Reversal of Cisplatin Resistance in Ovarian Cancer by the Multitargeted Nanodrug Delivery System Tf-Mn-MOF@Nira@CDDP

作者：Liu, Yuan; Wang, Yiru; Guan, Xue; Wu, Qiong; Zhang, Mengjun; Cui, Ping; Wang, Can; Chen, Xiuwei^*; Meng, Xianwei^*; Ma, Tengchuang^*

来源：ACS applied materials & interfaces, 2023, 15(22): 26484-26495.

DOI：10.1021/acsami.3c05374

• ovarian cancer
• cisplatin resistance
• niraparib
• glutathione
• metal-organic framework

Cisplatin (CDDP) is a widely used chemotherapeutic drugwith provenefficacy for treating tumors. However, its use has been associatedwith severe side effects and eventually leads to drug resistance,thus limiting its clinical application in patients with ovarian cancer(OC). Herein, we aimed to investigate the success rate of reversingcisplatin resistance using a synthetic, multitargeted nanodrug deliverysystem comprising a Mn-based metal-organic framework (Mn-MOF)containing niraparib (Nira) and CDDP alongside transferrin (Tf) conjugatedto the surface (Tf-Mn-MOF@Nira@CDDP; MNCT). Our results revealed thatMNCT can target the tumor site, consume glutathione (GSH), which ishighly expressed in drug-resistant cells, and then decompose to releasethe encapsulated Nira and CDDP. Nira and CDDP play a synergistic rolein increasing DNA damage and apoptosis, exhibiting excellent antiproliferation,migration, and invasion activities. In addition, MNCT significantlyinhibited tumor growth in tumor-bearing mice and exhibited excellentbiocompatibility without side effects. Furthermore, it depleted GSH,downregulated multidrug-resistant transporter protein (MDR) expression, and upregulated tumor suppressor protein phosphataseand tensin homolog (PTEN) expression, consequentlyreducing DNA damage repair and reversing cisplatin resistance. Theseresults indicate that multitargeted nanodrug delivery systems canprovide a promising clinical approach to overcoming cisplatin resistance.This study provides an experimental basis for further investigationinto multitargeted nanodrug delivery systems to reverse cisplatinresistance in patients with OC.

• 单位
  哈尔滨医科大学