Pharmacokinetics and oral absorption of different lipid nanocapsules: new quantitative FRET technique revealing PEGylation increasing the particle’s clearance

International audienc

Pharmacokinetics and oral absorption of different lipid nanocapsules: new quantitative FRET technique revealing PEGylation increasing the particle’s clearance

International audienc

Population pharmacokinetic modelling of intravenous LNCs FRET in rat

International audienc

Population pharmacokinetic modelling of intravenous LNCs FRET in rat

International audienc

New In Vitro Coculture Model for Evaluating Intestinal Absorption of Different Lipid Nanocapsules

International audienceStandard models used for evaluating the absorption of nanoparticles like Caco-2 ignore the presence of vascular endothelium, which is a part of the intestinal multi-layered barrier structure. Therefore, a coculture between the Caco-2 epithelium and HMEC-1 (Human Microvascular Endothelial Cell type 1) on a Transwell® insert has been developed. The model has been validated for (a) membrane morphology by transmission electron microscope (TEM); (b) ZO-1 and β-catenin expression by immunoassay; (c) membrane integrity by trans-epithelial electrical resistance (TEER) measurement; and (d) apparent permeability of drugs from different biopharmaceutical classification system (BCS) classes. Lipid nanocapsules (LNCs) were formulated with different sizes (55 and 85 nm) and surface modifications (DSPE-mPEG (2000) and stearylamine). Nanocapsule integrity and particle concentration were monitored using the Förster resonance energy transfer (FRET) technique. The result showed that surface modification by DSPE-mPEG (2000) increased the absorption of 55-nm LNCs in the coculture model but not in the Caco-2. Summarily, the coculture model was validated as a tool for evaluating the intestinal absorption of drugs and nanoparticles. The new coculture model has a different LNCs absorption mechanism suggesting the importance of intestinal endothelium and reveals that the surface modification of LNCs can modify the in vitro oral absorption

Structure-activity relationships of β-hydroxyphosphonate nucleoside analogues as cytosolic 5′-nucleotidase II potential inhibitors: Synthesis, in vitro evaluation and molecular modeling studies.

International audienceThe cytosolic 5′-nucleotidase II (cN-II) has been proposed as an attractive molecular target for the development of novel drugs circumventing resistance to cytotoxic nucleoside analogues currently used for treating leukemia and other malignant hemopathies. In the present work, synthesis of β-hydroxyphosphonate nucleoside analogues incorporating modifications either on the sugar residue or the nucleobase, and their in vitro evaluation towards the purified enzyme were carried out in order to determine their potency towards the inhibition of cN-II. In addition to the biochemical investigations, molecular modeling studies revealed important structural features for binding affinities towards the target enzyme

Stealth nanocarriers based sterosomes using PEG post-insertion process

Sterosomes (STEs), a new and promising non-phospholipidic liposome platform based on palmitic acid (PA) and cholesterol (Chol) mixtures, need to have polyethylene glycol (PEG) chains grafted to their surface in order to obtain long-circulating nanocarriers in the blood stream. A post-insertion method was chosen to achieve this modification. The post-insertion process of PEG-modified distearoylphosphoethanolamine (DSPE-PEG) was monitored using the zeta potential value of STEs. Various conditions including PEG chain length and the DSPE-PEG/PA-Chol ratio, were explored. Zeta potential of STEs changed from about −40 mV for non-modified STEs to values close to 0 mV by the end of the process, i.e. for PEG-modified STEs. The kinetics of DSPE-PEG insertion and the stability of the resulting PEG-modified STEs were not considerably influenced, within the investigated range, by changes in PEG chain lengths and in DSPE-PEG/PA-Chol proportion. The post-insertion of PEG chains reduced in vitro complement activation as well as in vitro macrophage uptake compared to the non-modified STEs. Moreover, longer blood circulation time in mice was established for PEG-modified STEs intravenously injected compared to non-modified STEs. These results establish that post-insertion process of PEG chains to STEs is a promising strategy for developing long-term circulating drug delivery nanocarriers.Fil: Cieślak, Anna. University Of Angers; FranciaFil: Wauthoz, Nathalie. University Of Angers; Francia. Université Libre de Bruxelles; BélgicaFil: Nieto Orellana, Alejandro. University Of Angers; FranciaFil: Lautram, Nolwenn. University Of Angers; FranciaFil: Béjaud, Jérôme. University Of Angers; FranciaFil: Hureaux, José. University Of Angers; FranciaFil: Lafleur, Michel. University of Montreal; CanadáFil: Benoit, Jean-Pierre. University Of Angers; FranciaFil: Salomon, Claudio Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; ArgentinaFil: Bastiat, Guillaume. University Of Angers; Franci

