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) (PEG₄₅-PAEMA_<i>n</i>, <i>n</i> = 8, 20, 43, 87, and 183), which displayed DP- and pH-dependent plasma membrane-disruptive capability and antitumor activity. Among these, PEG₄₅-PAEMA₄₃ 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.