Abstract 4427: LipoFufol, a triple stealth liposomal formulation of modulated 5-FU: Drugability, efficacy and phamacokinetics study
Authors: Fanciullino Raphaelle , Giacometti Sarah , Vacus Joel , Koob Zina , Iliadis Athanassios , Ciccolini Joseph 
Published: June 2012

Background: 5-Fu is a mainstay for treating colorectal carcinomas, despite modest efficacy/toxicity balance. Drug resistance and DPD-related toxicities are often limitations in clinical practice. To overcome this, we present a liposomal 5-FU designed to exhibit higher antiproliferative properties while being less affected by liver uptake and subsequent DPD-related toxicities. Methods: Formulation was optimized to allow proper stability while using time- and cost-effective manufacturing process. In vitro, antiproliferative activity of Lipofufol was carried out in the canonical 5-FU-resistant SW620 and 5-FU-sensitive HT29 human colorectal cell lines. Pharmacokinetics and biodistribution studies were performed in rodents (Wistar rats, nude mice). Comparative tolerance study in DPD-deficient rats was investigated. Finally, efficacy of LipoFufol in two different tumor-bearing mice models was studied, with survival and response as main endpoints. Results: Lipofufol is a 50-80 nm diameter, pegylated liposome that proved to be stable at room temperature for at least one month, with encapsulation rates comprised between 20 and 30% for the three active compounds. When used in vitro, antiproliferative activity of Lipofufol proved to be always higher than that of 5-FU, either when used alone or in combination with irinotecan or oxaliplatin. Drug monitoring studies in rats showed that Lipofufol exhibited a markedly different pharmacokinetics profile after I.V. administration as compared with standard 5-FU (e.g., 60% reduction in plasma clearance). Biodistribution study using fluorescent-labelled LipoFufol in tumor-bearing nude mice confirmed that Lipofufol reached quickly the tumor site, while partly bypassing liver uptake. Toxicity study was next undertaken to check whether Lipofufol could be less toxic in DPD-deficient individuals., and confirmed that milder (e.g., neutrophils count: -75% VS. -96%) and shorter (e.g., 6 VS. 11 days) neutropenia was observed in DPD-deficient rats treated with liposomal 5-FU, as compared with deficient animals exposed to standard 5-FU. Tolerance studies and search for MTD were further performed in tumor-bearing mice and showed that LipoFufol could be administered safely up to 20 mg/kg I.V. on a 3QW basis for 3 consecutive weeks. In mice bearing LS174t human colorectal orthotopic xenografts, longer survival was achieved in animals treated with 20 mg/kg Lipofufol, as compared with animals treated with 80 mg/kg of standard 5-FU (e.g., 80% VS. 40% survival at 3 weeks). In SW620-bearing mice, equi-efficacy study proved that Lipofufol could match efficacy of high dose 5-FU while being 5-time less toxic. Conclusions: This non-clinical study demonstrates that drug-resistance and 5-FU-related toxicities can be both addressed using a stealth liposomal form. Further investigations are ongoing in the perspective of a phase-I clinical trial.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4427. doi:10.1158/1538-7445.AM2011-4427