Evaluation of Drug-loaded Microparticles and Paclitaxel-based Monotherapy in Human Pancreatic Adenocarcinoma in vitro Models

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the US. Due to late-stage diagnosis, most patients are ineligible for surgical resection, and current systemic treatments have shown limited success in increasing surgical candidacy or improving survival rates. My project is built on the hypothesis that direct injection of chemotherapeutic-loaded PLGA microparticles (MPs) into PDAC tumors via endoscopic ultrasound-guided fine needle injection (EUS-FNI) can enhance treatment response. Although our laboratory has developed protocols for formulating gemcitabine- and paclitaxel-loaded microparticles (GMPs and PMPs), the in vitro cytotoxicity of these MPs had not been characterized, leaving their potential efficacy in the treatment of PDAC uncertain. A primary objective of my thesis was to evaluate the short-term cytotoxicity of GMPs and PMPs in in vitro models of PDAC. Nanoparticle albumin bound-PTX has only been approved for the treatment of PDAC in combination with gemcitabine (GEM), but the efficacy of PTX-based monotherapy of PDAC has not been adequately investigated so the potential benefit to patients had not been determined. To reach these goals: 1. I assessed the short-term in vitro cytotoxicity of drug-loaded MPs in human PDAC cell lines and patient derived organoids. During these studies, I incorporated a quality control step to ensure the removal of unencapsulated GEM from GMPs batches. 2. I investigated the efficacy of PTX-based monotherapy in human PDAC cell lines. I treated cells with the different drug-loaded MPs regimens or free drug (GEM, PTX, or their combination) to compare the responses of the cell lines to the various treatments. My results demonstrate that: 1. Treatment of PDAC in vitro models with our drug-loaded MPs treatments significantly reduced cell viability. 2. PTX exhibited efficacy in MIA PaCa-2 cells and was not inferior to, and in some cases superior to, GEM or GEM+PTX treatments of PANC-1 cells. I present treatments in which GEM antagonized the effects of PTX upon combination treatment of both cell lines. My work: 1. Establishes the in vitro efficacy of our MPs, therefore justifying more advanced preclinical studies into their efficacy against PDAC. 2. Presents a novel antagonism that supports the potential benefit of single-agent PTX in the treatment of PDAC and justifies additional studies that may call into question the use of the GEM/nab-PTX combination treatment in patients without stratification based on their response to these different treatments.