Yu Jinling, Hu Fengli, Zhu Qiankun, Li Xiaodong, Ren Haiyang, Fan Shengjie, Qian Bo, Zhai Bo, Yang Dongdong
Department of General Medicine, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
Department of Gastroenterology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
Nanoscale Res Lett. 2020 Mar 12;15(1):59. doi: 10.1186/s11671-019-3228-z.
Multidrug resistance (MDR) based on ATP-dependent efflux transporters (p-glycoprotein (p-gp)) remains a major obstacle in successful chemotherapy treatment. Herein, we have investigated the potential of PD-L1 mAb-conjugated nanoliposome to serve as a targeted delivery platform for the co-delivery of paclitaxel (PTX) and p-gp specific transport inhibitor (TQD, tariquidar) in drug-resistant gastric cancers. Two drugs, PTX and TQD, were co-loaded in a single vehicle in a precise ratio to enhance the prospect of combination chemotherapeutic effect. Cellular uptake study indicated that PD-PTLP had higher internalization efficiency in PD-L1 receptor overexpressing SGC7901/ADR cells than non-targeted PTLP. Highest synergy was observed at a weight fraction of 1/0.5 (PTX/TQD) and the combination of PTX and TQD resulted in obvious synergistic effect compared to that of individual drugs alone. Our in vitro results showed that TQD was effective in reversing the multidrug resistance in SGC7901/ADR cells. The IC50 value of PD-PTLP was 0.76 μg/ml compared to 6.58 μg/ml and 7.64 μg/ml for PTX and TQD, respectively. PD-TPLP triggered significantly higher levels of reactive oxygen species (ROS) and cell apoptosis compared to that of free PTX or TQD. Furthermore, the in vivo antitumor study showed that the combination chemotherapy of PD-PTLP displayed a significant inhibition of tumor burden of drug-resistant xenograft tumors with significantly higher terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells. Furthermore, free PTX resulted in significant increase in the levels of AST and ALT while PD-PTLP insignificantly different compared to that of control indicating the safety index. Overall, we believe that combination of anticancer drug with a p-gp inhibitor could provide a potential direction toward the treatment of drug-resistant gastric tumors.
基于ATP依赖的外排转运蛋白（P-糖蛋白（P-gp））的多药耐药性（MDR）仍然是化疗成功治疗的主要障碍。在此，我们研究了PD-L1单克隆抗体偶联纳米脂质体作为靶向递送平台，用于在耐药性胃癌中共递送紫杉醇（PTX）和P-gp特异性转运抑制剂（TQD， tariquidar）的潜力。两种药物PTX和TQD以精确比例共负载于单一载体中，以增强联合化疗效果的前景。细胞摄取研究表明，与非靶向PTLP相比，PD-PTLP在过表达PD-L1受体的SGC7901/ADR细胞中具有更高的内化效率。在重量比为1/0.5（PTX/TQD）时观察到最高的协同作用，与单独使用单一药物相比，PTX和TQD的组合产生了明显的协同效应。我们的体外结果表明，TQD可有效逆转SGC7901/ADR细胞中的多药耐药性。PD-PTLP的IC50值为0.76μg/ml，而PTX和TQD的IC50值分别为6.58μg/ml和7.64μg/ml。与游离PTX或TQD相比，PD-TPLP引发了更高水平的活性氧（ROS）和细胞凋亡。此外，体内抗肿瘤研究表明，PD-PTLP的联合化疗对耐药异种移植瘤的肿瘤负荷有显著抑制作用，且末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）阳性细胞明显增多。此外，游离PTX导致AST和ALT水平显著升高，而PD-PTLP与对照组相比无显著差异，表明其安全指数。总体而言，我们认为抗癌药物与P-gp抑制剂的联合应用可能为耐药性胃肿瘤的治疗提供一个潜在方向。
