Pharmaceutical Research

, Volume 22, Issue 12, pp 2051–2057 | Cite as

Development of Stealth Liposome Formulation of 2′-Deoxyinosine as 5-Fluorouracil Modulator: In Vitro and In Vivo Study

  • Raphaelle Fanciullino
  • Sarah Giacometti
  • Claude Aubert
  • Frederic Fina
  • Pierre-Marie Martin
  • Philippe Piccerelle
  • Joseph CiccoliniEmail author
Research Paper


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.


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.


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.


Our data show that liposomal d-Ino, through an optimized pharmacokinetic profile, displays apotenteffect as fluoropyrimidines modulator, both in vitro and in xenografted mice. Besides, we showed here that itispossible to reverse a resistant phenotype to 5-FU, a major drug extensively described in clinical oncology.

Key Words

2′-deoxyinosine 5-FU liposome pharmacokinetics thymidylate synthase xenografts 


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Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Raphaelle Fanciullino
    • 1
  • Sarah Giacometti
    • 1
  • Claude Aubert
    • 1
  • Frederic Fina
    • 2
  • Pierre-Marie Martin
    • 2
  • Philippe Piccerelle
    • 3
  • Joseph Ciccolini
    • 1
    Email author
  1. 1.Laboratoire de Pharmacocinétique, UFR PharmacieMarseille cedex 05France
  2. 2.EMI359UFR Médecine NordMarseilleFrance
  3. 3.Laboratoire de Pharmacie Galénique et IndustrielleUFR PharmacieMarseilleFrance

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