Overcoming drug resistance with a docetaxel and disulfiram loaded pH-sensitive nanoparticle

多西紫杉醇 体内 药理学 癌症研究 肿瘤微环境 抗药性 化学 癌症 Abcg2型 癌细胞 药物输送 二硫仑 紫杉醇 转移 医学 内科学 生物 ATP结合盒运输机 生物化学 有机化学 生物技术 运输机 基因 微生物学
作者
K. Laxmi Swetha,Milan Paul,Kavya Sree Maravajjala,Soniya Kumbham,Swati Biswas,Aniruddha Roy
出处
期刊:Journal of Controlled Release [Elsevier]
卷期号:356: 93-114 被引量:18
标识
DOI:10.1016/j.jconrel.2023.02.023
摘要

Previous studies have demonstrated that breast cancer cells deploy a myriad array of strategies to thwart the activity of anticancer drugs like docetaxel (DTX), including acquired drug resistance due to overexpression of drug-efflux pumps like P-glycoprotein (P-gp) and innate drug resistance by cancer stem cells (CSCs). As disulfiram (DSF) can inhibit both P-gp and CSCs, we hypothesized that co-treatment of DTX and DSF could sensitize the drug-resistant breast cancer cells. To deliver a fixed dose ratio of DTX and DSF targeted to the tumor, a tumor extracellular pH-responsive nanoparticle (NP) was developed using a histidine-conjugated star-shaped PLGA with TPGS surface decoration ([DD]NpH-T). By releasing the encapsulated drugs in the tumor microenvironment, pH-sensitive NPs can overcome the tumor stroma-based resistance against nanomedicines. In in-vitro studies, [DD]NpH-T exhibited increased drug release at pH 6.8, improved penetration in a 3D tumor spheroid, reduced serum protein adsorption, and enhanced cytotoxic efficacy against both innate and acquired DTX-resistant breast cancer cells. In in-vivo studies, a significant increase in plasma AUC and tumor drug delivery was observed with [DD]NpH-T, which resulted in an enhanced in-vivo anti-tumor efficacy against a mouse orthotopic breast cancer, with a significantly increased intratumoral ROS and apoptosis, while decreasing P-gp expression and prevention of lung metastasis. Altogether, the current study demonstrated that the DTX and DSF combination could effectively target multiple drug-resistance pathways in-vitro, and the in-vivo delivery of this drug combination using TPGS-decorated pH-sensitive NPs could increase tumor accumulation, resulting in improved anti-tumor efficacy.
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