College of Chemistry and Chemical Engineering, Anhui University , Hefei 230601, China.
Department of Oncology, First Affiliated Hospital, Anhui Medical University , Hefei 230022, China.
ACS Appl Mater Interfaces. 2017 Aug 2;9(30):25152-25163. doi: 10.1021/acsami.7b07219. Epub 2017 Jul 24.
Multidrug resistance (MDR) has been recognized as a major obstacle to successful chemotherapy for cancer in the clinic. In recent years, more and more nanoscaled drug delivery systems (DDS) are constructed to modulate drug efflux protein (P-gp) and deliver chemotherapeutic drugs for overcoming MDR. Among them, d-α-tocopheryl polyethylene glycol succinate (TPGS) has been widely used as a drug carrier due to its capability of inhibiting overexpression of P-gp and good amphiphilicity favorable for improving permeation and long-circulation property of DDS. In the present work, a novel kind of mitochondria-targeting nanomicelles-based DDS is developed to integrate chemotherapeutics delivery with fluorescence imaging functionalities on a comprehensive nanoplatform. The mitochondria-targeting nanomicelles are prepared by self-assembly of triphenylphosphine (TPP)-modified TPGS and fluorescent carbon quantum dots (CQDs) in an n-hexane/HO mixed solution, named CQDs-TPGS-TPP. Notably, although the drug loading content of doxorubicin (DOX) in the as-prepared nanomicelles is as low as 3.4%, the calculated resistant index (RI) is greatly decreased from 66.23 of free DOX to 7.16 of DOX-loaded nanomicelles while treating both parental MCF-7 cells and drug-resistant MCF-7/ADR cells. Compared with free DOX, the penetration efficiency of DOX-loaded nanomicelles in three-dimensional multicellular spheroids (MCs) of MCF-7/ADR is obviously increased. Moreover, the released DOX from the nanomicelles can cause much more damage to cells of drug-resistant MCs. These results demonstrate that our constructed mitochondria-targeting nanomicelles-based DDS have potential application in overcoming MDR of cancer cells as well as their MCs that mimic in vivo tumor tissues. The MDR-reversal mechanism of the DOX-loaded CQDs-TPGS-TPP nanomicelles is also discussed.
多药耐药（MDR）已被认为是临床癌症化疗成功的主要障碍。近年来，越来越多的纳米级药物传递系统（DDS）被构建用于调节药物外排蛋白（P-gp）并传递化疗药物以克服 MDR。其中，d-α-生育酚聚乙二醇琥珀酸酯（TPGS）由于能够抑制 P-gp 的过度表达和良好的两亲性，有利于提高 DDS 的渗透性和长循环性能，已被广泛用作药物载体。在本工作中，开发了一种新型的基于线粒体靶向的纳米胶束型 DDS，将化疗药物传递与荧光成像功能集成在一个综合的纳米平台上。线粒体靶向纳米胶束是由三苯基膦（TPP）修饰的 TPGS 和荧光碳量子点（CQDs）在正己烷/HO 混合溶液中自组装而成的，命名为 CQDs-TPGS-TPP。值得注意的是，尽管所制备的纳米胶束中阿霉素（DOX）的载药量低至 3.4%，但计算出的耐药指数（RI）从游离 DOX 的 66.23 大大降低至 DOX 负载纳米胶束的 7.16，同时处理亲本 MCF-7 细胞和耐药 MCF-7/ADR 细胞。与游离 DOX 相比，DOX 负载纳米胶束在 MCF-7/ADR 的三维多细胞球体（MCs）中的穿透效率明显提高。此外，从纳米胶束中释放的 DOX 对耐药 MCs 细胞造成的损伤更大。这些结果表明，我们构建的基于线粒体靶向的纳米胶束型 DDS 具有克服癌细胞及其模拟体内肿瘤组织的 MDR 的潜力。还讨论了 DOX 负载的 CQDs-TPGS-TPP 纳米胶束的 MDR 逆转机制。
