title: Combined delivery of paclitaxel and tanespimycin via micellar nanocarriers: pharmacokinetics, efficacy and metabolomic analysis.
abstract: BACKGROUND
  Despite 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.
  
  
  RESULTS
  Paclitaxel/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
  We 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.
authors.affiliation: Cancer Nanomedicine Laboratory, Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Mercer University, Atlanta, Georgia, United States of America.
authors.forename: Usha
authors.initials: U
authors.lastname: Katragadda
authors.forename: Wei
authors.initials: W
authors.lastname: Fan
authors.forename: Yingzhe
authors.initials: Y
authors.lastname: Wang
authors.forename: Quincy
authors.initials: Q
authors.lastname: Teng
authors.forename: Chalet
authors.initials: C
authors.lastname: Tan
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000737:chemistry; D005260:Female; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D055442:Metabolome; D055432:Metabolomics; D051379:Mice; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D019265:Spectroscopy, Near-Infrared; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D016227:Benzoquinones; D004337:Drug Carriers; D047029:Lactams, Macrocyclic; D008823:Micelles; C112765:tanespimycin; D017239:Paclitaxel