Glycosylation-mediated targeting of carriers

For safe and effective therapy, drugs should be delivered selectively to their target tissues or cells at an optimal rate. Drug delivery system technology maximizes the therapeutic efficacy and minimizes unfavorable drug actions by controlling their distribution profiles. Ligand-receptor binding is a typical example of specific recognition mechanisms in the body; therefore, ligand-modified drug carriers have been developed for active targeting based on receptor-mediated endocytosis. Among the various ligands reported thus far, sugar recognition is a promising approach for active targeting because of their high affinity and expression. Glycosylation has been applied for both macromolecular and liposomal carriers for cell-selective drug targeting. Recently, the combination of ultrasound exposure and glycosylated bubble liposomes has been developed. In this review, recent advances of glycosylation-mediated targeted drug delivery systems are discussed

Qu'en est-il des parabens dans les médicaments?

Les parabens sont largement utilisés depuis les années vingt dans les spécialités pharmaceutiques en raison de leur grande efficacité en tant que conservateur et de leur faible toxicité chez l'Homme. Cependant leur innocuité est remise en cause suite à la découverte de leur potentiel reprotoxique chez l'animal. A ce jour, les résultats des études toxicologiques et épidémiologiques ne permettent pas de remettre en question le rapport bénéfice/ risque des médicaments contenant des parabens. Malgré cela, l'éventuelle interdiction des parabens dans les médicaments suscite une grande inquiétude chez les industriels et les contraint à retrouver des alternatives moins sujettes à controverse.Since the 1920's, parabens are widely used in pharmaceutical products due to their well-known efficient anti-microbial activity and their low toxicity levels in humans. Nonetheless their safety is reappraised after discovery some potential reproductive toxicity in animals. Until now, data obtained from toxicological and epidemiological in depth studies do not cast the doubt on the benefit / risk ratio of drugs containing parabens. Nevertheless, the possibility of parabens being prohibited in medicines formulaions urges pharmaceutical companies to find less controversial alternatives.LYON1-BU Santé (693882101) / SudocRENNES1-BU Santé (352382103) / SudocSudocFranceF

De la directive 76/768/CEE au règlement (CE) n1223/2009 (l'évolution de la réglementation des produits cosmétiques)

La réglementation des produits cosmétiques est, depuis sa naissance, en constante évolution. La dernière grande modification, est l'harmonisation de la réglementation au sein de la Communauté européenne, par l'adoption d'un texte unique, le règlement (CE) n 1223/2009. Bien que les grands principes de la Directive 76/768/CEE modifiée soient maintenus, ce nouveau texte impose de nouvelles obligations, qui ont pour but de garantir toujours plus de sécurité pour le consommateur. Elles concernent notamment la désignation de la personne responsable, la mise en œuvre du Rapport sur la Sécurité du Produit Cosmétique et une cosmétovigilance renforcée. Les entreprises doivent s'adapter à ces nouvelles contraintes afin d'assurer la conformité et la sécurité de leurs produits cosmétiques pour l'entrée en vigueur du règlement (CE) n 1223/2009, le 11 juillet 2013.Since its birth the cosmetics regulation is constantly evolving. The last important modification is the regulation harmonization in the European Community, with the adoption of a unique text: the Regulation (EC) n 1223/2009. The main principles of the Directive 76/768/CEE are preserved. This new regulation requires new rules, to protect consumers safety. The responsible person, the Cosmetic Product Safety Report and a reinforced cosmetovigilance are the priorities. The cosmetics companies have to adapt to insure their cosmetic products conformity and safety with the Regulation, dated on July the 11th 2013.LYON1-BU Santé (693882101) / SudocRENNES1-BU Santé (352382103) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Évaluation de la réponse immunitaire systémique à une glycoprotéine virale recombinante E2 microencapsulée et optimisation de la capture cellulaire de microsphères par greffage de ligands

