Yang Caixia, Pang Xin, Chen Weihai, Wang Xiaoyong, Lin Gan, Chu Chengchao, Zhang Xianzheng, Deng Xianming, Chen Xiaoyuan, Liu Gang
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics and Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen 361102, China.
Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, China.
Sci Bull (Beijing). 2019 May 30;64(10):705-714. doi: 10.1016/j.scib.2019.04.019. Epub 2019 Apr 12.
The development of multiple drug resistance (MDR) to chemotherapy and subsequent treatment failures are major obstacles in cancer therapy. An attractive option for combating MDR is inhibiting the expression of P-glycoprotein (P-gp) in tumor cells. Here, we report a novel chemosensitizing agent, XMD8-92, which can down-regulate P-gp. To enhance the specificity of MDR chemotherapy, a promising nanotheranostic micelle system based on poly(ethylene glycol)-blocked-poly(L-leucine) (PEG-b-Leu) was developed to simultaneously carry the anticancer drug doxorubicin, chemosensitizing agent XMD8-92, and superparamagnetic iron oxide nanoparticles (SPIOs). Featured with MDR environmentally responsive dual-targeting capability, controllable drug delivery, and efficient magnetic resonance (MR) imaging characteristics, the prepared nanotheranostics (DXS@NPs) showed outstanding in vitro cytotoxicity on MDR cells (SCG 7901/VCR) with only 53% of cells surviving compared to 90% of DOX-treated cells. Furthermore, efficient tumor inhibition and highly reduced systemic toxicity were exhibited by MDR tumor-bearing mice treated with DXS@NPs. Overall, the environmentally responsive dual-targeting nanotheranostics represent a promising approach for overcoming cancer MDR.
对化疗产生多药耐药性（MDR）以及随后的治疗失败是癌症治疗中的主要障碍。对抗MDR的一个有吸引力的选择是抑制肿瘤细胞中P-糖蛋白（P-gp）的表达。在此，我们报告了一种新型的化学增敏剂XMD8-92，它可以下调P-gp。为了提高MDR化疗的特异性，开发了一种基于聚（乙二醇）-嵌段-聚（L-亮氨酸）（PEG-b-Leu）的有前景的纳米诊疗胶束系统，以同时携带抗癌药物阿霉素、化学增敏剂XMD8-92和超顺磁性氧化铁纳米颗粒（SPIOs）。所制备的纳米诊疗剂（DXS@NPs）具有MDR环境响应双靶向能力、可控药物递送和高效磁共振（MR）成像特性，对MDR细胞（SCG 7901/VCR）表现出出色的体外细胞毒性，与阿霉素处理的细胞90%的存活率相比，只有53%的细胞存活。此外，用DXS@NPs处理的荷MDR肿瘤小鼠表现出有效的肿瘤抑制和显著降低的全身毒性。总体而言，环境响应双靶向纳米诊疗剂代表了一种克服癌症MDR的有前景的方法。
