Etoposide-Entrapped Progesterone-Cationic Lipid Nanoaggregates as Selective Therapeutics against Etoposide-Resistant Colorectal Cancer Cells.

Drug resistance has a major impact on the treatment of several cancers. This is mainly due to the overexpression of cellular drug efflux proteins. Hence, drug-delivery systems that can avoid this resistance are needed. We report PR10, a progesterone-cationic lipid conjugate, as a self-assembling nanoaggregate that delivers a drug cargo of etoposide, a topoisomerase inhibitor, selectively to cancer cells. In this study, we observed that etoposide nanoaggregates (P : E) caused selective and enhanced toxicity in etoposide-resistant CT26 cancer cells (IC50 9 µM) compared to when etoposide (IC50 >20 µM) was used alone. Concurrently, no toxicity was observed in etoposide-sensitive HEK293 cells for P : E treatment (IC50 >20 µM). The P : E-treated cancer cells seem to have no effect on ABCB1 expression, but etoposide-treated cells exhibited a twofold increase in ABCB1 expression, a potent efflux protein for several xenobiotic compounds. This observation supports the notion that the enhanced toxicity of P : E nanoaggregates is due to their ability to keep the expression of ABCB1 low, thus allowing longer intracellular residence of etoposide. In a BALB/c orthotopic colorectal cancer model, the nanoaggregates led to enhanced survival (45 days) compared to etoposide-treated mice (39 days). These findings suggest that PR10 could be used as a potential cancer-selective etoposide delivery vehicle to treat several etoposide-resistant cancers with fewer side effects due to the nonspecific toxicity of the drug.