La majorité des infections débute par contact muqueux et l administration d un vaccin au site de pénétration de l agent pathogène est souvent nécessaire à l induction d une immunité protectrice. Notre travail porte sur la conception de vecteurs polymériques microparticulaires chargé avec un antigène d intérêt, la glycoprotéine purifiée recombinante E2 (rE2) destinés à une vaccination mucosale. Dans ce contexte, nous avons évalué le potentiel vaccinal de la rE2 après microencapsulation au sein de microsphères de copolymères d acides lactique et glycolique (PLGA) chez le lapin par différentes voies d administration (intramusculaire, orale et nasale). L administration nasale engendre une production d anticorps sériques spécifiques moins variable et plus intense que l administration orale. Afin d optimiser l accessibilité aux cellules immunocompétentes, nous avons étudié l influence du greffage de différents ligands (WGA, motif RGD, mannose) sur la capture de microsphères de PLGA par des macrophages. Ce travail a montré que le greffage de ligands augmente de manière significative la capture des microsphères. Nous avons également observé l implication de deux phénomènes simultanés, un phénomène actif, spécifique et un phénomène passif, non spécifique. La contribution relative de chacun de ces phénomènes sur la capture totale est variable selon le ligand et est dépendante du ratio particules/cellules.The majority of infections starts with mucosal contact and the administration of vaccine directly at the site of pathogen entry is often necessary to induce a protective immunity. Our study focused on the design of polymeric microparticles loaded with a purified recombinant glycoprotein E2 (rE2) for mucosal vaccination. For that purpose, we evaluated the vaccine potential of rE2 loaded in PLGA microspheres in rabbits after administration by different routes (intramuscular, oral and nasal). The nasal administration induced the production of specific serum antibodies which is less variable and more significant than after oral administration. To optimize the accessibility to immunocompetent cells, we studied the influence of ligand grafting (WGA, an RGD containing-peptide and mannose-PEG3-NH2) on the rate and intensity of uptake of PLGA microparticles by macrophages. This work showed that ligand grafting enhanced the uptake of microparticles. We also observed the simultaneous presence of two phenomena, i.e., a specific and a non-specific process. The relative contribution of specific and non-specific processes to the overall uptake varied greatly according to the ligands, and was dependent on the particle-to-cell ratio.RENNES1-BU Sciences Philo (352382102) / SudocSudocFranceF

Dermo-cosmetic products and anti-cancer treatments

National audienceDermo-cosmetic products and anti-cancer treatments. Supportive care, which includes the use of dermo-cosmetics, is an important part of oncology care. A survey was carried out to determine the expectations of cancer patients with regard to care products and to evaluate the perception of pharmacists with regard to their requests. (C) 2021 Elsevier Masson SAS.All rights reserve

Molybdenum cluster loaded PLGA nanoparticles: An innovative theranostic approach for the treatment of ovarian cancer

International audienc

Preparation and characterization of spironolactone-loaded nano-emulsions for extemporaneous applications

International audienceIn neonates as well as in adults having swallowing difficulty, oral medication is given through a nasogastric tube making liquid formulations preferable. In this study, we present the high potential of nanometric emulsions formulated by spontaneous surfactant diffusion, as extemporaneous formulations of hydrophobic drug. Spironolactone used as hydrophobic drug model, was incorporated in oil before formulation at a concentration of 13.5 mg/g oil. Then, all formulations were evaluated from pharmacotechnical and clinical standpoints, for their use in hospital or community pharmacy. The strength of this new liquid formulation lies on the simplicity, efficiency and reproducibility of their low energy process as on clinical aspects: high dose uniformity, facility to be administered through in nasogastric tube without any retention and a stability of 2 months at least compatible for an extemporaneous use. Moreover, this emulsion presented spironolactone content of 3.75 mg/ml among the most concentrated formulations published

PBPK model of methotrexate in cerebrospinal fluid ventricles using a combined microdialysis and MRI acquisition

International audienceThe objective of the study was to evaluate the distribution of methotrexate (MTX) in cerebrospinal fluid (CSF) lateral ventricles and in cisterna magna after 3rd intraventricular CSF administration in a rabbit model.MTX or gadolinium chelate (Gd-DOTA) was administered in the 3rd ventricle with a local microdialysis to study the pharmacokinetics at the site of administration and with a simultaneous magnetic resonance imaging (MRI) acquisition in the 3rd ventricle, the lateral ventricles and in the cisterna magna. A specific CSF Physiologically Based Pharmacokinetic (PBPK) model was then extrapolated for MTX from Gd-DOTA data.The relative contribution of elimination and distribution processes to the overall disposition of MTX and Gd-DOTA in the 3rd ventricle was similar (i.e., around 60% for CLE and 40% for CLI) suggesting that Gd-DOTA was a suitable surrogate marker for MTX disposition in ventricular CSF. The PBPK predictions for MTX both in CSF of the 3rd ventricle and in plasma were in accordance with the in vivo results.The present study showed that the combination of local CSF microdialysis with MRI acquisition of the brain ventricles and a PBPK model could be a useful methodology to estimate the drug diffusion within CSF ventricles after direct brain CSF administration. Such a methodology would be of interest to clinicians for a rationale determination and optimization of drug dosing parameters in the treatment of leptomeningeal metastases

