Remote loading paclitaxel-doxorubicin prodrug into liposomes for cancer combination therapy

作者：Yu J, Wang Y, Zhou S, Li J, Wang J, Chi D, Wang X, Lin G, He Z, Wang Y · 发表于：Acta pharmaceutica Sinica. B · 年份：2020 · DOI：10.1016/j.apsb.2020.04.011 · 研究领域：ALT, alanine transaminase、AST, aspartate transaminase、AUC, area under the curve、BUN, blood urea nitrogen、CHO, cholesterol、CO2, carbon dioxide、CR, creatinine、Combination therapy、Cu2+, copper ions、DL, drug loading、DLS, dynamic light scattering、DMSO, dimethyl sulfoxide、DNA, deoxyribonucleic acid、DOX, doxorubicin、DSPE-PEG2000, 2-distearoyl-snglycero-3-phosphoethanolamine-N-[methyl(polyethylene glycol)-2000、DTT, d,l-dithiothreitol、EDTA, ethylene diamine tetraacetic acid、EE, encapsulation efficacy、FBS, fetal bovine serum、GSH, glutathione、H&E, hematoxylin and eosin、H2O2, hydrogen peroxide、HEPES, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid、HPLC, high-performance liquid chromatography、HSPC, hydrogenated soybean phospholipids、IC50, half maximal inhibitory concentration、IVIS, in vivo imaging system、MLVs, multilamellar vesicles、MRT, mean residence time、MTD, maximum tolerated dose、MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide、Nanoparticles、PBS, phosphate buffer saline、PDI, polydispersity index、PSD LPs, PTX-S-DOX liposomes、PSD NPs, PTX-S-DOX self-assembled nanoparticles、PSD, PTX-S-DOX、PTX, paclitaxel、Paclitaxel–doxorubicin prodrug、Prodrug、ROS, reactive oxygen species、Remote loading liposomes、SD, standard deviation、Safety、TEM, transmission electron microscopy、UV, ultraviolet

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.