Enhanced Tumor Delivery of Gemcitabine via PEG-DSPE/TPGS Mixed Micelles

[Image: see text] Gemcitabine is a potent anticancer drug approved for the treatment of pancreatic, non-small-cell lung, breast, and ovarian cancers. The major deficiencies of current gemcitabine therapy, however, are its rapid metabolic inactivation and narrow therapeutic window. Herein, we employed polyethylene glycol-b-distearoylphosphatidylethanolamine (PEG-DSPE)/tocopheryl polyethylene glycol 1000 succinate (TPGS) mixed micelles as a delivery system, to improve the pharmacokinetic characteristics of gemcitabine and enhance its antitumor efficacy. By conjugating stearic acid to gemcitabine and subsequently encapsulating stearoyl gemcitabine (GemC18) within PEG-DSPE/TPGS mixed micelles, the deamination of gemcitabine was delayed in vitro and in vivo. Importantly, compared to free gemcitabine, GemC18-loaded micelles pronouncedly prolonged the circulation time of gemcitabine and elevated its concentration in the tumor by 3-fold, resulting in superior antitumor efficacy in mice bearing human pancreatic cancer BxPC-3 xenografts. Our findings demonstrate the promise of PEG-DSPE/TPGS mixed micelles as a nanocarrier system for the delivery of gemcitabine to achieve safer and more efficacious therapeutic outcomes.