title: Enhanced tumor delivery of gemcitabine via PEG-DSPE/TPGS mixed micelles.
abstract: 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.
authors.affiliation: Cancer Nanomedicine Laboratory, Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University , Atlanta, Georgia 30341, United States.
authors.forename: Yingzhe
authors.initials: Y
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Fan
authors.forename: Xin
authors.initials: X
authors.lastname: Dai
authors.forename: Usha
authors.initials: U
authors.lastname: Katragadda
authors.forename: DeAngelo
authors.initials: D
authors.lastname: Mckinley
authors.forename: Quincy
authors.initials: Q
authors.lastname: Teng
authors.forename: Chalet
authors.initials: C
authors.lastname: Tan
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D002401:Cathepsin B / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003564:Cytidine Deaminase / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D051379:Mice; D008823:Micelles; D010714:Phosphatidylethanolamines / Q000008:administration & dosage*; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D014810:Vitamin E / Q000008:administration & dosage / Q000031:analogs & derivatives*; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D008823:Micelles; D010714:Phosphatidylethanolamines; D003841:Deoxycytidine; D014810:Vitamin E; C038089:1,2-distearoylphosphatidylethanolamine; D011092:Polyethylene Glycols; D002401:Cathepsin B; D003564:Cytidine Deaminase; C014225:tocophersolan; D000093542:Gemcitabine