State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China.
School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
Sci Rep. 2017 May 4;7:46057. doi: 10.1038/srep46057.
One of the promising strategies to overcome tumor multidrug resistance (MDR) is to deliver anticancer drug along with P-glycoprotein (P-gp) inhibitor simultaneously. To enhance the cancer cellular internalization and implement the controlled drug release, herein an iRGD peptide-modified lipid-polymer hybrid nanosystem (LPN) was fabricated to coload paclitaxel (PTX) and tetrandrine (TET) at a precise combination ratio. In this co-delivery system, PTX was covalently conjugated to poly (D,L-lactide-co-glycolide) polymeric core by redox-sensitive disulfide bond, while TET was physically capsulated spontaneously for the aim to suppress P-gp in advance by the earlier released TET in cancer cells. As a result, the PTX+TET/iRGD LPNs with a core-shell structure possessed high drug loading efficiency, stability and redox-sensitive drug release profiles. Owing to the enhanced cellular uptake and P-gp suppression mediated by TET, significantly more PTX accumulated in A2780/PTX cells treated with PTX+TET/iRGD LPNs than either free drugs or non-iRGD modified LPNs. As expected, PTX+TET/iRGD LPNs presented the highest cytotoxicity against A2780/PTX cells and effectively promoted ROS production, enhanced apoptosis and cell cycle arrests particularly. Taken together, the co-delivery system demonstrated great promise as potential treatment for MDR-related tumors based on the synergistic effects of P-gp inhibition, enhanced endocytosis and intracellular sequentially drug release.
克服肿瘤多药耐药性（MDR）的一种有前途的策略是同时输送抗癌药物和 P-糖蛋白（P-gp）抑制剂。为了增强癌细胞的内化并实现控制药物释放，本文构建了一种 iRGD 肽修饰的脂质-聚合物杂化纳米系统（LPN），以精确的组合比例共载紫杉醇（PTX）和汉防己甲素（TET）。在这个共递药系统中，PTX 通过氧化还原敏感的二硫键共价连接到聚（D，L-丙交酯-共-乙交酯）聚合物核上，而 TET 则通过物理包封自发地进行，旨在通过早期在癌细胞中释放 TET 来预先抑制 P-gp。结果，具有核壳结构的 PTX+TET/iRGD LPNs 具有高载药效率、稳定性和氧化还原敏感的药物释放特性。由于 TET 介导的细胞摄取增强和 P-gp 抑制，与游离药物或非 iRGD 修饰的 LPNs 相比，用 PTX+TET/iRGD LPNs 处理的 A2780/PTX 细胞中积累了更多的 PTX。不出所料，PTX+TET/iRGD LPNs 对 A2780/PTX 细胞表现出最高的细胞毒性，并有效地促进了 ROS 产生，增强了细胞凋亡和细胞周期阻滞。综上所述，共递药系统基于 P-gp 抑制、增强内吞作用和细胞内顺序药物释放的协同作用，为治疗 MDR 相关肿瘤提供了很大的希望。
