title: Paclitaxel prodrugs with sustained release and high solubility in poly(ethylene glycol)-b-poly(epsilon-caprolactone) micelle nanocarriers: pharmacokinetic disposition, tolerability, and cytotoxicity.
abstract: OBJECTIVE
  Develop a Cremophor and solvent free formulation of paclitaxel using amphiphilic block co-polymer micelles of poly(ethylene glycol)-b-poly(epsilon-caprolactone) (PEG-b-PCL) and characterize their release, solubility, cytotoxicity, tolerability, and disposition.
  
  
  METHODS
  Hydrophobic prodrugs of paclitaxel were synthesized via DCC/DMAP or anhydride chemistry to overcome the poor loading (<1% w/w) of paclitaxel in micelles of PEG-b-PCL. Micelles were prepared by a co-solvent extraction technique. A micellar formulation of paclitaxel prodrug (PAX7'C(6)) was dosed intravenously to rats (10 mg/kg) and compared to Taxol (paclitaxel in CrEL:EtOH) and PAX7'C(6) in CrEL:EtOH as controls at the same dose. Pharmacokinetic parameters and tissue distribution were assessed.
  
  
  RESULTS
  Paclitaxel prodrugs had solubilities >5 mg/ml in PEG-b-PCL micelles. Resulting PEG-b-PCL micelles contained 17-22% w/w prodrug and were less than 50 nm in diameter. PEG-b-PCL micelles released paclitaxel prodrugs over several days, t(1/2)>3 d. Only the 7'derivative of paclitaxel with the shortest acylchain 7'hexonoate (PAX7'C(6)) maintained cytotoxic activity similar to unmodified paclitaxel. PAX7'C(6) micelles demonstrated an increase in area under the curve, half-life, and mean residence time while total clearance and volume of distribution decreased.
  
  
  CONCLUSIONS
  Paclitaxel prodrugs in PEG-b-PCL micelle nanocarriers augment the disposition and increase tolerability making further studies on tumor efficacy warranted.
authors.affiliation: College of Pharmacy, Department of Pharmaceutical Chemistry, The University of Kansas, Simons Labs, Lawrence, KS 66047-3729, USA. mforrest@ku.edu
authors.forename: M Laird
authors.initials: ML
authors.lastname: Forrest
authors.forename: Jaime A
authors.initials: JA
authors.lastname: Yáñez
authors.forename: Connie M
authors.initials: CM
authors.lastname: Remsberg
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ohgami
authors.forename: Glen S
authors.initials: GS
authors.lastname: Kwon
authors.forename: Neal M
authors.initials: NM
authors.lastname: Davies
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D007275:Injections, Intravenous; D008297:Male; D008823:Micelles; D053758:Nanoparticles; D000442:Octanols / Q000737:chemistry; D010078:Oxazines; D017239:Paclitaxel / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D010316:Particle Size; D011091:Polyesters; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014966:Xanthenes
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D008823:Micelles; D000442:Octanols; D010078:Oxazines; D011091:Polyesters; D014966:Xanthenes; C458722:polyethylene oxide-polycaprolactone copolymer; C005843:resazurin; D017239:Paclitaxel