Abstract 371: Exosomal paclitaxel formulation, alone and in combination with cisplatin, enhances drug’s efficacy against lung cancer

Abstract

Abstract Lung cancer is the second most common cancer in both men and women. Despite several treatment options, chemotherapy remains a major standard-of-care treatment modality. Over time cancer cells acquire drug resistance and evade its effects for survival. The combination of chemotherapeutic drugs with the non-overlapping mechanism of actions are one alternative approach to treat drug-resistant cancers. Paclitaxel (PAC) and cisplatin (CisPt) are widely used to treat non-small cell-lung cancer (NSCLC). However, dose-limiting toxicity, metastasis and chemoresistance have restricted its use. Our recent findings suggested that PAC, when loaded onto folic acid (FA)-functionalized colostrum exosomes (FA-ExoPAC) and administered orally, exceeded the efficacy of i.v. PAC but matched efficacy of i.v. albumin-bound PAC nanoformulation (Abraxane [Abx]) against A549 orthotopic lung tumors. Furthermore, unlike i.v. PAC and i.v. Abx, oral FA-ExoPAC lacked immune toxicity. In order to advance the FA-ExoPAC to clinical studies, we determined if the exosomal formulation will interfere in CisPt therapy. MTT assay showed similar antiproliferative activity of ExoPAC and PAC (IC50 6.25 nM) against drug-sensitive A549 lung cancer cells. However, the antiproliferative activity of ExoPAC (IC50 38 nM) was much greater than for PAC (IC50 >>100 nM) against drug-resistant A549TR lung cancer cells. The activity was further enhanced with FA-functionalized ExoPAC. The enhanced efficacy of the drug presumably resulted from higher cell uptake of ExoPAC and FA-ExoPAC by both drug-sensitive and drug-resistant cells. To determine the effect of the combination of ExoPAC and CisPt, A549 and A549TR cells were treated with increasing concentrations of both the drugs, alone and in combination, for 72 h. MTT assay showed that CisPt (20 µM) and ExoPAC (80 nM) inhibited the growth of A549 cells by 47% and 75%, respectively, the effect was significantly increased with the combination (>95% inhibition). The combination effect was likewise enhanced against the A549TR, except the respective concentration of CisPt (40 µM) and ExoPAC (200 nM) was increased to achieve >95% growth inhibition; the inhibition was lower (50–60%) when treated individually. Together, these data suggest that targeted oral therapy with FA-ExoPAC can potentially eliminate drug resistance and inhibit metastasis with minimal or no side effects and warrants testing in the clinical settings (Supported from the NIH grant R44-CA-221487 and Agnes Brown Duggan Endowment). Citation Format: Raghuram Kandimalla, Disha N. Moholkar, Jayaprakash Jeyabalan, Wendy Spencer, Ramesh C. Gupta, Farrukh Aqil. Exosomal paclitaxel formulation, alone and in combination with cisplatin, enhances drug’s efficacy against lung 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 371.