Abstract 3082: Synergistic inhibition of TNBC cell growth by novel doxorubicin/salinomycin-encapsulated dual drug-nanoparticles

Abstract

Abstract Triple negative breast cancer (TNBC) is an aggressive subtype with limited treatment options and a worse clinical outcome as compared with other breast cancer subtypes. Doxorubicin (DOX) is considered to be one of the most effective agents in the treatment. Unfortunately, resistance to DOX is very common due to drug efflux mediated by overexpression of ABC transporter. Recent studies suggest that cancer stem cells (CSCs) play an important role in tumorigenesis and biology of TNBC. Targeting CSCs may be a promising, novel strategy for the treatment of this aggressive disease. Recent studies have shown that salinomycin (SAL) preferentially targets the viability of CSCs. In the present study, SAL and DOX were co-encapsulated in polylactic acid (PLA)-based block copolymeric nanoparticles (NPs) (novel Quatramer Technology) to efficiently co-deliver these agents to treat TNBC cells. Generated SAL-DOX co-encapsulated dual drug NPs showed an average diameter of 91 ± 2 nm, zeta potential of -9.4 ± 1.1mV and PDI of less than 0.1. Both of these anti-cancer agents showed slow and sustained release profile in non-physiological buffer (PBS, pH 7.4) from these dual drug-encapsulated NPs. Additionally, multiple ratios (DOX:SAL = 3:1, 1:1, 1:3) were encapsulated to generate diverse dual drug NPs. The results demonstrate that, in contrast to 1:1 and 1:3, treatment of TNBC cells with 3:1 ratio of DOX:SAL dual drug NPs, was associated with significant inhibition of growth in vitro and more interestingly, was synergistic as compared to either agent alone. The IC50 of DOX and SAL in single drug-encapsulated NPs is 0.56 uM and 3.56 uM respectively. Importantly, the IC50 of DOX and SAL in dual drug-encapsulated NPs is 0.13 uM and 0.034 uM respectively. Furthermore, bi-weekly treatment of BALB/c wild-type mice harboring EAT cells (as syngeneic mouse model) with DOX-SAL (3:1) dual drug NPs at a dose of 3 mg/kg i.v. resulted in significant tumor growth inhibition (TGI). The TGI effect was synergistic with dual-NPs as compared to either agent alone. The TGI by dual drug NPs was without any significant effect on the body weights of the mice. These results demonstrate that a novel dual drug NP formulation of DOX and SAL in a unique ratio (3:1) represents an approach for successful targeting of CSCs and bulk tumor cells in TNBC and potentially other cancer types. Citation Format: Anees Mohammad, Sachchidanand Tiwari, Neha Mehrotra, Bozena Korczak, Sireesh Appajosyula, Steve Laumas, Surender M. Kharbanda, Harpal Singh. Synergistic inhibition of TNBC cell growth by novel doxorubicin/salinomycin-encapsulated dual drug-nanoparticles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3082.