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Development of stealth liposome formulation of 2'-deoxyinosine as 5-fluorouracil modulator: in vitro and in vivo study.

AbstractPURPOSE:
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.
METHOD:
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.
CONCLUSION:
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.
AuthorsRaphaelle Fanciullino, Sarah Giacometti, Claude Aubert, Frederic Fina, Pierre-Marie Martin, Philippe Piccerelle, Joseph Ciccolini
JournalPharmaceutical research (Pharm Res) Vol. 22 Issue 12 Pg. 2051-7 (Dec 2005) ISSN: 0724-8741 [Print] United States
PMID16222443 (Publication Type: Journal Article)
Chemical References
  • Antimetabolites, Antineoplastic
  • Enzyme Inhibitors
  • Liposomes
  • Inosine
  • Thymidylate Synthase
  • deoxyinosine
  • Fluorouracil
Topics
  • Animals
  • Antimetabolites, Antineoplastic (pharmacology)
  • Apoptosis (drug effects)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Chemistry, Pharmaceutical
  • Chromatography, High Pressure Liquid
  • Drug Delivery Systems
  • Drug Synergism
  • Enzyme Inhibitors (pharmacology)
  • Fluorouracil (pharmacology)
  • Inosine (administration & dosage, analogs & derivatives, pharmacology)
  • Lasers
  • Liposomes
  • Male
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Rats
  • Rats, Wistar
  • Scattering, Radiation
  • Thymidylate Synthase (antagonists & inhibitors)

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