Transport de nanovecteurs dans des matrices complexes

Avec le développement des nanomédecines, le transport des nanovecteurs (à vocation thérapeutique ou diagnostique) et leur capacité à pouvoir franchir ou non des barrières biologiques sont devenus des champs de recherche très actifs [1, 2]. Ces barrières peuvent être des hydrogels. Elles sont alors constituées d\u27une matrice macromoléculaire complexe, leur conférant une tenue mécanique, baignée par une phase aqueuse. Ce fluide joue un rôle majeur dans le transport et, lorsqu’il est à l\u27arrêt, le mouvement des nanovecteurs résulte uniquement de l’agitation thermique. Comprendre les relations entre la structure de la matrice, ses interactions avec les nanovecteurs et leur diffusion est l\u27objectif de mes recherches à Angers. Il constitue un défi scientifique en physico-chimie mais contribue également à une conception plus rationnelle des matrices et/ou des nanovecteurs dans le but d’applications ciblées. Ce projet combine une approche expérimentale et numérique sur la diffusion de nanovecteurs à travers des hydrogels biologiques d’intérêt (mucus, matrice extra-cellulaire, surfactant pulmonaire, coupes organotypiques, hydrogels synthétiques...). Il nécessite le développement de méthodologies expérimentales nouvelles sur le site d’Angers, en collaboration avec le SCIAM et PRIMEX : Microscopie confocale en mode FRAP et « particle tracking ». RMN à gradient de champ. Diffusion de la lumière en milieu turbide. Ces techniques permettent une mesure fiable du coefficient de diffusion, in situ, dans la matrice sans recourir aux techniques plus classiques de mesure de perméation. Les expériences de microscopie confocale permettent également de quantifier les phénomènes d’adsorption et de convection au sein de la matrice. Au-delà de l’unité MINT, le développement de ces techniques peut intéresser d’autres équipes sur le site. 1.            Nance, E.A., Woodworth, G.F., Sailor, K.A., Shih, T.-Y., Xu, Q., Swaminathan, G., Xiang, D., Eberhart, C., and Hanes, J., A Dense Poly(Ethylene Glycol) Coating Improves Penetration of Large Polymeric Nanoparticles Within Brain Tissue. Science Translational Medicine, 2012. 4(149): p. 149ra119. 2.            Lai, S.K., Wang, Y.-Y., and Hanes, J., Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues. Advanced Drug Delivery Reviews, 2009. 61(2): p. 158-171.

Self-diffusion of non-interacting hard spheres in particle gels

International audienceDifferent kinds of particle gels were simulated using a process of random aggregation of hard spheres. The mean square displacement of Brownian spherical tracer particles through these rigid gels was monitored and the average diffusion coefficient, normalized with the free diffusion coefficient (D), was obtained. For each gel structure the effect of the gel volume fraction (φ) and size ratio of the tracer (d) on the relative diffusion coefficient was investigated systematically. The volume fraction that is accessible to the tracers (φa) was determined in eachcase. D was found to be approximately the same if φa was the same, independent of φ, d and the gel structure. However a different behaviour is found if the tracers can penetrate the strands of the gel. A state diagram of d versus φ is given that shows the critical values (dc, φc) at whichall tracers become trapped. Different values are found for different gel structures. The dependence of D on φ/φc is independent of d, while the dependence of D on d/dc is independent of φ

Diffusion limited cluster aggregation with irreversible slippery bonds

Irreversible diffusion limited cluster aggregation (DLCA) of hard spheres was simulated using Brownian cluster dynamics. Bound spheres were allowed to move freely within a specified range, but no bond breaking was allowed. The structure and size distribution of the clusters was investigated before gelation. The pair correlation function and the static structure factor of the gels were determined as a function of the volume fraction and time. Slippery bonds led to local densification of the clusters and the gels, with a certain degree of order. At low volume fractions densification of the clusters occurred during their growth, but at higher volume fractions it occurred mainly after gelation. At very low volume fractions, the large-scale structure (fractal dimension), size distribution and growth kinetics of the clusters was found to be close to that known for DLCA with rigid bonds. Restructuring of the gels continued for long times, indicating that aging processes in systems with strong attraction do not necessarily involve bond breaking. The mean-square displacement of particles in the gels was determined. It is shown to be highly heterogeneous and to increase with decreasing volume fraction

Self-diffusion of reversibly aggregating spheres

Reversible diffusion limited cluster aggregation of hard spheres with rigid bonds was simulated and the self diffusion coefficient was determined for equilibrated systems. The effect of increasing attraction strength was determined for systems at different volume fractions and different interaction ranges. It was found that the slowing down of the diffusion coefficient due to crowding is decoupled from that due to cluster formation. The diffusion coefficient could be calculated from the cluster size distribution and became zero only at infinite attraction strength when permanent gels are formed. It is concluded that so-called attractive glasses are not formed at finite interaction strength.Comment: 10 figure

Step polymerization in various solvent conditions. A computer simulation approach using "Patchy Brownian Cluster Dynamics".

