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

Xi Wang; Guiquan Liu; Xueyu Pu; Tangjun Ren; Fan Zhang; MengJie Shen; Yan Zhu; Alexander Kros; Jian Yang

doi:10.1016/j.jconrel.2025.01.004

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

J Control Release. 2025 Jan 8:379:45-58. doi: 10.1016/j.jconrel.2025.01.004. Online ahead of print.

Authors

Xi Wang¹, Guiquan Liu¹, Xueyu Pu¹, Tangjun Ren¹, Fan Zhang¹, MengJie Shen², Yan Zhu¹, Alexander Kros³, Jian Yang⁴

Affiliations

¹ State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, China.
² Leiden Institute of Chemistry-Supramolecular and Biomaterial Chemistry, Leiden University, Einsteinweg 55, 2333CC Leiden, the Netherlands.
³ Leiden Institute of Chemistry-Supramolecular and Biomaterial Chemistry, Leiden University, Einsteinweg 55, 2333CC Leiden, the Netherlands. Electronic address: a.kros@chem.leidenuniv.nl.
⁴ State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, China. Electronic address: yang.j2017@tjutcm.edu.cn.

PMID: 39756686
DOI: 10.1016/j.jconrel.2025.01.004

Abstract

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 (CP₈K₄/CP₈E₄). The lipopeptide CP₈K₄ was pre-incubated firstly and decorated on the surface of A549-DDP cells, and then the cells interacted with the lipopeptide CP₈E₄ modified on the lipid bilayer (LB) coated PLGA nanoparticles loading DDP (PLGA-DDP@LB-CP₈E₄), leaded to the direct cytosolic DDP delivery and cancer cell death. Compared with free DDP, this MF-DDS achieved a 13.42-folds reduced IC₅₀ 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.

Keywords: Cisplatin; Coiled-coil lipopeptide; Drug-resistant lung cancer; Membrane fused drug delivery system.