Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
Colloids Surf B Biointerfaces. 2020 Dec;196:111284. doi: 10.1016/j.colsurfb.2020.111284. Epub 2020 Jul 29.
Multidrug resistance (MDR) in tumor has long been considered a major factor in the failure of tumor chemotherapy. P-glycoprotein (P-gp)-mediated drug efflux plays a significant role in the MDR of tumor. Herein, paclitaxel (PTX) and P-gp inhibitor quercetin (QC) co-loaded and chondroitin sulfate (ChS)-coated mesoporous silica nanoparticles (MSNs) (MSNs-ChS@PQ) were developed to reverse MDR in breast cancer and improve chemotherapy efficacy. The dual drug-loaded nanoparticles (NPs) showed a nanoscale size of ∼ 227.2 nm and redox-responsive drug release property. In vitro cell experiments showed that NPs exhibited CD44 receptor-mediated active targeting in MCF-7/ADR cells. The dual drug-loaded NPs had lower IC value, higher apoptosis rate, obvious G2M phase arrest as well as stronger microtubule destruction in MCF-7/ADR cells compared to PTX-loaded NPs, suggesting that QC addition, significantly, improved the sensitivity of MCF-7/ADR cells to PTX. Further study found that QC-loaded NPs down-regulated the expression of P-gp. Notably, the dual drug-loaded NPs exhibited tumor-targeting ability, prolonged tumor retention time and effective anti-tumor effect without obvious toxicity to normal tissues in vivo. Taken together, our research provides a viable approach to overcome MDR in breast cancer.
多药耐药（MDR）在肿瘤中一直被认为是肿瘤化疗失败的主要因素。P-糖蛋白（P-gp）介导的药物外排在肿瘤的 MDR 中起着重要作用。在此，我们开发了紫杉醇（PTX）和 P-gp 抑制剂槲皮素（QC）共载和硫酸软骨素（ChS）包覆的介孔硅纳米粒子（MSNs）（MSNs-ChS@PQ），以逆转乳腺癌的多药耐药并提高化疗疗效。双载药纳米粒子（NPs）表现出约 227.2nm 的纳米级尺寸和氧化还原响应性药物释放特性。体外细胞实验表明，NPs 在 MCF-7/ADR 细胞中表现出 CD44 受体介导的主动靶向。与载 PTX 的 NPs 相比，双载药 NPs 在 MCF-7/ADR 细胞中具有更低的 IC 值、更高的凋亡率、明显的 G2M 期阻滞以及更强的微管破坏，表明 QC 的加入显著提高了 MCF-7/ADR 细胞对 PTX 的敏感性。进一步的研究发现，QC 载药 NPs 下调了 P-gp 的表达。值得注意的是，双载药 NPs 表现出肿瘤靶向能力、延长肿瘤滞留时间和有效的抗肿瘤作用，而对正常组织无明显毒性。综上所述，我们的研究为克服乳腺癌的多药耐药提供了一种可行的方法。