Pharmacokinetics of intact lipid nanocapsules using new quantitative FRET technique

International audienceThe present study investigated the pharmacokinetics of intact lipid nanocapsules (LNCs) after intravenous administration in rats. Six different Förster resonance energy transfer LNCs (FRET-LNCs) have been studied with 2 sizes (50 and 85 nm) and 3 coating types (none, DSPE-mPEG 2000 or stearylamine). A FRET-LNCs blood extraction method was developed to retain an accurate FRET signal. Intact FRET-LNCs were specifically quantified through combination of FRET signal and Nano Tracker Analysis. Pharmacokinetic data were first described by non-compartmental analysis, then used to develop a population pharmacokinetic model. The pharmacokinetic elimination of FRET-LNCs was non-linear and dependent on size and surface modification, while the distribution was dependent on size. The LNCs 85 nm volume of distribution was lower than LNCs 50 nm. As expected, LNCs 85 nm with PEG coating displayed a lower clearance than other formulations. Surprisingly, this study highlighted a faster elimination of LNCs 50 nm with PEG compared to other formulations which could be explained by instability in blood. This first pharmacokinetic model of intact LNCs allowed a thorough understanding of the influence of size and coating on pharmacokinetic properties and paves the way for future mechanistic modeling approaches to predict the fate of LNCs in vivo

Polymer-free hydrogel made of lipid nanocapsules, as a local drug delivery platform

International audienceNanoparticle-loaded hydrogels are attractive pharmaceutical drug delivery systems that combine the advantages of both hydrogel (local administration and/or sustained drug release) and nanoparticle (stealthiness, targeting and decreased toxicity). The design of nanoparticle-loaded hydrogels is largely conventional, consisting of the dispersion of nanoparticles in a natural or synthetic polymer matrix to form a gel network. Novel nanoparticle-loaded hydrogels architecture could provide advantages in terms of innovation and application. We focused on the development of lipid nanocapsule (LNC)-based hydrogels without the use of a polymer matrix as a platform for drug delivery. Cytidine was modified by grafting palmitoyl chains (CytC16) and the new entity was added during the LNC phase-inversion formulation process allowing spontaneous gelation. Positioned at the oil/water interface, CytC16 acts as a crosslinking agent between LNCs. Association of the LNCs in a three-dimensional network led to the formation of polymer-free hydrogels. The viscoelastic properties of the LNC-based hydrogels depended on the LNC concentration and CytC16 loading but were not affected by the LNC size distribution. The LNC and drug-release profiles were controlled by the mechanical properties of the LNC-based hydrogels (slower release profiles correlated with higher viscoelasticity). Finally, the subcutaneous administration of LNC-based hydrogels led to classic inflammatory reactions of the foreign body-reaction type due to the endogenous character of CytC16, shown by cellular viability assays. New-generation nanoparticle-loaded hydrogels (LNC-based polymer-free hydrogels) show promise as implants for pharmaceutical applications. Once LNC release is completed, no gel matrix remains at the injection site, minimizing the additional toxicity due to the persistence of polymeric implants. Sustained drug-release profiles can be controlled by the mechanical properties of the hydrogels and could be tailor-made, depending on the therapeutic strategy chosen