RESUMEN
Lipophilicity vs hydrophicility physicochemical traits are extremely important variables that are active considerations for optimizing drug delivery systems. The comparative anti-inflammatory delivery potential of dexamethasone (dex) in an encapsulation-based (liposome-lipophilic) and poly (amidoamine) (PAMAM) dendrimer prodrug conjugation-based delivery systems (hydrophilic) was performed in this work. Dendrimer prodrug conjugates were characterized by (1)H NMR. The drug encapsulation efficiency for drug in liposomes was observed to be 14.02% and this was correlated with a dose-dependent tumor necrosis factor (TNF)-α inhibition (39-57% inhibition). The biological evaluation of nanocarriers for drug was demonstrated in a standard, conventionally used in vitro cell-based system for TNF-α inhibition. This served as a comparative tool to demonstrate a quantitatively higher TNF-α inhibition (67-71.48%) produced by the dendrimer-dex drug conjugate. The structure activity relationship (dose-for-dose) was inferred by relatively lesser inhibition of TNF-α by variants of PAMAM G4 (NH2) dendrimer-dex conjugates and was compared with liposomes carrying dex. In vitro results suggest that the prodrug conjugates of PAMAM dendrimer deliver dex to be more efficient in comparison with liposome-based dex in terms of higher TNF-α inhibition. This study has implications in designing efficient prodrug nanocarrier systems for delivering dex.
Asunto(s)
Antiinflamatorios/farmacología , Dendrímeros/química , Dexametasona/farmacología , Sistemas de Liberación de Medicamentos , Antiinflamatorios/administración & dosificación , Antiinflamatorios/química , Células Cultivadas , Dexametasona/administración & dosificación , Dexametasona/química , Relación Dosis-Respuesta a Droga , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Liposomas , Profármacos , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
Macrophage migration inhibitory factor (MIF) is known to contribute to the pathogenesis of inflammatory hyperalgesia and neuropathic pain. Prior studies have shown that Vitamin E treatment is associated with attenuated hyperalgesia and reduced neuropathic pain in rodents. Given these observations, we investigated the possibility that Vitamin E is a MIF inhibitor. Dopachrome tautomerase assays revealed that Vitamin E inhibits the enzymatic activity of purified human recombinant MIF (rhMIF) in a dose-dependent manner (45%, 74%, 92% and 100% inhibition at 3, 10, 30 and 100µM, respectively). Cell-free ELISA based assays showed that Vitamin E binds onto rhMIF thereby blocking its recognition (48% inhibition at 100µM). Circular dichroism studies indicated the Vitamin E has a strong affinity to bind to rhMIF (binding constant 19.52±1.4µM). In silico studies demonstrated that Vitamin E docks well in the active site of MIF with the long aliphatic chain of Vitamin E exhibiting strong van der Waals interactions with MIF. Most importantly, human cell-based assays revealed that Vitamin E significantly inhibits rhMIF-induced production of pro-inflammatory cytokines in a dose-dependent manner (77%, 80%, and 96% inhibition of IL-6 production, respectively, at 10, 30 and 100µM). Taken together, these results demonstrate that Vitamin E inhibits not only the enzymatic activity of MIF but more importantly the biological function of MIF. Our findings suggest that Vitamin E may be attenuating hyperalgesia and reducing neuropathic pain at least in part by inhibiting MIF activity.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Inhibidores Enzimáticos/farmacología , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Factores Inhibidores de la Migración de Macrófagos/antagonistas & inhibidores , Vitamina E/farmacología , Antiinflamatorios no Esteroideos/química , Sitios de Unión , Células Cultivadas , Humanos , Oxidorreductasas Intramoleculares/química , Factores Inhibidores de la Migración de Macrófagos/química , Conformación Proteica , Vitamina E/químicaRESUMEN
Synthesis and anti-inflammatory activity of novel diarylheptanoids [5-hydroxy-1-phenyl-7-(pyridin-3-yl)-heptan-3-ones and 1-phenyl-7-(pyridin-3-yl)hept-4-en-3-ones] as inhibitors of tumor necrosis factor-α (TNF-α) production is described in the present article. The key reactions involve the formation of a ß-hydroxyketone by the reaction of substituted 4-phenyl butan-2-ones with pyridine-3-carboxaldehyde in presence of LDA and the subsequent dehydration of the same to obtain the α,ß-unsaturated ketones. Compounds 4i, 5b, 5d, and 5g significantly inhibit lipopolysaccharide (LPS)-induced TNF-α production from human peripheral blood mononuclear cells in a dose-dependent manner. Of note, the in vitro TNF-α inhibition potential of 5b and 5d is comparable to that of curcumin (a naturally occurring diarylheptanoid). Most importantly, oral administration of 4i, 5b, 5d, and 5g (each at 100 mg/kg) but not curcumin (at 100 mg/kg) significantly inhibits LPS-induced TNF-α production in BALB/c mice. Collectively, our findings indicate that these compounds may have potential therapeutic implications for TNF-α-mediated auto-immune/inflammatory disorders.