Department of Biopharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, PR China.
Biomaterials. 2012 Oct;33(28):6877-88. doi: 10.1016/j.biomaterials.2012.06.019. Epub 2012 Jul 6.
A star-shape copolymer of nanostructure-forming material, P-glycoprotein (P-gp) reversible inhibitor and anticancer enhancer, lysine-linked di-tocopherol polyethylene glycol 2000 succinate (PLV(2K)), was synthesized to overcome multidrug resistance (MDR) in cancer chemotherapy. The critical micellar concentration of PLV(2K) was as low as 1.14 μg/mL, which can endow nanoassemblies good physical stability. Doxorubicin (DOX) was encapsulated into the hydrophobic core of PLV(2K) (PLV(2K)-DOX), with encapsulation efficiency as high as 94.5% and a particle size of 16.4 nm. DOX released from PLV(2K)-DOX nanomicelles was pH-dependent, which ensures micelles stable in blood circulation and releases DOX within tumor cells. Facilitated by the cytotoxicity and uncompetitive P-gp ATPase inhibition by PLV(2K), PLV(2K)-DOX showed greater cytotoxicity compared with DOX solution with increased intracellular accumulation in resistant MCF-7/Adr cells. PLV(2K)-DOX nanomicelles were uptaken into MCF-7/Adr cells via macropinocytosis and caveolae-mediated endocytosis, which further facilitate escapement of P-gp efflux. The anticancer efficacy in vivo was evaluated in 4T1-bearing mice and inhibition of tumor by PLV(2K)-DOX was more effective than TPGS-DOX and DOX solution. In summary, PLV(2K) copolymer has striking functions such as uncompetitive P-gp ATPase reversible inhibitor and anticancer efficacy, and could be a promising nanocarrier in improving the chemotherapy of hydrophobic anticancer drugs.
一种具有星形结构的纳米结构形成材料、P 糖蛋白（P-gp）可逆抑制剂和抗癌增强剂的共聚物，赖氨酸连接的二生育酚聚乙二醇 2000 琥珀酸酯（PLV(2K)）被合成以克服癌症化疗中的多药耐药性（MDR）。PLV(2K)的临界胶束浓度低至 1.14μg/mL，可赋予纳米组装体良好的物理稳定性。阿霉素（DOX）被包裹在 PLV(2K)的疏水性核心中（PLV(2K)-DOX），包封效率高达 94.5%，粒径为 16.4nm。PLV(2K)-DOX 纳米胶束中的 DOX 释放呈 pH 依赖性，这确保了胶束在血液循环中稳定，并在肿瘤细胞内释放 DOX。PLV(2K)通过细胞毒性和非竞争性 P-gp ATP 酶抑制作用促进了 DOX 的释放，与 DOX 溶液相比，PLV(2K)-DOX 在耐药 MCF-7/Adr 细胞中表现出更高的细胞毒性，并且具有更高的细胞内积累。PLV(2K)-DOX 纳米胶束通过巨胞饮作用和小窝蛋白介导的内吞作用被 MCF-7/Adr 细胞摄取，这进一步促进了 P-gp 外排的逃逸。在 4T1 荷瘤小鼠中评估了体内抗癌疗效，PLV(2K)-DOX 抑制肿瘤的效果优于 TPGS-DOX 和 DOX 溶液。总之，PLV(2K)共聚物具有非竞争性 P-gp ATP 酶可逆抑制剂和抗癌功效等显著功能，可能成为提高疏水性抗癌药物化疗效果的有前途的纳米载体。
