Cholesterol-Stabilized Membrane-Active Nanopores with Potent and Specific Anticancer Activities

Cholesterol-enhanced pore formation is one evolutionary means cholesterol-free bacterial cells utilize to specifically target cholesterol-rich eukaryotic cells, thus escaping the toxicity these membrane-lytic pores might have brought onto themselves. Interestingly however, this phenomenon has not been recaptured by any of the hitherto known artificially created transmembrane transporters. Here, we present the first class of artificial cholesterol-dependent nanopores, manifesting such a Nature-inspired nanopore formation sensitively and up-regulated by cholesterol of up to 50 mol% (relative to the lipid molecules). The high modularity in the amphiphilic molecular backbone enables a facile tuning of pore size and consequently channel activity. Possessing a nano-sized cavity of ~ 1.5 nm in diameter, the most active channel Ch-C1 is able to transport nanometer-sized molecules as large as 5(6)-carboxyfluorescein and display potent anticancer activity (IC₅₀= 3.8 µM) toward human hepatocellular carcinomas, with high selectivity index values of 18.5 and > 130 against normal human liver and kidney cells, respectively.