RESUMEN
The impact of the polyunsaturated fatty acids (PUFAs) at physiological concentrations on the composition of eicosanoids transported within the extracellular vesicles (EVs) of rat bone marrow mesenchymal stem cells and cardiomyoblasts was reported by our group in 2020. The aim of this article was to extend this observation to cells from the cardiac microenvironment involved in the processes of inflammation, namely mouse J774 macrophages and rat heart mesenchymal stem cells cMSCs. Moreover, to enhance our capacity to understand the paracrine exchange between these orchestrators of cardiac inflammation, we investigated some machinery involved in the eicosanoid's synthesis transported by the EVs produced by these cells (including the two formerly described cells: bone marrow mesenchymal stem cells BM-MSC and cardiomyoblasts H9c2). We analyzed the oxylipin and the enzymatic content of the EVs collected from cell cultures supplemented (or not) with PUFAs. We prove that large eicosanoid profiles are exported in the EVs by the cardiac microenvironment cells, but also that these EVs carry some critical and functional biosynthetic enzymes, allowing them to synthesize inflammation bioactive compounds by sensing their environment. Moreover, we demonstrate that these are functional. This observation reinforces the hypothesis that EVs are key factors in paracrine signaling, even in the absence of the parent cell. We also reveal a macrophage-specific behavior, as we observed a radical change in the lipid mediator profile when small EVs derived from J774 cells were exposed to PUFAs. To summarize, we prove that the EVs, due to the carried functional enzymes, can alone produce bioactive compounds, in the absence of the parent cell, by sensing their environment. This makes them potential circulating monitoring entities.
Asunto(s)
Vesículas Extracelulares , Ratones , Ratas , Animales , Corazón , Ácidos Grasos Insaturados , Eicosanoides , InflamaciónRESUMEN
AIMS: Apelin and vitamin E have been proposed as signaling molecules, but their synergistic role is unknown. The aim of this work was to develop vitamin E TPGS/Apelin system to test their cardioprotective and metabolic efficacy in vitro and in vivo. METHODS: FDA-approved surfactant D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS-1000) and Apelin complex were characterized by physico-chemical methods (CMC determination, dynamic light scattering and circular dichroism). In vitro studies were carried out on H9C2 cardiomyoblasts and isolated murine cardiomyocytes. In vivo studies were performed in isoproterenol- and high-fat diet-induced cardiac remodeling models in mice. RESULTS: We found that vitamin E TPGS/Apelin provide cardioprotective and metabolic efficacy in vitro and in vivo. In vitro studies revealed that vitamin E TPGS/Apelin reduces hypoxia-induced mitochondrial ROS production in cultured cardiomyocytes and H9C2 cardiomyoblasts. In addition, vitamin E TPGS/Apelin confers apoptotic response to hypoxic stress in cells. In a mouse model of isoproterenol-induced cardiac injury, TPGS is not able to affect cardiac remodeling, however combination of vitamin E TPGS and Apelin counteracts myocardial apoptosis, oxidative stress, hypertrophy and fibrosis. Furthermore, combination treatment attenuated obesity-induced cardiometabolic and fibrotic remodeling in mice. CONCLUSION: Together, our data demonstrated the therapeutic benefits of vitamin E TPGS/Apelin complex to combat cardiovascular and metabolic disorders.
Asunto(s)
Apelina/farmacología , Cardiotónicos/farmacología , Vitamina E/farmacología , Animales , Apoptosis/efectos de los fármacos , Cardiomegalia/complicaciones , Cardiomegalia/patología , Hipoxia de la Célula/efectos de los fármacos , Línea Celular , Cardiomiopatías Diabéticas/complicaciones , Cardiomiopatías Diabéticas/patología , Dieta Alta en Grasa , Fibrosis , Isoproterenol , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Especies Reactivas de Oxígeno/metabolismo , Remodelación Vascular/efectos de los fármacosRESUMEN
We performed a systematic study on the spectroscopic and aggregation properties of stoichiometric mixtures (1:4) of the tetracationic meso-tetrakis(4-N-methylpyridinium)porphyrin (H2 TMPyP) and three sodium alkylsulfate surfactants (tetradecyl, hexadecyl, and octadecylsulfate) in an aqueous solution. The objective was to build a supramolecular aggregate, which would favor the internalization of tetracationic porphyrins in cells without chemical modification of the structure of the porphyrin. We show that stoichiometric H2 TMPyP/alkylsulfate (1:4) mixtures lead to the formation of large hollow spherical aggregates (60-160â nm). The TEM images show that the membrane of these aggregates are composed of smaller aggregates, which are probably rod-like micelles. These rod-like micelles have a hydrophobic core composed of the alkyl chains of the alkylsulfate surfactant, whereas the charged surface corresponds to the tetracationic porphyrins.