Maternal and fetal blood pharmacokinetics and organ distribution of atrazine, propazine, simazine and their metabolites in pregnant rats after chronic oral administration

International audienceEnvironmental contamination by chlorotriazines has been evidenced in mother-child cohort suggesting more detailed risk assessment of these compounds in drinking water. Exposure of rodents to atrazine (ATZ) has been associated with alterations of endocrine and reproductive functions by disrupting neuroendocrine control at hypothalamus level. Perinatal exposure to low doses of ATZ has been associated with reproductive dysfunction, and to behavioral abnormalities in adult exposed during embryogenesis. The objectives of the current investigation were to (1) evaluate the influence of physicochemical properties of chlorotriazines on tissue distribution in pregnant rats and in fetuses and (2) gain a better understanding of fetal distribution of chlorotriazines in specific tissues, particularly in brain. Serial blood samples were obtained from pregnant rats after administration of ATZ, propazine (PRO), and simazine (SIM) via oral route at a dose of 10 mg/kg from day 15 to day 19. Maternal and fetal tissues were harvested at day 20, 24 h after the last dosing. The metabolic extraction ratio was estimated to 87% suggesting a significant first-pass effect explaining the low oral bioavailability. Blood exposure to parent compounds (ATZ, PRO, and SIM) was negligible (lower than 5%) compared with metabolite exposure. The main metabolite exposure involved diamino-s-chlorotriazine, ranging from 60% to 90% depending on the molecules administered. A correlation between tissue-to-blood ratio and physicochemical descriptors was observed for fat and mammary gland tissues but not for brain in adult rats. A more pronounced distribution in fetal brain was observed for ATZ and PRO, the 2 most lipophilic compounds

PLGA nanoparticles embedding molybdenum cluster salts: Influence of chemical composition on physico-chemical properties, encapsulation efficiencies, colloidal stabilities and in vitro release

International audienceWe present a screening of poly (D,L-lactide-co-glycolide) (PLGA) nanoparticles embedding a series of inorganic molybdenum octahedral clusters intended for photodynamic therapy (PDT) of cancer. Three cluster compounds from 2 cluster units, [{Mo6Br8}Br6]2− and [{Mo6I8}(OOC2F5)6]2− were studied. [{Mo6Br8}Br6]2−cluster units are found in the soluble ternary salt Cs2[{Mo6Br8}Br6] (CMB) prepared by solid state chemistry at high temperature. In solution Cs+ cations are replaced by tetrabutyl ammonium cations (C4H9)4N+) to form the salt ((C4H9)4N)2[{Mo6Br8}Br6] (TBA2). [{Mo6I8}(OOC2F5)6]2− was prepared combining solid state and solution chemistries; it is paired with Cs+ cations to form Cs2[{Mo6I8}(OOC2F5)6] (CMIF). All tested cluster-based salts could efficiently be incorporated in PLGA nanoparticles as seen with encapsulation efficiencies always higher than 60%. Cluster loaded nanoparticles (CNPs) freshly prepared by solvent displacement method showed spherical shapes, zeta potential values between −20 and −47 mV, polydispersity index in the range 0.123–0.167 and sizes in the range 75–150 nm according to the cluster compound and the polymer-to-cluster mass ratio (P/C), suggesting a good cellular uptake. CNPs colloidal stability was maintened for 3 months when they were stored refrigerated and protected from light but the chemical stability was shorter, i.e. 4 weeks, 1 week and 1 day for CMIF, TBA2 and CMB, respectively, CMIF penta-fluoropropionate apical ligands being less rapidly substituted by hydroxyles groups than TBA2 and CMB halogen apical ligands. FT-IR analysis revealed the lack of strong chemical interaction between cluster compounds and polymer within the nanoparticles. An interesting quick cluster in vitro release driven by diffusion outside the nanoparticles porous matrix was observed for all cluster compounds when P/C ratio was ≤2.5 and only a higher P/C ratio not studied in this work (i.e. >5) could significantly affect the release of the encapsulated cluster compound. Photophysical properties of cluster compounds were preserved following PLGA incorporation. This work presents PLGA nanoparticles as a stable and efficient cluster compound delivery systems for further in vitro and vivo evaluations in cancer models