Pickering emulsions: Preparation processes, key parameters governing their properties and potential for pharmaceutical applications

International audienceAn increased interest in Pickering emulsions has emerged over the last 15 years, mainly related to their very attractive properties compared to regular emulsions, namely their excellent stability and their numerous possible applications. In this review, after detailing the interest of Pickering emulsions, their main preparation processes are presented and their advantages and disadvantages discussed. In the third part, the key parameters that govern Pickering emulsions type, droplet size and stability are analyzed. Finally, the interest and the potential of Pickering emulsions for pharmaceutical applications are exposed and discussed, taking all the administration routes into consideration and focusing on organic particles

Dexamethasone palmitate large porous particles: A controlled release formulation for lung delivery of corticosteroids

International audienceWe have optimized a formulation of a prodrug of dexamethasone (DXM), dexamethasone palmitate (DXP) for pulmonary delivery as a dry powder. Formulations were prepared by spray drying DXP with 1,2-Dipalmitoyl-sn-Glycero-3-Phosphocholine (DPPC) and Hyaluronic Acid (HA) as excipients. Large porous particles around 13 μm were produced with a tap density of 0.05 g/cm 3 and a Fine particle fraction around 40%. The palmitate moiety favors DXP insertion into DPPC bilayers therefore limiting its in vitro release as shown by differential scanning calorimetry. After administering DXP powder intratracheally to rats by insufflation, bronchoalveolar lavage fluid (BALF) and blood samples were collected up to 24 h and DXP and DXM concentrations were determined by HPLC analysis after extraction. PK parameters were evaluated according to a non-compartmental model. We observe that DXP remains for up to 6 h in the epithelial lining fluid (ELF) of the lungs at very high concentration. In addition, DXP concentration decreases according to two characteristic times. Consequently, DXM can be detected at rather important concentration in ELF up to 24 h. The passage of DXP from the lungs to the bloodstream is very poor whereas DXM seems to be absorbed in the blood more easily. These results suggest that once administered DXP undergoes two different processes: hydrolysis into DXM due to the presence of esterases in the lungs and distribution in the lung tissue. This formulation appears promising to reduce systemic exposure and prolong the effect of the drug locally

The crucial role of macromolecular engineering, drug encapsulation and dilution on the thermoresponsiveness of UCST diblock copolymer nanoparticles used for hyperthermia

International audiencePoly(acrylamide-co-acrylonitrile) (P(AAm-co-AN)), an upper critical solution temperature (UCST)-type copo-lymer in water, was synthesized by reversible addition fragmentation chain transfer (RAFT) copolymerization and used as a macro-RAFT agent for the polymerization of oligo(ethylene glycol) methyl ether methacrylate (OEGMA) to yield amphiphilic diblock P(AAm-co-AN)-b-POEGMA copolymer. A series of copolymers with different AN content was obtained allowing to finely tune the UCST behavior (cloud point (T t-UCST) from 35 to 78°C). Addition of the POEGMA block did not modify the T t-UCST regardless its Mn but provided a lower critical solution temperature behavior at high temperature. Nanoparticles were then formulated by the nanoprecipita-tion technique revealing that copolymers with higher T t-UCST yield smaller, better-defined nanoparticles. Eventually, doxorubicin (Dox) was encapsulated into nanoparticles made from the copolymer having a T t-UCST close to mild hyperthermia (~43°C). Surprisingly, Dox encapsulation increased T t-UCST and gave smaller na-noparticles as opposed to their unloaded counterparts. The dilution of the suspension also led to a decrease of Tt-UCST. No obvious hyperthermia effect was observed on the cytotoxicity of Dox-loaded nanoparticles. Our study highlighted the influence of macromolecular engineering, drug encapsulation and nanoparticle dilution on UCST behavior, important features often overlooked despite their crucial impact in the development of thermo-sensitive nanoscale drug delivery systems

Biodegradable Pickering emulsions of Lipiodol for liver trans-arterial chemo-embolization