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Porfirinas/química , Tensoactivos/química , Aniones , Cationes , Microscopía Electrónica de Transmisión , Espectroscopía de Protones por Resonancia Magnética , Agua/químicaRESUMEN
The self-association properties of anti-HIV catanionic dendrimers as multivalent galactosylceramide (GalCer)-derived inhibitors are presented. The study was designed to elucidate the origin of the relatively high cytotoxicity values of these anti-HIV catanionic dendrimers, which have previously been found to exhibit in vitro anti-HIV activity in the submicromolar range. The physicochemical properties of these catanionic dendrimers were studied to tentatively correlate the structural parameters with self-association and biological properties. We can conclude from this study that the absence of correlation between the hydrophobicity and the cytotoxicity of the catanionic systems could be explained by the partial segregation of the different partners of the catanionic entities.
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Fármacos Anti-VIH/química , Dendrímeros/química , Fármacos Anti-VIH/metabolismo , Dendrímeros/síntesis química , Dendrímeros/metabolismo , Dispersión Dinámica de Luz , Galactosilceramidas/química , Proteína gp120 de Envoltorio del VIH/antagonistas & inhibidores , Proteína gp120 de Envoltorio del VIH/metabolismo , VIH-1/metabolismo , Humanos , Tensoactivos/químicaRESUMEN
Lactose-derived catanionic vesicles offer unique opportunities to overcome cellular barriers. These potential nanovectors, very easy to formulate as drug delivery systems, are able to encapsulate drugs of various hydrophilicity. This article highlights versatile interaction mechanisms between these catanionic vesicles, labeled with hydrophilic and amphiphilic fluorescent probes, and a mammalian cell line, Chinese Hamster Ovary. Confocal microscopy and flow cytometry techniques show that these vesicles are internalized by cells through cellular energy dependent processes, as endocytosis, but are simultaneously able to spontaneously fuse with cell plasma membranes and release their hydrophilic content directly inside the cytosol. Such innovative and polyvalent nanovectors, able to deliver their content via different internalization pathways, would positively be a great progress for the coadministration of drugs of complementary efficiency.
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Endocitosis , Fusión de Membrana , Membranas Artificiales , Animales , Células CHO , Cationes , Línea Celular , Membrana Celular/metabolismo , Separación Celular , Cricetulus , Citosol , Sistemas de Liberación de Medicamentos , Citometría de Flujo , Colorantes Fluorescentes/química , Glucolípidos/química , Cinética , Lactosa/química , Microscopía Confocal , TensoactivosRESUMEN
Skin deep: A bioactive formulation for dermal delivery of antihistamines is obtained by using the original properties of catanionic associations towards self-assembly in water. The drug, which participates in its own transport, is preserved from photodegradation when solubilised in the bioactive formulation. The drug release through the skin is also delayed.
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Monosacáridos/química , Tensoactivos/química , Antialérgicos/administración & dosificación , Portadores de Fármacos/química , Furanos/administración & dosificación , Humanos , Hipersensibilidad/tratamiento farmacológico , Prometazina/administración & dosificación , Piridonas/administración & dosificación , Absorción CutáneaRESUMEN
A painless and non-invasive method to deliver drugs using dermal and transdermal administration routes has been expanding for more than 30 years as it reduces the risk of drug overdoses that can be associated with oral administrations or injections. To understand the particularities of this drug delivery pathway, we will present a rapid review of the skin, including its structure and the parameters that influence drug diffusion into it, and then discuss the strategies that improve dermal drug delivery. Of the multitude of existing systems used for topical dermal and transdermal applications, this review will focus on the breakthroughs in drug delivery systems made of hydrogels. Specifically, we will firstly present the use of hydrogels as innovative drug delivery vehicles to carry the active ingredient and penetrate the skin barrier. We will discuss the structure of hydrogels and the physicochemical parameters to master for improving drug delivery, as well as the drug encapsulation and release processes from hydrogels. In the last part, we will review the use of hydrogels as pharmaceutical forms associated with other vehicles - as emulsions, lipid nanoparticles, vesicles, capsules and polymeric or inorganic nanoparticles - suitable for skin penetration enhancement and drug protection, as well as side effects that may limit their use.
