Cocrystal pleomorphism-inspired drug nanoassembly for pulmonary-endothelium targeting and pulmonary hypertension treatment  

作　　者：Makhloufi Zoulikha Jiahui Zou Pei Yang Jun Wu Wei Wu Kun Hao Wei He 

机构地区：[1]School of Pharmacy,China Pharmaceutical University,Nanjing 2111198,China [2]School of Science,China Pharmaceutical University,Nanjing 2111198,China [3]Department of Geriatric Cardiology,Jiangsu Provincial Key Laboratory of Geriatrics,The First Affiliated Hospital of Nanjing Medical University,Nanjing 210029,China [4]Key Laboratory of Smart Drug Delivery of MOE,School of Pharmacy,Fudan University,Shanghai 201203,China [5]Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics,China Pharmaceutical University,Nanjing 2111198,China

出　　处：《Acta Pharmaceutica Sinica B》2025年第1期557-570,共14页药学学报(英文版)

基　　金：supported by the National Natural Science Foundation of China(Nos.82073782 and 82241002);the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(21KJA320003);the Scientific Research Project of Jiangsu Commission of Health(LKZ2023001,China);the Clinical Competence Improvement Project of Jiangsu Province Hospital(JSPH-MB-2022-13,China).

摘　　要：Endothelial dysfunction is one of the early triggers of vascular remodeling during pulmonary hypertension(PH)with complex predisposing mechanisms,mainly via an unbalanced generation of vasoactive factors,increased expression of growth factors,prothrombotic elements,and inflammatory markers.Conventional treatment regimens are restricted to a single therapeutic pathway,which usually leads to limited clinical outcomes.Combination therapies targeting multiple cells and several signaling pathways are increasingly adopted in PH treatment.Herein,inspired by the cocrystal pleomorphism theory,we prepared rod-shaped nanococrystals of the endothelin-1(ET-1)receptor antagonist(bosentan,BST)and the anti-inflammatory drug(andrographolide,AG)for targeting the pulmonary endothelium and alleviating PH.The 525 nm-sized co-delivery system displayed a rod-like morphology,preferentially accumulated in the pulmonary endothelium and alleviated pulmonary artery(PA)remodeling.A three-week treatment with the preparation significantly alleviated the monocrotaline(MCT)-or Sugen 5416/hypoxia(SuHx)-induced PH by reducing the pulmonary artery pressure,increasing the survival rate,improving the hemodynamics,and inhibiting vascular remodeling.Mechanistically,the nanococrystals collaboratively repaired endothelial dysfunction by suppressing the pathways of ET-1/NF-kB/ICAM-1/TNF-a/IL-6.In conclusion,the cocrystal-based strategy offers a promising approach for constructing co-delivery systems.The developed rosurvival rate,improving the hemodynamics,and inhibiting vascular remodeling.Mechanistically,the nanococrystals collaboratively repaired endothelial dysfunction by suppressing the pathways of ET-1/NF-kB/ICAM-1/TNF-a/IL-6.In conclusion,the cocrystal-based strategy offers a promising approach for constructing co-delivery systems.The developed rod-shaped nanococrystals effectively target the pulmonary endothelium and relieve experimental PH.

关 键 词：Pulmonary hypertension Inflammation Endothelial dysfunction ENDOTHELIN COCRYSTALS Nanorods BOSENTAN ANDROGRAPHOLIDE 

分 类 号：R54[医药卫生—心血管疾病]