International audienceWater-in-oil (W/O) Lipiodol emulsions remain the preferable choice for local delivery of chemotherapy in the treatment of hepatocellular carcinoma. However, their low stability severely hampers their efficiency. Here, remarkably stable W/O Lipiodol emulsion stabilized by biodegradable particles was developed thanks to Pickering technology. The addition of poly(lactide-co-glycolide) nanoparticles (NPs) into the aqueous-phase of the formulation led to W/O Pickering emulsion by a simple emulsification process through two connected syringes. Influence of nanoparticles concentration and water/oil ratio on emulsion stability and droplet size were studied. All formulated Pickering emulsions were W/O type, stable for at least one month and water droplets size could be tuned by controlling nanoparticle concentration from 24 mm at 25 mg/mL to 69 mm at 5 mg/mL. The potential of these emulsions to efficiently encapsulate chemotherapy was studied through the internalization of doxorubicin (DOX) into the aqueous phase with a water/oil ratio of 1/3 as recommended by the medical community. Loaded-doxorubicin was released from conventional emulsion within a few hours whereas doxorubicin from stable Pickering emulsion took up to 10 days to be completely released. In addition, in vitro cell viability evaluations performed on the components of the emulsion and the Pickering emulsion have shown no significant toxicity up to relatively high concentrations of NPs (3 mg/mL) on two different cell lines: HUVEC and HepG2. Statement of Significance We present an original experimental research in the field of nanotechnology for biomedical applications. In particular, we have formulated, thanks to Pickering technology, a new therapeutic emulsion stabilized with biodegradable PLGA nanoparticles. As far as we know, this is the first therapeutic Pickering emulsion reported in the literature for hepatocellular carcinoma. Such a new emulsion allows to easily prepare a predictable and stable lipiodolized emulsion having all the required characteristics for optimum tumor uptake. As demonstrated throughout our manuscript, emulsions stabilized with these nanoparticles have the advantage of being biodegradable, biocompatible and less toxic compared to usual emulsions stabilized with synthetic surfactants. These findings demonstrate the plausibility of the use of Pickering emulsions for chemoembolization as a therapeutic agent in extended release formulations

Echogenicity enhancement by end-fluorinated polylactide perfluorohexane nanocapsules: Towards ultrasound-activable nanosystems

International audienc

Liposomal antagomiR-155-5p restores anti-inflammatory macrophages and improves arthritis in preclinical models of rheumatoid arthritis

Objective: We previously reported an increased expression of microRNA‐155 (miR‐155) in the blood monocytes of patients with rheumatoid arthritis (RA) that could be responsible for impaired monocyte polarization to anti‐inflammatory M2‐like macrophages. In this study, we employed two preclinical models of RA, collagen‐induced arthritis and K/BxN serum transfer arthritis, to examine the therapeutic potential of antagomiR‐155‐5p entrapped within PEGylated (polyethylene glycol [PEG]) liposomes in resolution of arthritis and repolarization of monocytes towards the anti‐inflammatory M2 phenotype. Methods: AntagomiR‐155‐5p or antagomiR‐control were encapsulated in PEG liposomes of 100 nm in size and −10 mV in zeta potential with high antagomiR loading efficiency (above 80%). Mice were injected intravenously with 1.5 nmol/100 μL PEG liposomes containing antagomiR‐155‐5p or control after the induction of arthritis. Results: We demonstrated the biodistribution of fluorescently tagged PEG liposomes to inflamed joints one hour after the injection of fluorescently tagged PEG liposomes, as well as the liver's subsequent accumulation after 48 hours, indicative of hepatic clearance, in mice with arthritis. The injection of PEG liposomes containing antagomiR‐155‐5p decreased arthritis score and paw swelling compared with PEG liposomes containing antagomiR‐control or the systemic delivery of free antagomiR‐155‐5p. Moreover, treatment with PEG liposomes containing antagomiR‐155‐5p led to the restoration of bone marrow monocyte defects in anti‐inflammatory macrophage differentiation without any significant functional change in other immune cells, including splenic B and T cells. Conclusion: The injection of antagomiR‐155‐5p encapsulated in PEG liposomes allows the delivery of small RNA to monocytes and macrophages and reduces joint inflammation in murine models of RA, providing a promising strategy in human disease.imag