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Hidrogeles , Absorción Cutánea , Administración Cutánea , Hidrogeles/química , Piel , Sistemas de Liberación de Medicamentos , ExcipientesRESUMEN
1,8-cineole is a monoterpene commonly used by the food, cosmetic, and pharmaceutical industries owing to its flavor and fragrances properties. In addition, this bioactive monoterpene has demonstrated bactericidal and fungicidal activities. However, such activities are limited due to its low aqueous solubility and stability. This study aimed to develop nanoemulsion containing cineole and assess its stability and antibacterial activity in this context. The spontaneous emulsification method was used to prepare nanoemulsion (NE) formulations (F1, F2, F3, F4, and F5). Following the development of NE formulations, we chose the F1 formulation that presented an average droplet size (in diameter) of about 100 nm with narrow size distribution (PdI <0.2) and negative zeta potential (â¼ - 35 mV). According to the analytical centrifugation method with photometric detection, F1 and F5 formulations were considered the most stable NE with lower droplet migration velocities. In addition, F1 formulation showed high incorporation efficiency (> 80 %) and TEM analyses demonstrated nanosized oil droplets with irregular spherical shapes and without any aggregation tendency. Antibacterial activity assessment showed that F1 NE was able to enhance the cineole action against Staphylococcus aureus, Enterococcus faecalis, and Streptococcus pyogenes. Therefore, using a simple and reproducible method of low energy emulsification we designed a stable nanoemulsion containing 1,8-cineole with improved antibacterial activity against Gram-positive strains.
Asunto(s)
Antibacterianos/química , Emulsiones/química , Eucaliptol/química , Nanoestructuras/química , Antibacterianos/farmacología , Estabilidad de Medicamentos , Enterococcus faecalis/efectos de los fármacos , Eucaliptol/farmacología , Pruebas de Sensibilidad Microbiana , Tamaño de la Partícula , Staphylococcus aureus/efectos de los fármacosRESUMEN
The synthesis and characterization of a new series of catanionic multivalent analogs of GalCer is described. These systems are based on phosphonic acid terminated dendrimers and N-hexadecylamino lactitol moieties. Despite important structural differences that affect the dendrimers' outer-shell, these supramolecular assemblies showed a fairly comparable anti-HIV-1 activity. All compounds have submicromolar IC(50) in a cell-based HIV-infection model but also a high general cytotoxicity.
Asunto(s)
Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Galactosilceramidas/química , Galactosilceramidas/farmacología , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Fármacos Anti-VIH/síntesis química , Línea Celular , Supervivencia Celular , Dendrímeros/síntesis química , Dendrímeros/química , Dendrímeros/farmacología , Galactosilceramidas/síntesis química , Humanos , Pruebas de Sensibilidad Microbiana , Organofosfonatos/síntesis química , Organofosfonatos/química , Organofosfonatos/farmacologíaRESUMEN
Dermal/transdermal drug delivery continues to grow in importance as a means of enhancing treatment activity while reducing toxicity by avoiding the systemic absorption of the drug. At the same time, this has led to the adjustment of a wide diversity of drug carriers. This paper begins with a review of the skin, including its structure and the parameters that influence drug diffusion, followed by strategies to improve dermal drug delivery. Of the multitude of existing carriers, we will focus on the most advanced vectors in dermal/transdermal delivery, and in particular, on vesicular systems. This review will present the state of the art as well as the new trends in this domain. Through the description of these systems, we will try to obtain information on the ideal properties that the carrier must have in order to improve the cutaneous and transcutaneous penetration of the drug.
