Abstract 1082: The dual delivery of y15 and metformin in a PLGA scaffold for the treatment of platinum resistant ovarian cancer

Abstract

Abstract Ovarian cancer is the fifth leading cause of cancer mortality among women in the US. The high mortality rates are linked to the development of resistance to first line chemotherapy with platinum compounds. Currently there is no standard second-line treatment for platinum resistant ovarian cancer (OCpt). Resistance to platinum-based therapy 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 OCpt cells and the combination of a FAK inhibitor, Y15 and metformin may be a promising treatment for OCpt. Oftentimes, drugs have a short half-life which results in low bioavailability at the target site of interests. 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 exposure and toxicity. Poly(lactic-co-glycolic acid) (PLGA) is an α-hydroxy acid-derived polyester copolymer that has a variety of biomaterial applications due to its great biocompatibility and versatility. The degradation rate of PLGA can be easily tailored from days to years providing versatility in the delivery of different drugs. PLGA scaffolds can be fabricated using a mold-less technique that provides controlled release of drugs from such scaffolds. The objective of this study was to utilize biomaterials as a dual drug delivery system and investigate if the combined delivery of both Y15 and Metformin, would result in synergistic effects on cell viability compared to the release of each drug alone. We also evaluated if controlled release of the drugs could be achieved using the scaffolds. To evaluate this, PLGA 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 in PBS, to form a globular scaffold. An MTT assay was used to analyze cell viability in platinum resistant OVCAR3 ovarian cancer cells at an absorbance of 570 nm with a microplate reader. Drug release from the scaffolds were determined in PBS using a microplate reader at absorbance wavelengths of 233 and 380 nm for Metformin and Y15, respectively. Metformin and Y15 treatment reduced cell viability by 34 and 46%, respectively. In combination, both drugs reduced cell viability by 76%. In studies with the fabricated PLGA scaffolds, Y15 and metformin single treatments reduced cell viability by 36% and 11% respectively. However, when the drugs were combined, there was a 95% reduction in cell viability. Furthermore, the delivery of the drugs from the PLGA scaffolds resulted in a sustained release. In conclusion, the delivery of Y15 and Metformin in a biomaterial scaffold can result in controlled released of the drugs and a synergistic effect on cell viability and thus, can be further explored as promising approach for the treatment of platinum resistant ovarian cancer. Citation Format: Emily M. Jordan, Hannah Obregon, Marco Arriaga, Arkene Levy, Sue Anne Chew. The dual delivery of y15 and metformin in a PLGA scaffold for the treatment of platinum resistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1082.