Agents de contraste pour l’imagerie médicale

Les techniques d’imagerie médicale telles que l’imagerie par résonance magnétique (IRM) ou l’ultrasonographie sont désormais bien ancrées dans la pratique clinique. Néanmoins, afin d’améliorer encore le diagnostic de certaines pathologies, des agents de contraste s’avèrent nécessaires. Les matériaux utilisés pour formuler ces agents de contraste doivent être judicieusement choisis pour interagir avec le stimulus physique de sorte que le signal recueilli soit le plus intense possible. Ces agents doivent présenter une toxicité nulle ou, du moins, faible vis-à-vis du service médical rendu. Nous présentons dans cette revue l’état de l’art pour les agents de contraste pour l’IRM et l’ultrasonographie

Influence d'inclusions sur les paramètres élastiques de membrane non-ioniques

Replacing small amounts of nonionic surfactant by an ionic one does not modify structural and elastic parameters of a reverse lamellar phase because of counterions self-screening. On the other hand, as the surface charge density increases in a direct lamellar phase, steric repulsions between in-plane charges "iron" membranes fluctuations, leading to a decrease of the periodicity. The Caillé parameter eta decreases, whereas the membrane rigidity increases, in good agreement with Fogden et al. predictions. The smectic compressibility modulus Bbar increases because of electrostatic repulsions and then decreases slightly either because of a renormalization of the membrane thickness due to counterions condensation or because of fluctuations correlations predicted by Lukatsky et al. A hydrophobic-hydrophilic-hydrophobic peptide, globally neutral was inserted in lamellar and sponge phases. In these phases, it lies on the membrane and its hydrophilic part is organized in a rigid alpha helix. Its insertion leads to a decrease of the Caillé parameter eta but steric repulsions still stabilize the phase and the periodicity remains unchanged. The decrease of eta is explained either by an increase of the effective membrane thickness, or by the Sens and Turner model. The peptide also induces a rigidification of the membrane. Because of their restrictive hypotheses, existing models cannot account for the spectacular rigidification, which is well correlated to the increase of the membrane thickness. The light-harvesting complex LH2 was inserted in the Q230 cubic phase of monoolein. We investigated the absorption and fluorescence properties of this oligomeric membrane protein. The insertion of LH2 in the cubic phase induced modifications in the pigments binding sites. Despite these significant structural perturbations, the protein seems to keep an oligomeric structure. These observations ruled out crystallization trials in the cubic phase for this protein, leading to some caution in the use of the cubic phase as a crystallization matrix. We also showed that LH2 was denaturated in sponge phases of surfactants.Charger faiblement la surface des membranes ne modifie en rien les paramètres structuraux et élastiques d'une phase lamellaire inverse, car les contre-ions s'auto-écrantent. En revanche, pour la phase lamellaire directe, les répulsions électrostatiques entre charges dans le même plan "repassent" les fluctuations de la membrane, entraînant une diminution de la périodicité. Le paramètre de Caillé eta diminue etla rigidité de la membrane augmente, en accord avec les prédictions de Fogden et al. Le module de compressibilité smectique Bbar augmente à cause des répulsions électrostatiques puis diminue, soit car la couche de contre-ions renormalise l'épaisseur de la membrane, soit sous l'effet des corrélations de fluctuations prédit par Lukatsky et al. Un peptide hydrophobe-hydrophile-hydrophobe globalement neutre a été inséré dans des phases lamellaire et éponge: il se couche sur les membranes et sa partie hydrophile s'organise en hélice alpha rigide. Dans la phase lamellaire, il entraîne une diminution du paramètre de Caillé eta, sans modifier ni la stabilisation par les répulsions stériques, ni la périodicité. La diminution de eta peut s'expliquer soit par une augmentation de l'épaisseur effective de la membrane, soit par le modèle de Sens et Turner. Le peptide induit aussi une importante augmentation de la rigidité. Les hypothèses restrictives des modèles ne leur permettent pas d'expliquer cette augmentation, cependant corrélée à l'augmentation de l'épaisseur effective de la membrane. Les mesures d'absorption et de fluorescence sur la protéine transmembranaire collectrice de la lumière LH2 insérée dans une phase cubique Q230 de monooléine ont montré qu'elle subit des modifications affectant certains de ses pigments, l'état oligomérique de la protéine étant préservé. Ces effets proviennent de la forte concentration en monooléine (et/ou de la faible teneur en eau), et pas de la forte courbure de la membrane. Ces observations nous ont conduits à ne pas tenter la cristallisation du LH2 dans la phase cubique et mettent un bémol à l'utilisation de cette phase comme matrice de cristallisation. Nous avons en outre montré que l'insertion du LH2 dans des phase éponges de tensioactifs le dénaturait

