RESUMO
The purpose of this study was to prepare and characterize antioxidant nanospheres composed of multiple alpha-lipoic acid-containing compounds (mALAs). It was found that the nanospheres were remarkably stable under physiologic conditions, maintained the antioxidant property of alpha-lipoic acid, and could be destabilized oxidatively and enzymatically. The preparations were simple and highly reproducible providing a new strategy for the development of nanometer-sized antioxidant biomaterials. The nanospheres may find applications as antioxidant therapeutics and oxidation-responsive antioxidant nanocontainers in drug delivery for pathological conditions characterized by oxidative stress including cancer and neurodegenerative diseases.
Assuntos
Antioxidantes/química , Nanosferas/química , Nanotecnologia/métodos , Ácido Tióctico/química , Antioxidantes/síntese química , Materiais Biocompatíveis/química , Química/métodos , Desenho de Fármacos , Modelos Químicos , Doenças Neurodegenerativas/metabolismo , Oxigênio/química , Temperatura , Fatores de TempoRESUMO
A novel group of alpha-lipoic acid-containing hydrophobic prodrugs of non-steroidal anti-inflammatory drugs (NSAIDs) was synthesized and transformed into nanometer-sized prodrugs (nanoprodrugs). Three NSAIDs, indomethacin, ibuprofen and naproxen were linked to alpha-lipoic acid via tetraethylene glycol through hydrolytically degradable ester bonds. The three bifunctional derivatives were dissolved in organic solvents and capable of forming stable nanoprodrugs upon addition of the organic solutions into aqueous phase through the spontaneous emulsification mechanism. Antioxidant property and stimuli-responsiveness of the nanoprodrugs were demonstrated by hypochlorous acid (HOCl) scavenging followed by oxidative destabilization of the nanoprodrugs. The effect of varying NSAIDs on the in vitro hydrolytic prodrug activation catalyzed by porcine liver esterase was investigated by monitoring the rates of NSAIDs hydrolysis from the nanoprodrugs. The remarkable feature of these nanoprodrugs is that despite the highly hydrophobic nature of the derivatives NSAIDs were readily hydrolyzed enzymatically from the nanoprodrugs. Furthermore, the rate of hydrolysis was higher when the nanoprodrugs were oxidized and destabilized upon HOCl scavenging suggesting an enhanced activation of the nanoprodrugs in the oxidative environment.
