Abstract 2010: The application of a PLGA scaffold for the dual delivery of Y15 and metformin for the treatment of platinum resistant ovarian cancer

Abstract Ovarian cancer is the fifth leading cause of cancer mortality among women. This high mortality rate is linked to the development of resistance to first line chemotherapy with platinum compounds which has been attributed in part to increased activity of focal adhesion kinase (FAK). The anti-diabetic drug metformin was previously shown to induce cytotoxicity in PROC cells and thus, the combination of a FAK inhibitor, Y15 and metformin may be a promising treatment for PROC. Biomaterial scaffolds can be utilized to deliver drugs locally to maximize the drug concentration and bioactivity at the target site while minimizing non-target systemic toxicity. The Poly(lactic-co-glycolic acid) (PLGA) is a polyester copolymer and its degradation rate can be easily tailored from days to years providing versatility in the delivery of different drugs. The objectives of this study were to investigate the ability of the PLGA scaffold to control the release of the drugs and if the combined delivery of both Y15 and Metformin would result in additive effects on cell viability compared to the release of each drug alone. Scaffolds were fabricated from an easy and economical mold-less technique by combining PLGA and the drugs (i.e. metformin and/or Y15) in tetraglycol and injected into PBS, to form a globular morphology. An MTT assay was used to analyze cell viability in PROC OVCAR3 cells at an absorbance of 570 nm with a microplate reader. Drug loading from the scaffolds were determined using HPLC at absorbance wavelengths of 233 and 376 nm for Metformin and Y15, respectively. Release kinetics were determined using a spectrometer at absorbance wavelengths of 233 and 380 nm for Metformin and Y15 respectively at each timepoint. Metformin and Y15 treatment reduced cell viability by 34 and 46%, respectively, and 76% when combined. In studies with the fabricated PLGA scaffolds, Y15 only and metformin only scaffolds reduced cell viability by 36 and 11% respectively. When the drugs were combined in the scaffolds, there was a 95% reduction in cell viability. Drug loading and loading efficiency for Metformin only and combination scaffolds were 0.577 and 0.584%, respectively and 6.35 and 6.45%, respectively. Drug loading and loading efficiency for Y15 were 0.059 and 0.064%, respectively, and 12.01 and 14.23%, respectively. A lot of drug was lost into the setting solvent during fabrication. This can be improved by optimizing the setting solvent for Metformin and Y15. Only a short term sustained release was observed from the drug encapsulated scaffolds but may be improved by incorporating the drugs into particles prior to loading into the scaffolds. Although drug loading was low, it was still effective at resulting in cell death. In conclusion, the delivery of Y15 and Metformin in a PLGA biomaterial scaffold can result in an additive effect on cell viability and can be further explored as a promising approach for the treatment of PROC. Citation Format: Hannah Obregon, Viviana Villalobos, Manuel A. Duarte, Emily Jordan, Arkene Levy, Sue Anne Chew. The application of a PLGA scaffold for the dual delivery of Y15 and metformin for the treatment of platinum resistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2010.