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Remote loading paclitaxel–doxorubicin prodrug into liposomes for cancer combination therapy
Acta Pharmaceutica Sinica B ( IF 14.7 ) Pub Date : 2020-04-26 , DOI: 10.1016/j.apsb.2020.04.011
Jiang Yu , Yingli Wang , Shuang Zhou , Jinbo Li , Jiamei Wang , Dongxu Chi , Xue Wang , Guimei Lin , Zhonggui He , Yongjun Wang

The combination of paclitaxel (PTX) and doxorubicin (DOX) has been widely used in the clinic. However, it remains unsatisfied due to the generation of severe toxicity. Previously, we have successfully synthesized a prodrug PTX-S-DOX (PSD). The prodrug displayed comparable in vitro cytotoxicity compared with the mixture of free PTX and DOX. Thus, we speculated that it could be promising to improve the anti-cancer effect and reduce adverse effects by improving the pharmacokinetics behavior of PSD and enhancing tumor accumulation. Due to the fact that copper ions (Cu2+) could coordinate with the anthracene nucleus of DOX, we speculate that the prodrug PSD could be actively loaded into liposomes by Cu2+ gradient. Hence, we designed a remote loading liposomal formulation of PSD (PSD LPs) for combination chemotherapy. The prepared PSD LPs displayed extended blood circulation, improved tumor accumulation, and more significant anti-tumor efficacy compared with PSD NPs. Furthermore, PSD LPs exhibited reduced cardiotoxicity and kidney damage compared with the physical mixture of Taxol and Doxil, indicating better safety. Therefore, this novel nano-platform provides a strategy to deliver doxorubicin with other poorly soluble antineoplastic drugs for combination therapy with high efficacy and low toxicity.



中文翻译:

将紫杉醇-阿霉素前药远程装载到脂质体中进行癌症联合治疗

紫杉醇(PTX)和阿霉素(DOX)的组合已在临床中广泛使用。然而,由于产生严重的毒性,它仍然不能令人满意。以前,我们已经成功地合成了前药PTX- S -DOX(PSD)。与游离PTX和DOX的混合物相比,前药显示出可比的体外细胞毒性。因此,我们推测通过改善PSD的药代动力学行为和增强肿瘤蓄积来改善抗癌作用并减少不良反应是有希望的。由于铜离子(Cu 2+)可以与DOX的蒽核配位,因此我们推测前药PSD可以被Cu 2+主动加载到脂质体中。梯度。因此,我们设计了PSD(PSD LPs)的远程加载脂质体制剂,用于联合化疗。与PSD NPs相比,制备的PSD LPs显示出延长的血液循环,改善的肿瘤蓄积和更显着的抗肿瘤功效。此外,与紫杉醇和多西尔的物理混合物相比,PSD LPs表现出降低的心脏毒性和肾脏损害,表明安全性更高。因此,该新颖的纳米平台提供了将阿霉素与其他难溶性抗肿瘤药一起递送的策略,以具有高功效和低毒性的联合疗法。

更新日期:2020-04-26
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