Chitosan nanoparticles encapsulated with BEZ235 prevent acute rejection in mouse heart transplantation.
Int Immunopharmacol
; 124(Pt A): 110922, 2023 Nov.
Article
em En
| MEDLINE
| ID: mdl-37699303
ABSTRACT
Acute rejection may manifest following heart transplantation, despite the implementation of relatively well-established immunosuppression protocols. The significance of the mTOR signaling pathway in rejection is widely acknowledged. BEZ235, a second-generation mTOR inhibitor with dual inhibitory effects on PI3K and mTOR, holds promise for clinical applications. This study developed a nanodelivery system, BEZ235@NP, to facilitate the intracellular delivery of BEZ235, which enhances efficacy and reduces adverse effects by improving the poor solubility of BEZ235. In the complete MHCII-mismatched model, BEZ235@NP significantly prolonged cardiac allografts survival compared to free BEZ235, which was attributed to more effective suppression of effector T cell activation and promotion of greater expansion of Tregs. These nanoparticles demonstrated excellent biosafety and exhibited no short-term biotoxicity upon investigation. To elucidate the mechanism, primary T cells were isolated from the spleen and it was observed that BEZ235@NP treatment resulted in the arrest of these cells in the G0/G1 phase. As indicated by Western blot analysis, BEZ235@NP substantially reduced mTOR phosphorylation. This, in turn, suppressed downstream pathways and ultimately exerted an anti-proliferative and anti-activating effect on cells. Furthermore, it was observed that inhibition of the mTOR pathway stimulated T-cell autophagy. In conclusion, the strategy of intracellular delivery of BEZ235 presents promising applications for the treatment of acute rejection.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quinolinas
/
Transplante de Coração
/
Quitosana
/
Nanopartículas
Tipo de estudo:
Guideline
Limite:
Animals
Idioma:
En
Revista:
Int Immunopharmacol
Assunto da revista:
ALERGIA E IMUNOLOGIA
/
FARMACOLOGIA
Ano de publicação:
2023
Tipo de documento:
Article