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.
BackgroundDespite the promising anticancer efficacy observed in preclinical studies, paclitaxel and tanespimycin (17-AAG) combination therapy has yielded meager responses in a phase I clinical trial. One serious problem associated with paclitaxel/17-AAG combination therapy is the employment of large quantities of toxic organic surfactants and solvents for drug solubilization. The goal of this study was to evaluate a micellar formulation for the concurrent delivery of paclitaxel and 17-AAG in vivo.Methodology/Principal FindingsPaclitaxel/17-AAG-loaded micelles were assessed in mice bearing human ovarian tumor xenografts. Compared with the free drugs at equivalent doses, intravenous administration of paclitaxel/17-AAG-loaded micelles led to 3.5- and 1.7-fold increase in the tumor concentrations of paclitaxel and 17-AAG, respectively, without significant altering drug levels in normal organs. The enhanced tumor accumulation of the micellar drugs was further confirmed by the whole-body near infrared imaging using indocyanine green-labeled micelles. Subsequently, the anticancer efficacy of paclitaxel/17-AAG-loaded micelles was examined in comparison with the free drugs (weekly 20 mg/kg paclitaxel, twice-weekly 37.5 mg/kg 17-AAG). We found that paclitaxel/17-AAG-loaded micelles caused near-complete arrest of tumor growth, whereas the free drug-treated tumors experienced rapid growth shortly after the 3-week treatment period ended. Furthermore, comparative metabolomic profiling by proton nuclear magnetic resonance revealed significant decrease in glucose, lactate and alanine with simultaneous increase in glutamine, glutamate, aspartate, choline, creatine and acetate levels in the tumors of mice treated with paclitaxel/17-AAG-loaded micelles.Conclusions/SignificanceWe have demonstrated in the current wok a safe and efficacious nano-sized formulation for the combined delivery of paclitaxel and 17-AAG, and uncovered unique metabolomic signatures in the tumor that correlate with the favorable therapeutic response to paclitaxel/17-AAG combination therapy.
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