RESUMEN
Skin is our biggest organ. It interfaces our body with its environment. It is an efficient barrier to control the loss of water, the regulation of temperature, and infections by skin-resident and environmental pathogens. The barrier function of the skin is played by the stratum corneum (SC). It is a lipid barrier associating corneocytes (the terminally differentiated keratinocytes) and multilamellar lipid bilayers. This intricate association constitutes a very cohesive system, fully adapted to its role. One consequence of this efficient organization is the virtual impossibility for active pharmaceutical ingredients (API) to cross the SC to reach the inner layers of the skin after topical deposition. There are several ways to help a drug to cross the SC. Physical methods and chemical enhancers of permeation are a possibility. These are invasive and irritating methods. Vectorization of the drugs through nanocarriers is another way to circumvent the SC. This mini-review focuses on supramolecular and macromolecular matrices designed and implemented for skin permeation, excluding vesicular nanocarriers. Examples highlight the entrapment of anti-inflammatory API to treat inflammatory disorders of the skin.
RESUMEN
Polyglycerol esters (PGEs), produced by esterification of fatty acids on polyglycerols, were analysed by High Resolution Mass Spectrometry (HRMS), HPLC-MS and U-HPLC-MS. A structural study of PGEs in 4 samples synthesised by the Gattefossé company was carried out using an elemental analysis of HRMS spectra and modelling of all probable isomers and cyclic structures. The results were used to construct a structural database of all species present in the 4 samples. After an assessment of the selectivity of 5 reversed phase columns: Aeris Widepore XB-C8, 3.6 µm, 2.1 × 150 mm (Phenomenex), Acquity CSH C18 1.7 µm 2.1 × 50 mm, Acquity CSH Phenyl-Hexyl 1.7 µm 2.1 × 50 mm, Acquity CSH Fluoro-Phenyl 1.7 µm 2.1 × 50 mm (Waters Co.) and Kinetex F5 1.7 µm 2.1 × 100 mm (Phenomenex), HPLC-MS and U-HPLC-MS analyses were performed on an Aeris Widepore XB-C8 (Phenomenex) column (HPLC) and Acquity CSH Fluoro-Phenyl (Waters) column (U-HPLC) with aqueous formic acid /acetonitrile in gradient mode. The separation was optimised with 10 min (HPLC) and 5 min (U-HPLC) of gradient. The detection, performed on a QDA detector (Waters), produced extracted ion chromatograms (XICs) based on all adducts identified in the HRMS analysis. HPLC and U-HPLC analyses showed the different mono- and di-ester species and provided relative quantification of all identified constituents. The combined analyses of the HRMS, HPLC-MS and U-HPLC-MS results were used to compare the different PGE batches and quantify the molecular constituents according to their relative abundance, for these complex mixtures. With HPLC and U-HPLC analyses, using 2 different gradient times and 2 different selectivity columns, and comparing the retention factors and log P of the different species, it was possible to link structural identification and relative quantification of all PGEs identified in the samples.
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Cromatografía Liquida/métodos , Ésteres/análisis , Ésteres/química , Glicerol/análisis , Glicerol/química , Espectrometría de Masas/métodos , Polímeros/análisis , Polímeros/química , Acetonitrilos/química , Cromatografía Líquida de Alta Presión , Formiatos/química , Modelos TeóricosRESUMEN
Recent works reported the relevance of cellular exosomes in the evolution of different pathologies. However, most of these studies focused on the ability of exosomes to convey mi-RNA from cell to cell. The level of knowledge concerning the transport of lipid mediators by these nanovesicles is more than fragmented. The role of lipid mediators in the inflammatory signaling is fairly well described, in particular concerning the derivatives of the arachidonic acid (AA), called eicosanoïds or lipid mediators. The aim of the present work was to study the transport of these lipids within the extracellular vesicles of rat bone marrow mesenchymal stem cells (BM-MSC) and the cardiomyoblast cell line H9c2. We were able to characterize, for the first time, complete profiles of oxilipins within these nanovesicles. We studied also the impact on these profiles, of the polyunsaturated fatty acids (PUFAs) know to be precursors of the inflammatory signaling molecules (AA, eicosapentaenoic acid EPA and Docosahexaenoic acid DHA), at physiological concentrations. By growing the progenitor cells under PUFAs supplementation, we provide a comprehensive assessment of the beneficial effect of ω-3 PUFA therapy. Actually, our results tend to support the resolving role of the inflammation that stromal cell-derived extracellular vesicles can have within the cardiac microenvironment.