INFLUENCE D'INCLUSIONS SUR LES PARAMETRES ELASTIQUES DE MEMBRANES NON IONIQUES

CHARGER FAIBLEMENT LA SURFACE DES MEMBRANES NE MODIFIE EN RIEN LES PARAMETRES STRUCTURAUX ET ELASTIQUES D'UNE PHASE LAMELLAIRE (L ) INVERSE, CAR LES CONTRE-IONS S'AUTOECRANTENT. PAR CONTRE POUR LA L DIRECTE, LES REPULSIONS ELECTROSTATIQUES ENTRE CHARGES DANS LE MEME PLAN REPASSENT LES FLUCTUATIONS, ENTRAINANT UNE DIMINUTION DE LA PERIODE. LE PARAMETRE DE CAILLE DIMINUE ET LA RIGIDITE DE LA MEMBRANE AUGMENTE, EN ACCORD AVEC LES PREDICTIONS DE FOGDEN ET AL. LE MODULE DE COMPRESSIBILITE SMECTIQUE $B AUGMENTE A CAUSE DES REPULSIONS ELECTROSTATIQUES PUIS DIMINUE, SOIT CAR LA COUCHE DE CONTRE-IONS RENORMALISE L'EPAISSEUR DE LA MEMBRANE, SOIT SOUS L'EFFET DES CORRELATIONS DE FLUCTUATIONS PREDIT PAR LUKATSKY ET AL. UN PEPTIDE HYDROPHOBE-HYDROPHILE-HYDROPHOBE GLOBALEMENT NEUTRE A ETE INSERE DANS DES PHASES L ET EPONGE : IL SE COUCHE SUR LES MEMBRANES ET SA PARTIE HYDROPHILE S'ORGANISE EN HELICE . DANS LA PHASE L , IL ENTRAINE UNE DIMINUTION DE , SANS MODIFIER NI LA STABILISATION PAR LES REPULSIONS STERIQUES, NI LA PERIODE. UNE AUGMENTATION DE L'EPAISSEUR EFFECTIVE DE LA MEMBRANE EXPLIQUE LA DIMINUTION DE . LE PEPTIDE INDUIT AUSSI UNE IMPORTANTE AUGMENTATION DE LA RIGIDITE. LES HYPOTHESES DES MODELES NE LEUR PERMETTENT PAS D'EXPLIQUER CETTE AUGMENTATION, CEPENDANT CORRELEE A L'AUGMENTATION DE L'EPAISSEUR EFFECTIVE DE LA MEMBRANE. LES MESURES D'ABSORPTION ET DE FLUORESCENCE SUR LA PROTEINE TRANSMEMBRANAIRE LH2 INSEREE DANS UNE PHASE CUBIQUE Q230 DE MONOOLEINE ONT MONTRE QU'ELLE SUBIT DES MODIFICATIONS AFFECTANT CERTAINS DE SES PIGMENTS, L'ETAT OLIGOMERIQUE DE LA PROTEINE ETANT PRESERVE. CES EFFETS VIENDRAIENT DE LA FORTE CONCENTRATION EN MONOOLEINE OU DE LA FORTE COURBURE DE LA MEMBRANE. CES OBSERVATIONS NOUS ONT CONDUITS A NE PAS TENTER LA CRISTALLISATION DU LH2 DANS LA PHASE CUBIQUE ET METTENT UN BEMOL A L'UTILISATION DE CETTE PHASE COMME MATRICE DE CRISTALLISATION. EN OUTRE, L'INSERTION DU LH2 DANS DES PHASE EPONGES DE TENSIOACTIFS LE DENATURE.PARIS-BIUSJ-Thèses (751052125) / SudocCentre Technique Livre Ens. Sup. (774682301) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF