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

Abstract 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 (IC 50 9 μM) compared to when etoposide (IC 50 >20 μM) was used alone. Concurrently, no toxicity was observed in etoposide‐sensitive HEK293 cells for P : E treatment (IC 50 >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.