Development of stealth liposome formulation of 2'-deoxyinosine as 5-fluorouracil modulator: in vitro and in vivo study.
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.
Fanciullino
Raphaelle
R
Laboratoire de Pharmacocinétique, UFR Pharmacie, 27 Bd Jean Moulin, 13385, Marseille cedex 05, France.
Giacometti
Sarah
S
Aubert
Claude
C
Fina
Frederic
F
Martin
Pierre-Marie
PM
Piccerelle
Philippe
P
Ciccolini
Joseph
J
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
D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D008081:Liposomes; D007288:Inosine; D013940:Thymidylate Synthase; C012271:deoxyinosine; D005472:Fluorouracil