Pancreatic cancer is the fourth leading cause of cancer death in the United States with only 7% of diagnosed patients surviving 5 years. Current systemic chemotherapies have not been very effective at decreasing tumor burden, but nonetheless expose patients to the adverse side effects of treatment. Poly(lactic-co-glycolic acid)-based microparticles (MPs) are a promising tool for localized drug delivery within the tumor due to their high biocompatibility, flexibility in drug encapsulation and extended drug release. A previous in vivo experiment from our laboratory demonstrated minimal penetration of systemic gemcitabine into the tumor resulting in low levels of apoptosis compared to locally injected gemcitabine-loaded microparticles (GMPs), which demonstrated much higher levels of intratumoral apoptosis. The present study investigated whether paclitaxel-loaded microparticles (PMPs), alone or in combination with GMPs, decreased gemcitabine resistance, colony formation and promoted cell death in two human pancreatic cancer cell lines, PANC-1 and MIAPaCa-2. In vitro studies with PANC-1 cells treated with PMPs or GMPs showed enhanced cell killing and a significant decrease in colony formation in the higher MPs volume groups. Moreover, the combination treatment of PMPs followed by GMPs, showed a greater decrease in colony formation in comparison with the single treatments. Subsequently, we tested the effect of single and combination treatments on two well-known resistance markers for gemcitabine, ribonucleotide reductase catalytic subunit M1 (RRM1) and cytidine deaminase (CDA), as well as on the promotion of cell death measuring cleaved caspase-3 (CC3). Interestingly, PANC-1 cells treated with PMPs alone showed an increase in CC3 expression and a significant decrease in the expression of both markers when treated with different volumes of PMPs. MIAPaCa-2 cells exhibited similar results. The combination treatment also showed a modulation in RRM1 and CDA proteins and an increase in CC3 expression. However, when PANC-1 cells were treated with GMPs alone, both markers went up suggesting an increase in resistance against gemcitabine. These experiments are in progress for the MIAPaCa-2 cells. In addition, preliminary drug release studies with GMPs demonstrated detection of gemcitabine up to 14 days. In conclusion, our data demonstrated that PMPs and GMPs promote an increase in cancer cell death. Furthermore, the combination of the drug-loaded MPs indicated a reduction in drug resistance and clear impairment in colony formation. Further studies are in progress to investigate combination MPs injections in a mouse model of pancreatic cancer to confirm in vivo efficacy. The described drug delivery method has the potential to be a more efficient local treatment modality than systemic drug against pancreatic cancer.
Citation Format: Maria Munoz-Sagastibelza, Ariella Moshchinsky, Oluwafeyikemi Okome, Jenny E. Paredes Sanchez, Raavi Gupta, Laura Martello-Rooney. Paclitaxel-loaded microparticles in combination with gemcitabine-loaded microparticles decreases gemcitabine resistance and promotes cell death in pancreatic cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1091. doi:10.1158/1538-7445.AM2017-1091