Impact of Anticancer Polymers on Model Cancerous Membranes: Molecular-Level Insight from Computer Simulations

Abstract Anticancer polymers represent a novel, promising class of therapeutical agents aimed to combat emerging multidrug resistance. Here, we employ atomic-scale computer simulations to explore for the first time the molecular-level impact of anticancer polymers on model cancerous membranes. To this end, we focused on methacrylate-based random copolymers with proven anticancer activity. Our computational findings show that phosphatidylserine lipids on the surface of cancerous membranes serve as the primary targets for protonated amine groups of anticancer polymers. Adsorption of cationic anticancer polymers induces the lateral ordering and clustering of anionic phosphatidylserines in line with existing experimental data. Embedding polymers into the membrane results in an expansion of the membrane, which is accompanied by a drop in its thickness and by disordering of lipid acyl chains. Within the membrane, anticancer polymers adopt a comb-like conformation with the backbones being buried in the hydrophobic membrane core and the protonated side groups being bound to lipid phosphate groups. The polymer-induced thinning of the membrane turns out to depend non-monotonically on polymer hydrophobicity. This highlights the importance of a balance between the overall charge and the hydrophobicity of polymers for promoting anticancer activity. Although spontaneous pore formation was shown to be beyond the time scales accessible through atomic-scale simulations, membrane thinning can be considered a first step toward the nucleation of transmembrane pores and subsequent membrane collapse. Our electroporation tests showed that the membrane became more prone to poration upon adsorption of anticancer polymers. All in all, our computational findings provide valuable microscopic information for further optimization of anticancer polymeric agents.