The preparation of nanoparticles by emulsion solvent evaporation is a very popular method. The purpose of the present study was to clarify the mechanism by which nanoparticles of ethylcellulose (EC) and poly(lactic acid) (PLA) are formed during the emulsion solvent evaporation procedure. This study was mainly based on the measure of the variation of the emulsion and nanoparticle surface charge and size during the solvent evaporation process. From the data obtained and depending on the polymer used (EC or PLA), two different models are proposed to explain the nanoparticle formation. In the EC model, after shrinkage of the emulsion droplets as the direct consequence of solvent evaporation, coalescence occurred before stable and solvent-free nanoparticles were formed. On the contrary, in the PLA model, no or limited coalescence was found to occur so that the picture is that one PLA nanoparticle originated from one (or only a few) PLA emulsion droplet after its shrinkage.

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Background This study aimed to investigate compounds acting on the host cell machinery to impair parasite installation with the possible advantage of limiting drug resistance. The strategy therefore consisted of selecting compounds that are poorly active on the axenic parasite, but very active on the intramacrophage form of Leishmania. Objectives To identify a drug candidate from focused screening of adamantamine derivatives that can inhibit the development of Leishmania infantum in macrophages. Methods In vitro screening was performed on a library of 142 adamantamine derivatives with axenic and intramacrophage forms of L. infantum, as well as cytotoxicity assays, allowing selection of the most promising compound. Absorption, distribution, metabolism and excretion (ADME) experiments, including pharmacokinetics and microsomal stability, were performed and finally the physicochemical stability of the compound was investigated to assess its suitability for further drug development. Results VP343 was identified first in vitro, with a CC50 value of 63.7 μM and an IC50 value of 0.32 μM for L. infantum intramacrophage amastigotes and then in vivo, with a 59% reduction of the liver parasite burden after oral administration at 10 mg/kg/day for 5 days. In addition, the ADME data were compatible with moving this compound further through the antileishmanial drug candidate pipeline. Conclusions VP343 has the properties of a good drug candidate and merits further investigations.

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2-n-propylquinoline is presently a drug-candidate for the treatment of visceral leishmaniosis in pre-clinical development. As this compound is in an oily state, it needs to be formulated and the objectives of this study are: to prepare a formulation; to demonstrate that the new salted formulation did not alter the activity of the active ingredient; and finally, that this activity was quite good compared to the reference oral drug, miltefosine. Therefore, a 2-n-propylquinoline formulation, as camphorsulfonic salt, was prepared and characterised. On the Leishmania donovani / Balb/c mice model, a treatment by oral route at 60 μmoles/kg/day for ten consecutive days with this formulation was compared to 2-n-propylquinoline alone and to miltefosine, the oral reference drug. The salt formulation did not alter the activity of the 2-n-propylquinoline. The formulation reduced the parasite burden of 76% compared to 89% for miltefosine (not significant). The characteristics of this formulation results in a suitable drugability of 2-n-propylquinoline for further studies.

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

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