CAS Key Laboratory of Brain Function and Disease, and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, P. R. China.
ACS Nano. 2011 May 24;5(5):3679-92. doi: 10.1021/nn200007z. Epub 2011 Apr 12.
Multidrug resistance (MDR) is a major impediment to the success of cancer chemotherapy. Through the development of a drug delivery system that tethers doxorubicin onto the surface of gold nanoparticles with a poly(ethylene glycol) spacer via an acid-labile linkage (DOX-Hyd@AuNPs), we have demonstrated that multidrug resistance in cancer cells can be significantly overcome by a combination of highly efficient cellular entry and a responsive intracellular release of doxorubicin from the gold nanoparticles in acidic organelles. DOX-Hyd@AuNPs achieved enhanced drug accumulation and retention in multidrug resistant MCF-7/ADR cancer cells when it was compared with free doxorubicin. It released doxorubicin in response to the pH of acidic organelles following endocytosis, opposite to the noneffective drug release from doxorubicin-tethered gold nanoparticles via the carbamate linkage (DOX-Cbm@AuNPs), which was shown by the recovered fluorescence of doxorubicin from quenching due to the nanosurface energy transfer between the doxorubicinyl groups and the gold nanoparticles. DOX-Hyd@AuNPs therefore significantly enhanced the cytotoxicity of doxorubicin and induced elevated apoptosis of MCF-7/ADR cancer cells. With a combined therapeutic potential and ability to probe drug release, DOX-Hyd@AuNPs represent a model with dual roles in overcoming MDR in cancer cells and probing the intracellular release of drug from its delivery system.
多药耐药性（MDR）是癌症化疗成功的主要障碍。通过开发一种药物传递系统，将阿霉素通过酸不稳定键（DOX-Hyd@AuNPs）与聚乙二醇间隔臂连接到金纳米粒子的表面，我们已经证明，通过高效的细胞内进入和响应酸性细胞器中金纳米粒子内阿霉素的释放，可以显著克服癌细胞的多药耐药性。与游离阿霉素相比，DOX-Hyd@AuNPs 在多药耐药 MCF-7/ADR 癌细胞中实现了增强的药物积累和保留。它在细胞内摄取后响应酸性细胞器的 pH 释放阿霉素，与通过氨基甲酸酯键（DOX-Cbm@AuNPs）连接的阿霉素结合的金纳米粒子的无效药物释放相反，这是通过阿霉素荧光从纳米表面能量转移之间的淬灭恢复证明的阿霉素基组和金纳米粒子。因此，DOX-Hyd@AuNPs 显著增强了阿霉素的细胞毒性，并诱导 MCF-7/ADR 癌细胞的凋亡增加。具有联合治疗潜力和探测药物释放的能力，DOX-Hyd@AuNPs 代表了一种克服癌细胞多药耐药性和探测其药物传递系统从细胞内释放的双重作用的模型。
