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

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Purpose

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 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.

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Authors and Affiliations

  1. Laboratoire de Pharmacocinétique, UFR Pharmacie, 27 Bd Jean Moulin, 13385, Marseille cedex 05, France

    Raphaelle Fanciullino, Sarah Giacometti, Claude Aubert & Joseph Ciccolini

  2. EMI359, UFR Médecine Nord, Marseille, France

    Frederic Fina & Pierre-Marie Martin

  3. Laboratoire de Pharmacie Galénique et Industrielle, UFR Pharmacie, Marseille, France

    Philippe Piccerelle

Authors
  1. Raphaelle Fanciullino
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  2. Sarah Giacometti
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  3. Claude Aubert
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  4. Frederic Fina
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  5. Pierre-Marie Martin
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  6. Philippe Piccerelle
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  7. Joseph Ciccolini
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Correspondence to Joseph Ciccolini.

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Fanciullino, R., Giacometti, S., Aubert, C. et al. Development of Stealth Liposome Formulation of 2′-Deoxyinosine as 5-Fluorouracil Modulator: In Vitro and In Vivo Study. Pharm Res 22, 2051–2057 (2005). https://doi.org/10.1007/s11095-005-8355-9

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  • DOI: https://doi.org/10.1007/s11095-005-8355-9

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