RESUMO
Rhein (RH) has many bioactivities, but the application was limited of its poor solubility. The present study aimed to establish an efficient method for the synthesis of rhein amide derivatives (RAD) to increase the solubility and anti-tumour activity. RAD exhibited stronger anti-tumour activity than RH in MTT assay. The solubility and oil/water partition coefficient results indicated that rhein-phenylalanine and rhein-isoleucine have better absorption effect, which was consolidated in pharmacokinetic study. Then, rhein-phenylalanine and rhein-isoleucine were prepared into nanocrystals via the precipitation high-pressure homogenisation method. Additionally, the nanocrystals both displayed much higher dissolution profiles than the bulk drugs. Pharmacokinetics study indicated that the AUC0-∞ and Cmax of nanocrystals increased markedly (p < 0.01). However, the concentration of RH-Phe-NC was far less than RH-Ile-NC in plasma. Consequently, RH-Ile-NC was validated to be an applicable way to improve the bioavailability of RH, which owns a promising future in clinical application.
Assuntos
Antraquinonas/sangue , Antraquinonas/química , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/química , Nanopartículas/química , Amidas/sangue , Amidas/síntese química , Amidas/química , Animais , Antraquinonas/síntese química , Disponibilidade Biológica , Inibidores Enzimáticos/síntese química , Células Hep G2 , Humanos , Isoleucina/análogos & derivados , Isoleucina/sangue , Isoleucina/síntese química , Masculino , Fenilalanina/análogos & derivados , Fenilalanina/sangue , Fenilalanina/síntese química , Ratos Sprague-Dawley , SolubilidadeRESUMO
The objective of this study was to develop and evaluate the morphology, biodistribution and antitumor activity of bexarotene nanocrystals delivery system. The morphology was investigated using scanning electron microscopy (SEM), transmission electron microscopy (TEM), atomic force microscope and bexarotene nanocrystals exhibited the advantages of making the efficacy more steady and durable compared with control group in lung with less cardiac accumulation as shown by biodistribution studies in vivo. In addition, MTT assay, flow cytometry analysis, observation of morphological changes and apoptotic body demonstrated that bexarotene nanocrystals could significantly enhance the in vitro cytotoxicity and induced G1 cycle arrest and apoptosis against A549 cells. Also, bexarotene nanocrystals had significant antitumor activity in mice bearing A549 cell line. This finding was correlated with both in vitro and in vivo. Thereby, the overall results suggest that the bexarotene nanocrystals represent a potential source of medicine, which made bexarotene nanocrystals a promising candidate for the treatment of lung cancer.