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In Vitro and In Vivo Evaluation of Lipofufol, a New Triple Stealth Liposomal Formulation of Modulated 5-Fu: Impact on Efficacy and Toxicity

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Abstract

Purpose

Drug resistance and severe toxicities are limitations when handling 5-FU. We have developed a triple liposomal formulation of 5-FU combined to 2′-deoxyinosine and folinic acid to improve its efficacy-toxicity balance.

Methods

Stealth liposomes were obtained using the thin-film method. Antiproliferative activity was tested on human colorectal and breast cancer models using sensitive (HT29) and resistant (SW620, LS174t, MDA231) cell lines. In vivo, pharmacokinetics, biodistribution and safety studies were performed in rodents. Finally, efficacy was evaluated using two tumor-bearing mice models (LS174 and MDA231) with response and survival as main endpoints.

Results

LipoFufol is a 120-nm pegylated liposome, displaying 20–30% encapsulation rates. In vitro, antiproliferative activities were higher than 5-FU, and matched that of FolFox combination in colorectal models, but not in breast. Drug monitoring showed an optimized pharmacokinetics profile with reduced clearance and prolonged half-life. Liposome accumulation in tumors was shown by fluorescence-based biodistribution studies. Beside, milder neutropenia was observed when giving LipoFufol to animals with transient partial DPD-deficiency, as compared with standard 5-FU. In LS174t-bearing mice, higher response and 55% longer survival were achieved with Lipofufol, as compared with 5-FU.

Conclusion

The issues of drug-resistance and drug-related toxicity can be both addressed using a stealth liposomal formulation of modulated 5-FU.

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Acknowledgments

This study was supported by generous grants from the GEFLUC Marseille-Provence and the Association pour la Recherche sur le Cancer (ARC, Grant #1026).

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Authors and Affiliations

  1. Pharmacokinetics Unit, School of Pharmacy, Aix Marseille University, Inserm U911 Cro-2, 27 Bd Jean Moulin, 13385, Marseille, France

    Raphaelle Fanciullino, Sarah Giacometti, Athanassios Iliadis & Joseph Ciccolini

  2. UMR-MD3, Aix-Marseille University, Marseille, France

    Séverine Mollard, Mohamed Chefrour & Claude Aubert

  3. Haematology Unit, La Conception University Hospital of Marseille, Marseille, France

    Yael Berda-Haddad

Authors
  1. Raphaelle Fanciullino
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  2. Séverine Mollard
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  3. Sarah Giacometti
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  4. Yael Berda-Haddad
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  5. Mohamed Chefrour
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  6. Claude Aubert
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  7. Athanassios Iliadis
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  8. Joseph Ciccolini
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Correspondence to Joseph Ciccolini.

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Fanciullino, R., Mollard, S., Giacometti, S. et al. In Vitro and In Vivo Evaluation of Lipofufol, a New Triple Stealth Liposomal Formulation of Modulated 5-Fu: Impact on Efficacy and Toxicity. Pharm Res 30, 1281–1290 (2013). https://doi.org/10.1007/s11095-012-0967-2

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  • DOI: https://doi.org/10.1007/s11095-012-0967-2

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