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Eicosanoides/química , Eicosanoides/metabolismo , Vesículas Extracelulares/química , Vesículas Extracelulares/metabolismo , Células Madre Mesenquimatosas/química , Células Madre Mesenquimatosas/metabolismo , Mioblastos Cardíacos/química , Mioblastos Cardíacos/metabolismo , Animales , Médula Ósea/química , Médula Ósea/efectos de los fármacos , Médula Ósea/metabolismo , Línea Celular , Vesículas Extracelulares/efectos de los fármacos , Humanos , Inflamación/metabolismo , Mediadores de Inflamación/química , Mediadores de Inflamación/metabolismo , Metabolismo de los Lípidos , Células Madre Mesenquimatosas/efectos de los fármacos , Mioblastos Cardíacos/efectos de los fármacos , Oxilipinas/química , Oxilipinas/metabolismo , RatasRESUMEN
Dendrimers are nanosized, arborescent macromolecules synthesized in a stepwise fashion with attractive degrees of functionality and structure definition. This is one of the reasons why they are widely used for biomedical applications. Previously, we have shown that a poly(phosphorhydrazone) (PPH) dendrimer capped with anionic azabisphosphonate groups (so-called ABP dendrimer) has immuno-modulatory and anti-inflammatory properties towards human immune cells in vitro. Thereafter, we have shown that the ABP dendrimer has a promising therapeutic efficacy to treat models of acute and chronic inflammatory disorders in animal models. In these models, the active pharmaceutical ingredient was administered systematically (intravenous and oral administrations), but also loco-regionally in the vitreous tissue. Herein, we assessed the therapeutic efficacy of the ABP dendrimer in the preclinical mouse model of psoriasis induced by imiquimod. The ABP dendrimer was administered in phosphate-buffered saline solution via either systemic injection or topical application. We show that the topical application enabled the control of both the clinical and histopathological scores, and the control of the infiltration of macrophages in the skin of treated mice.
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Antiinflamatorios no Esteroideos/uso terapéutico , Dendrímeros/uso terapéutico , Hidrazonas/uso terapéutico , Polímeros/uso terapéutico , Psoriasis/tratamiento farmacológico , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Compuestos Aza/química , Compuestos Aza/uso terapéutico , Dendrímeros/síntesis química , Dendrímeros/química , Difosfonatos/química , Difosfonatos/uso terapéutico , Modelos Animales de Enfermedad , Hidrazonas/síntesis química , Hidrazonas/química , Imiquimod , Masculino , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Polímeros/síntesis química , Polímeros/química , Psoriasis/inducido químicamente , Psoriasis/patologíaRESUMEN
The synthesis, characterization and in vitro anti-HIV activity of a series of generation one dendrimers having phosphonate groups with pendant alkyl chains are described. The influence of the lateral alkyl chains on the biological properties was correlated to (1)H-(1)H NOESY experiments.
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Dendrímeros/química , VIH-1/efectos de los fármacos , Organofosfonatos/química , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Línea Celular , Dendrímeros/síntesis química , Dendrímeros/farmacología , Humanos , Espectroscopía de Resonancia Magnética , Relación Estructura-ActividadRESUMEN
The increasing need for drug delivery systems that improve specificity and activity and at the same time reduce toxicity to ensure maximum treatment safety has led to the development of a great variety of drug vectors. Carriers based on soft matter have particularly interesting characteristics. Herein we present the current standing of the research in this area, and focus on two main families, namely matrix systems and vesicles. We outline the structure, properties, and potential applications of these vectors, and discuss their main advantages and drawbacks in their synthesis.
