title: Development of stealth liposome formulation of 2'-deoxyinosine as 5-fluorouracil modulator: in vitro and in vivo study.
abstract: OBJECTIVE
  The aims of this study were to develop a stealth, pegylated liposomal formulation of 2'-deoxyinosine (d-Ino), a 5-fluorouracil (5-FU) modulator, to evaluate its efficacy in vitro and in tumor-bearing mice, and to study its pharmacokinetics in rats.
  
  
  METHODS
  After designing a pegylated liposome encapsulating d-Ino (L-d-Ino), we evaluated its efficacy as 5-FU modulator in vitro. Antiproliferative assays, thymidylate synthase (TS) inhibition, and apoptosis studies were carried out to check whether an optimization of 5-FU action was achieved on the 5-FU-resistant SW620 cell line. Animal pharmacokinetic and ex vivo studies were next performed to confirm that L-d-Ino displayed a slower plasma elimination pattern than free d-Ino. Finally, effects on tumor growth of L-d-Ino + 5-FU combination was evaluated in xenografted mice.
  
  
  RESULTS
  We developed a stable, sterile, and homogenous 100-nm population of pegylated liposomes encapsulating 30% of d-Ino. Liposomal d-Ino exhibited a strong potential as 5-FU modulator in vitro by enhancing TS inhibition and subsequent apoptosis induction, while displaying a better pharmacokinetic profile in animals, with a near seven times clearance reduction as compared with the free form. When used in tumor-bearing mice in combination with 5-FU, our results showed next that the association led to 70% of tumor reduction with a doubling median survival time as compared with untreated animals, whereas 5-FU alone was ineffective.
  
  
  CONCLUSIONS
  Our data show that liposomal d-Ino, through an optimized pharmacokinetic profile, displays a potent effect as fluoropyrimidines modulator, both in vitro and in xenografted mice. Besides, we showed here that it is possible to reverse a resistant phenotype to 5-FU, a major drug extensively described in clinical oncology.
authors.affiliation: Laboratoire de Pharmacocinétique, UFR Pharmacie, 27 Bd Jean Moulin, 13385, Marseille cedex 05, France.
authors.forename: Raphaelle
authors.initials: R
authors.lastname: Fanciullino
authors.forename: Sarah
authors.initials: S
authors.lastname: Giacometti
authors.forename: Claude
authors.initials: C
authors.lastname: Aubert
authors.forename: Frederic
authors.initials: F
authors.lastname: Fina
authors.forename: Pierre-Marie
authors.initials: PM
authors.lastname: Martin
authors.forename: Philippe
authors.initials: P
authors.lastname: Piccerelle
authors.forename: Joseph
authors.initials: J
authors.lastname: Ciccolini
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D016503:Drug Delivery Systems; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology*; D007288:Inosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D007834:Lasers; D008081:Liposomes; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D051381:Rats; D017208:Rats, Wistar; D012542:Scattering, Radiation; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors
chemical_list: D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D008081:Liposomes; D007288:Inosine; D013940:Thymidylate Synthase; C012271:deoxyinosine; D005472:Fluorouracil