摘要
Pulmonary artery remodeling is a critical pathological feature of pulmonary arterial hypertension(PAH),a fatal lung disease without cure,resulting in poor pulmonary hemodynamics and compliance.The remodeling could be aggravated by various factors,particularly by the hyperproliferation of pulmonary artery smooth muscle cells(PASMCs)and perivascular inflammation.Meanwhile,the hyperproliferation of PASMCs can be driven by the overexpression of miR138.In this study,we developed anti-inflammatory baicalein-assisted anti-miR138 gene therapy against PAH.The system was fabricated by anchoring the nucleic acid onto the nanocrystals through electrostatic interaction,followed by glucuronic acid(GA)coating for targeting the glucose transport-1(GLUT-1)receptor.The results demonstrated that the system had a 201-nm in diameter with a rod shape and allowed a 12-fold increase in pulmonary artery(PA)targeting versus free drug administration.The preparation injection reduced the PA thickness by 20%via effectively promoting PASMC apoptosis,likely by strengthening the pathway of Bcl-2 associated X protein/B-cell lymphoma-2/caspase 3(Bax/Bcl-2/Cas-3).The in vivo efficacy in the monocrotaline(MCT)-PAH model demonstrated significant improvement in the pulmonary hemodynamics,e.g.,a 50%decrease in mean pulmonary artery pressure(mPAP),61%increase in pulmonary artery acceleration time(PAAT),and 82%increase in cardiac output(CO).In conclusion,targeted codelivery of the inflammation inhibitor and anti-miR138 to PAs is promising to combat PAH.Rod-shaped nanomedicines represent an effective PA-targeting strategy.
基金
supported by the National Natural Science Foundation of China(Nos.81872823,82073782,and 82241002)
the Shanghai Science and Technology Committee(No.19430741500).