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Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Coloides/síntesis química , Coloides/química , Dendrímeros/síntesis química , Dendrímeros/química , Portadores de Fármacos/síntesis química , Portadores de Fármacos/química , Liposomas/síntesis química , Liposomas/química , Micelas , Polímeros/síntesis química , Polímeros/química , Tensoactivos/síntesis química , Tensoactivos/químicaRESUMEN
Dendrimers are nanosized, arborescent polymers of which size and structure are perfectly controlled. This is one reason why they are widely used for biomedical purposes. Previously, we showed that a phosphorus-based dendrimer capped with anionic azabisphosphonate groups (so-called ABP dendrimer) has immuno-modulatory and anti-inflammatory properties towards human immune cells in vitro. Thereafter, we have shown that the ABP dendrimer has a promising therapeutic efficacy to treat models of chronic inflammatory disorders. On the way to clinical translation, the biodistribution and the safety of this drug-candidate has to be thoroughly assessed. In this article, we present preliminary non-clinical data regarding biodistribution, hematological safety, genotoxicity, maximal tolerated doses, and early cardiac safety of the ABP dendrimer. One of the genotoxicity assays reveals a potential mutagen effect of the item at a concentration above 200 µM, i.e., up to 100 times the active dose in vitro on human immune cells. However, as the results obtained for all the other assays show that the ABP dendrimer has promising biodistribution and safety profiles, there is no red flag raised to hamper the regulatory pre-clinical development of the ABP dendrimer.
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Antiinflamatorios/efectos adversos , Antiinflamatorios/farmacocinética , Dendrímeros/efectos adversos , Dendrímeros/farmacocinética , Hidrazonas/química , Seguridad , Animales , Antiinflamatorios/química , Dendrímeros/química , Femenino , Ratones , Ratas , Distribución TisularRESUMEN
Dendrimers are nano-materials with perfectly defined structure and size, and multivalency properties that confer substantial advantages for biomedical applications. Previous work has shown that phosphorus-based polyphosphorhydrazone (PPH) dendrimers capped with azabisphosphonate (ABP) end groups have immuno-modulatory and anti-inflammatory properties leading to efficient therapeutic control of inflammatory diseases in animal models. These properties are mainly prompted through activation of monocytes. Here, we disclose new insights into the molecular mechanisms underlying the anti-inflammatory activation of human monocytes by ABP-capped PPH dendrimers. Following an interdisciplinary approach, we have characterized the physicochemical and biological behavior of the lead ABP dendrimer with model and cell membranes, and compared this experimental set of data to predictive computational modelling studies. The behavior of the ABP dendrimer was compared to the one of an isosteric analog dendrimer capped with twelve azabiscarboxylate (ABC) end groups instead of twelve ABP end groups. The ABC dendrimer displayed no biological activity on human monocytes, therefore it was considered as a negative control. In detail, we show that the ABP dendrimer can bind both non-specifically and specifically to the membrane of human monocytes. The specific binding leads to the internalization of the ABP dendrimer by human monocytes. On the contrary, the ABC dendrimer only interacts non-specifically with human monocytes and is not internalized. These data indicate that the bioactive ABP dendrimer is recognized by specific receptor(s) at the surface of human monocytes.
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Antiinflamatorios/química , Dendrímeros/química , Monocitos/metabolismo , Antiinflamatorios/metabolismo , Rastreo Diferencial de Calorimetría , Células Cultivadas , Dendrímeros/metabolismo , Humanos , Membrana Dobles de Lípidos/química , Membrana Dobles de Lípidos/metabolismo , Microscopía Confocal , Simulación de Dinámica Molecular , Monocitos/citología , Fosfatidilcolinas/química , Fósforo/químicaRESUMEN
The self-association process of catanionic analogues of galactosylceramide and in particular the arrangement of their hydrophobic part seems to play a key role in their cellular toxicity
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Fármacos Anti-VIH/química , Supervivencia Celular/efectos de los fármacos , Galactosilceramidas/síntesis química , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/toxicidad , Dimerización , Galactosilceramidas/farmacología , Galactosilceramidas/toxicidad , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Estructura Molecular , Relación Estructura-ActividadRESUMEN
We report the synthesis and the supramolecular auto-assembly of catanionic phosphorus-containing dendrimers mimicking multisite analogs of galactosylceramide.