RESUMEN
The blood - brain barrier (BBB) prevents the majority of therapeutic drugs from reaching the brain following intravenous or oral administration. In this context, polymer nanoparticles are a promising alternative to bypass the BBB and carry drugs to brain cells. Amphiphilic cyclodextrins can form self-assemblies whose nanoparticles have a 100-nm-diameter range and are thus able to encapsulate drugs for controlled release. Our goal is to propose an optimized chemical synthesis of amphiphilic cyclodextrin, which remains a challenging task which commonly leads to only a low-milligram level of the high purity compound. Such cyclodextrin derivatives were used to prepare vesicles and to study their ability to vectorize a drug through the BBB. As a result, we introduced a convergent synthesis for a family of lipophosphoramidyl permethylated ß-CDs (Lip-ß-CDs) with various chain lengths. It was demonstrated that mixed vesicles comprised of phosphatidylcholine (POPC) and LipCDs were able to encapsulate atazanavir (ATV), a well-known protease inhibitor used as an antiretroviral drug against HIV. We highlighted that neo-vesicles promote the penetration of ATV in endothelial cells of the BBB, presumably due to the low fusogenicity of Lip-ß-CDs.
Asunto(s)
Sulfato de Atazanavir , Barrera Hematoencefálica , Ciclodextrinas , Nanopartículas , Animales , Bovinos , Células Cultivadas , Células Endoteliales , RatasAsunto(s)
Depsipéptidos/química , Inhibidores de Histona Desacetilasas/química , Hidrazinas/química , Depsipéptidos/síntesis química , Diseño de Fármacos , Histona Desacetilasa 1/antagonistas & inhibidores , Histona Desacetilasa 1/química , Histona Desacetilasa 6/antagonistas & inhibidores , Histona Desacetilasa 6/química , Inhibidores de Histona Desacetilasas/síntesis química , Histona Desacetilasas/química , Humanos , Hidrazinas/síntesis química , Simulación del Acoplamiento MolecularRESUMEN
RATIONALE: Recent preclinical research suggested that histone deacetylase inhibitors (HDACIs) and specifically class I HDAC selective inhibitors might be useful to treat alcohol use disorders (AUDs). OBJECTIVE: The objective of this study was to find a new inhibitor of the HDAC-1 isoenzyme and to test its efficacy in an animal model of AUDs. METHODS: In the present study, we prepared new derivatives bearing sulfonylhydrazide-type zinc-binding group (ZBG) and evaluated these compounds in vitro on HDAC-1 isoenzyme. The most promising compound was tested on ethanol operant self-administration and relapse in rats. RESULTS: We showed that the alkylsulfonylhydrazide-type compound (ASH) reduced by more than 55% the total amount of ethanol consumed after one intracerebroventricular microinjection, while no effect was observed on motivation of the animals to consume ethanol. In addition, one ASH injection in the central amygdala reduced relapse. CONCLUSIONS: Our study demonstrated that a new compound designed to target HDAC-1 is effective in reducing ethanol intake and relapse in rats and further confirm the interest of pursuing research to study the exact mechanism by which such inhibitor may be useful to treat AUDs.