Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China.
Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China.
Int J Pharm. 2021 Jun 15;603:120691. doi: 10.1016/j.ijpharm.2021.120691. Epub 2021 May 7.
The high expression of multidrug resistance-associated protein 1 (MRP1) in cancer cells caused serious multidrug resistance (MDR), which limited the effectiveness of paclitaxel (PTX) in non-small cell lung cancer (NSCLC) chemotherapy. Indomethacin (IND), a kind of non-steroidal anti-inflammatory drugs (NSAIDs), which has been confirmed to be a potential MRP1 inhibitor. Taking into account the advantages of old drugs without extra controversial biosafety issue, in this manuscript, the disulfide bond (-S-S-) was employed for connecting IND and PTX to construct conjugate IND-S-S-PTX, which was further self-assembled and formed nanodrug (IND-S-S-PTX NPs). The particle size of IND-S-S-PTX NPs was ~160 nm with a narrow PDI value of 0.099, which distributed well in water and also exhibited a stable characteristic. Moreover, due to the existence of disulfide bond, the NPs were sensitive to the high level of glutathione (GSH) in tumor microenvironment. Molecular dynamics (MD) simulation presented the process of self-assembly in detail. Density functional theory (DFT) calculations revealed that the main driving force in self-assembly process was originated from the van der waals force. In addition, this carrier-free nano drug delivery systems (nDDs) could reverse the MDR by downregulating the expression of MRP1 protein in A549/taxol.
多药耐药相关蛋白 1（MRP1）在癌细胞中的高表达导致严重的多药耐药（MDR），限制了紫杉醇（PTX）在非小细胞肺癌（NSCLC）化疗中的疗效。吲哚美辛（IND），一种非甾体抗炎药（NSAIDs），已被证实是一种有潜力的 MRP1 抑制剂。考虑到老药的优势，没有额外的有争议的生物安全问题，在本手稿中，采用二硫键（-S-S-）将 IND 和 PTX 连接起来构建共轭物 IND-S-S-PTX，进一步自组装形成纳米药物（IND-S-S-PTX NPs）。IND-S-S-PTX NPs 的粒径约为 160nm，PDI 值窄为 0.099，在水中分布良好，且表现出稳定的特性。此外，由于二硫键的存在，纳米颗粒对肿瘤微环境中高水平的谷胱甘肽（GSH）敏感。分子动力学（MD）模拟详细呈现了自组装过程。密度泛函理论（DFT）计算表明，自组装过程的主要驱动力来源于范德华力。此外，这种无载体的纳米药物递送系统（nDDs）可以通过下调 A549/taxol 中 MRP1 蛋白的表达来逆转 MDR。