I will present a novel simulation technique derived from Brownian cluster dynamics used so far to study the isotropic colloidal aggregation [1]. It now implements irreversible patchy interactions between particles [2]. This technique gives access to static properties, dynamics and kinetics of the system, even far from the equilibrium. Particle thermal motions are modeled using billions of independent small random translations and rotations, constrained by the excluded volume and the connectivity. This algorithm, applied to a single polymer chain leads to correct static and dynamic properties, in the framework where hydrodynamic interactions are ignored. By varying patch angles, various local chain flexibilities can be obtained. We have used this new algorithm to model step-growth polymerization under various solvent qualities. The polymerization reaction is modeled by an irreversible aggregation between patches while an isotropic finite squarewell potential is superimposed to mimic the solvent quality. In bad solvent conditions, a competition between a phase separation (due to the isotropic interaction) and polymerization (due to patches) occurs. Surprisingly, an arrested network with a very peculiar structure appears. It is made of strands and nodes. Strands gather few stretched chains that dip into entangled globular nodes. These nodes act as reticulation points between the strands. The system is kinetically driven and we observe a trapped arrested structure. That demonstrates one of the strengths of this new simulation technique. It can give valuable insights about mechanisms that could be involved in the formation of stranded gels. [1] Babu, S., Gimel, J.-C., and Nicolai, T., Phase separation and percolation of reversibly aggregating spheres with a square-well attraction potential. Journal of Chemical Physics, 2006. 125(19): p. 184512. [2] Prabhu, A., Babu, S.B., Dolado, J.S., and Gimel, J.-C., Brownian cluster dynamics with short range patchy interactions: Its application to polymers and step-growth polymerization. Journal of Chemical Physics, 2014. 141(2): p. 024904

Crystallization and dynamical arrest of attractive hard spheres

International audienceCrystallization of hard spheres interacting with a square well potential was investigated by numerical simulations using so-called Brownian cluster dynamics. The phase diagram was determined over a broad range of volume fractions. The crystallization rate was studied as a function of the interaction strength expressed in terms of the second virial coefficient. For volume fractions below about 0.3 the rate was found to increase abruptly with increasing attraction at the binodal of the metastable liquid-liquid phase separation. The rate increased until a maximum was reached after which it decreased with a power law dependence on the second virial coefficient. Above a critical percolation concentration, a transient system spanning network of connected particles was formed. Crystals were formed initially as part of the network, but eventually crystallization led to the breakup of the network. The lifetime of the transient gels increased very rapidly over a small range of interaction energies. Weak attraction destabilized the so-called repulsive crystals formed in pure hard sphere systems and shifted the coexistence line to higher volume fractions. Stronger attraction led to the formation of a denser, so-called attractive, crystalline phase. Nucleation of attractive crystals in the repulsive crystalline phase was observed close to the transition

Lipid nanocapsules maintain full integrity after crossing a human intestinal epithelium model

Lipid nanocapsules (LNCs) have demonstrated great potential for the oral delivery of drugs having very limited oral bioavailability (BCS class II, III and IV molecules). It has been shown previously that orally-administered LNCs can permeate through mucus, increase drug absorption by the epithelial tissue, and finally, increase drug bioavailability. However, even if transport mechanisms through mucus and the intestinal barrier have already been clarified, the preservation of particle integrity is still not known. The aim of the present work is to study in vitro the fate of LNCs after their transportation across an intestinal epithelium model (Caco-2 cell model). For this, two complementary techniques were employed: Förster Resonance Energy Transfer (FRET) and Nanoparticle Tracking Analysis (NTA). Results showed, after 2 h, the presence of nanoparticles in the basolateral side of the cell layer and a measurable FRET signal. This provides very good evidence for the transcellular intact crossing of the nanocarriers