Glutathione-triggered dual release of doxorubicin and camptothecin for highly efficient synergistic anticancer therapy
2018
Abstract An amphiphilic biodegradable prodrug (PLG- g -mPEG/CPT) was synthesized by conjugating disulfide-containing camptothecin (CPT) to poly(L-glutamic acid)- graft -methoxy poly(ethylene glycol) (PLG- g -mPEG) through esterification reaction. The amphiphilic prodrugs could self-assemble into micellar nanoparticles and encapsulate doxorubicin (DOX) in aqueous solution at pH 7.4. The treatment of the nanoparticles with reducing glutathione (GSH) at cytosolic concentration (10 mM) significantly promoted the in vitro dual release of DOX and CPT from the micelles. The results of flow cytometry (FCM) and confocal laser scanning microscopy (CLSM) manifested that the intracellular release of DOX and CPT from the micelles was enhanced by increasing the intracellular GSH level. Consistently, the MCF-7 cell killing mediated by the micelles was also intracellular GSH concentration-dependent. The low combination index (CI) value of
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