Ke Lingjie, Li Zhiguo, Fan Xiaoshan, Loh Xian Jun, Cheng Hongwei, Wu Yun-Long, Li Zibiao
School of Pharmaceutical Science, Xiamen University, Xiamen 361102, China.
State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Donghua University, Shanghai 201620, China.
Polymers (Basel). 2021 Apr 13;13(8):1254. doi: 10.3390/polym13081254.
Drug resistance always reduces the efficacy of chemotherapy, and the classical mechanisms of drug resistance include drug pump efflux and anti-apoptosis mediators-mediated non-pump resistance. In addition, the amphiphilic polymeric micelles with good biocompatibility and high stability have been proven to deliver the drug molecules inside the cavity into the cell membrane regardless of the efflux of the cell membrane pump. We designed a cyclodextrin (CD)-based polymeric complex to deliver chemotherapeutic doxorubicin (DOX) and Nur77ΔDBD gene for combating pumps and non-pump resistance simultaneously. The natural cavity structure of the polymeric complex, which was comprised with β-cyclodextrin-graft-(poly(ε-caprolactone)-adamantly (β-CD-PCL-AD) and β-cyclodextrin-graft-(poly(ε-caprolactone)-poly(2-(dimethylamino) ethyl methacrylate) (β-CD-PCL-PDMAEMA), can achieve the efficient drug loading and delivery to overcome pump drug resistance. The excellent Nur77ΔDBD gene delivery can reverse Bcl-2 from the tumor protector to killer for inhibiting non-pump resistance. The presence of terminal adamantyl (AD) could insert into the cavity of β-CD-PCL-PDMAEMA via host-guest interaction, and the releasing rate of polymeric inclusion complex was higher than that of the individual β-CD-PCL-PDMAEMA. The polymeric inclusion complex can efficiently deliver the Nur77ΔDBD gene than polyethylenimine (PEI-25k), which is a golden standard for nonviral vector gene delivery. The higher transfection efficacy, rapid DOX cellular uptake, and significant synergetic tumor cell viability inhibition were achieved in a pump and non-pump drug resistance cell model. The combined strategy with dual drug resistance mechanisms holds great potential to combat drug-resistant cancer.
耐药性总是会降低化疗效果，经典的耐药机制包括药物泵外排和抗凋亡介质介导的非泵耐药。此外，具有良好生物相容性和高稳定性的两亲性聚合物胶束已被证明能够将腔内的药物分子递送至细胞膜，而不受细胞膜泵外排的影响。我们设计了一种基于环糊精（CD）的聚合物复合物，用于同时递送化疗药物阿霉素（DOX）和Nur77ΔDBD基因，以对抗泵耐药和非泵耐药。该聚合物复合物的天然腔结构由β-环糊精-接枝-（聚（ε-己内酯）-金刚烷基）（β-CD-PCL-AD）和β-环糊精-接枝-（聚（ε-己内酯）-聚（甲基丙烯酸2-（二甲氨基）乙酯）（β-CD-PCL-PDMAEMA）组成，能够实现高效的药物负载和递送，以克服泵介导的耐药性。优异的Nur77ΔDBD基因递送能够将Bcl-2从肿瘤保护因子转变为杀伤因子，从而抑制非泵耐药。末端金刚烷基（AD）的存在可通过主客体相互作用插入β-CD-PCL-PDMAEMA的腔内，且聚合物包合物的释放速率高于单独的β-CD-PCL-PDMAEMA。与聚乙烯亚胺（PEI-25k，非病毒载体基因递送的金标准）相比，该聚合物包合物能够更有效地递送Nur77ΔDBD基因。在泵耐药和非泵耐药细胞模型中均实现了更高的转染效率、快速的DOX细胞摄取以及显著的协同肿瘤细胞活力抑制。这种具有双重耐药机制的联合策略在对抗耐药性癌症方面具有巨大潜力。
