Combating cisplatin-resistant lung cancer using a coiled-coil lipopeptides modified membrane fused drug delivery system

Drug resistance to chemotherapy in treating cancers becomes an increasingly serious challenge, which leads to treatment failure and poor patient survival. Drug-resistant cancer cells normally reduce intracellular accumulation of drugs by controlling drug uptake and promoting drug efflux, which severely limits the efficacy of chemotherapy. To overcome this problem, a membrane fused drug delivery system (MF-DDS) was constructed to treat cisplatin (DDP)-resistant lung cancer (A549-DDP) by delivering DDP via membrane fusion using a complementary coiled-coil forming peptides (CP 8 K 4 /CP 8 E 4 ). The lipopeptide CP 8 K 4 was pre-incubated firstly and decorated on the surface of A549-DDP cells, and then the cells interacted with the lipopeptide CP 8 E 4 modified on the lipid bilayer (LB) coated PLGA nanoparticles loading DDP (PLGA-DDP@LB-CP 8 E 4 ), leaded to the direct cytosolic DDP delivery and cancer cell death. Compared with free DDP, this MF-DDS achieved a 13.42-folds reduced IC 50 value of A549-DDP cells in vitro , and tumor size was down-regulated, showing only 1/5.26 of the original weight in vivo . Meanwhile, the anti-drug resistant mechanism was explored, where the MF-DDS inhibited the expression of efflux protein genes, including MRP1, MRP2, and ABCG2, leading to increased intracellular drug accumulations. Altogether, this MF-DDS effectively delivered DDP into DDP-resistant cancer cells, making it a promising and improved pharmacological therapeutic approach for drug-resistant tumor treatment.