new drug delivery technologies are needed to overcome the limitations of current treatments e g no mechanism for tumor targeting rapid drug clearance from the peritoneal cavity and tumor tissue and dose limiting toxicities This SBIR Phase I 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 and determines the maximum tolerated dose and maximum therapeutic efficacy compared to the clinically used formulation the outcome will answer whether this technology meets the prospective quantitative Go No Go criteria necessary for further development