Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University, Department of Lymphoma, Sino-US Center for Lymphoma and Leukemia, Tianjin 300060, China.
Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Tianjin Medical University, Tianjin 300060, China.
Mater Sci Eng C Mater Biol Appl. 2018 Mar 1;84:108-117. doi: 10.1016/j.msec.2017.11.040. Epub 2017 Nov 28.
Multidrug resistance (MDR) has become a very serious problem in cancer therapy. To effectively reverse MDR in tumor treatments, a new pH-sensitive nano drug delivery system (NDDS) composed of mesoporous silica nanoparticles (MSNs) and d-a-tocopheryl poly-ethylene glycol 1000 succinate (TPGS) copolymers was synthesized to deliver doxorubicin (DOX) into drug-resistant breast cancer cell line (MCF-7/ADR). DOX@MSNs-TPGS were characterized to have a single peak size distribution, high DOX loading efficiency and a pH-dependent drug release profile. MSNs-TPGS were internalized via caveolae, clathrin-mediated endocytosis and energy-dependent cellular uptake. The DOX@MSNs-TPGS exhibited 10-fold enhanced cell killing potency compared to free DOX and DOX@MSNs. The enhanced MDR reversal effect was ascribed to the higher amount of cellular uptake of DOX@MSNs-TPGS in MCF-7/ADR cells than that of free DOX and DOX@MSNs, as a result of the inhibition of P-gp mediated drug efflux by TPGS. In vivo studies of NDDS in tumor-bearing mice showed that DOX@MSNs-TPGS displayed better efficacy against MDR tumors in mice and reached the tumor site more effectively than DOX and DOX@MSNs, with minimal toxicity. These results suggest DOX@MSNs-TPGS developed in this study have promising applications to overcome drug resistance in tumor treatments.
多药耐药（MDR）已成为癌症治疗中一个非常严重的问题。为了有效地逆转肿瘤治疗中的 MDR，合成了一种由介孔硅纳米粒子（MSNs）和 d-a-生育酚聚乙二醇 1000 琥珀酸酯（TPGS）共聚物组成的新型 pH 敏感的纳米药物传递系统（NDDS），以将阿霉素（DOX）递送至耐药乳腺癌细胞系（MCF-7/ADR）。对 DOX@MSNs-TPGS 进行了表征，结果表明其具有单峰尺寸分布、高 DOX 负载效率和 pH 依赖性药物释放特性。MSNs-TPGS 通过 caveolae、网格蛋白介导的内吞作用和能量依赖性细胞摄取被内化。与游离 DOX 和 DOX@MSNs 相比，DOX@MSNs-TPGS 表现出 10 倍增强的细胞杀伤效力。增强的 MDR 逆转作用归因于 DOX@MSNs-TPGS 在 MCF-7/ADR 细胞中的细胞摄取量高于游离 DOX 和 DOX@MSNs，这是由于 TPGS 抑制了 P-糖蛋白介导的药物外排。在荷瘤小鼠的 NDDS 体内研究中，DOX@MSNs-TPGS 对小鼠 MDR 肿瘤的疗效优于 DOX 和 DOX@MSNs，到达肿瘤部位的效率更高，毒性最小。这些结果表明，本研究中开发的 DOX@MSNs-TPGS 具有克服肿瘤治疗中耐药性的应用前景。
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