Host Defense Peptide Mimics Synergize with Pt(IV) Prodrugs for Surmounting Cisplatin Resistance via Selective Cancer Membrane Disruption

Drug resistance has emerged as a great challenge for achieving satisfactory therapeutic efficacy in platinum-based chemotherapy. Specifically, we synthesized a series of host defense peptide mimics with different degrees of polymerization (DP), i.e., poly(ethylene glycol)-poly(2-azepane ethyl methacrylate) (PEG 45 -PAEMA n, n = 8, 20, 43, 87, and 183), which displayed DP- and pH-dependent plasma membrane-disruptive capability and antitumor activity. Among these, PEG 45 -PAEMA 43 exhibited the highest cytotoxicity at tumor acidity (pH 6.7), selectivity index, and in vivo antitumor activity, and was selected to encapsulate the hydrophobic Pt(IV) prodrug to form the PEG-PAEMA-Pt(IV) nanoprodrug. The nanoprodrug boosted the membrane-disruptive capability and antitumor activity of A549 and cisplatin-resistant A549/DDP cells at tumor acidity. Notably, it exhibited a much higher cellular uptake for A549/DDP cells and in vivo antitumor activity than PEG-PAEMA or cisplatin alone. This indicated that the PEG-PAEMA-Pt(IV) nanoprodrug could break the drug diffusion barrier posed by the cell membrane and disable even reverse efflux resistance.