Cao Xi, Luo Jingwen, Gong Tao, Zhang Zhi-Rong, Sun Xun, Fu Yao
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, Sichuan University , Chengdu, Sichuan, People's Republic of China.
Mol Pharm. 2015 Jan 5;12(1):274-86. doi: 10.1021/mp500637b. Epub 2014 Dec 12.
Multidrug resistance has remained a major cause of treatment failure in chemotherapy due to the presence of P-glycoproteins (P-gp) that actively pump drugs from inside the cell to the outside. P-gp inhibitors were developed and coadministered with chemotherapeutic drugs to overcome the effect of efflux pumps thus enhancing the chemosensitivity of therapeutics. Our study aimed at developing a lipid nanoemulsion system for the coencapsulation of doxorubicin (DOX) and bromotetrandrine (W198) to reverse multidrug resistance (MDR) in breast cancer. W198 was a potent P-gp inhibitor, and DOX was selected as a model compound which is a common substrate for P-gp. Coencapsulated DOX and W198 lipid nanoemulsions (DOX/W198-LNs) displayed significantly enhanced cytotoxicity in DOX-resistant human breast cancer cells (MCF-7/ADR) compared with DOX loaded lipid nanoemulsions (DOX-LNs) (p < 0.05), which is due to the enhanced intracellular uptake of DOX in MCF-7/ADR cells. The biodistribution study was performed using a nude mice xenograft model, which demonstrates enhanced tumor uptake of DOX in the DOX/W198-LN treated group. Compared with DOX solution, DOX/W198-LNs showed reduced cardiac toxicity and gastrointestinal injury in rats. Taken together, DOX/W198-LNs represent a promising formulation for overcoming MDR in breast cancer.
多药耐药性一直是化疗治疗失败的主要原因，这是由于存在P-糖蛋白（P-gp），它能将药物从细胞内主动泵出到细胞外。P-gp抑制剂被开发出来并与化疗药物联合使用，以克服外排泵的作用，从而增强治疗药物的化学敏感性。我们的研究旨在开发一种脂质纳米乳剂系统，用于共包封阿霉素（DOX）和溴粉防己碱（W198），以逆转乳腺癌中的多药耐药性（MDR）。W198是一种有效的P-gp抑制剂，DOX被选为P-gp常见底物的模型化合物。与载DOX脂质纳米乳剂（DOX-LNs）相比，共包封DOX和W198的脂质纳米乳剂（DOX/W198-LNs）在耐DOX的人乳腺癌细胞（MCF-7/ADR）中显示出显著增强的细胞毒性（p<0.05），这是由于MCF-7/ADR细胞中DOX的细胞内摄取增加。使用裸鼠异种移植模型进行了生物分布研究，结果表明DOX/W198-LN治疗组中DOX在肿瘤中的摄取增加。与DOX溶液相比，DOX/W198-LNs在大鼠中显示出心脏毒性和胃肠道损伤降低。综上所述，DOX/W198-LNs是一种有前途的克服乳腺癌多药耐药性的制剂。
