Alleviating experimental pulmonary hypertension via co-delivering FoxO1 stimulus and apoptosis activator to hyperproliferating pulmonary arteries.
10.1016/j.apsb.2022.12.002
- Author:
Bingbing LI
1
;
Chao TENG
2
;
Huiling YU
1
;
Xiaohong JIANG
2
;
Xuyang XING
2
;
Qi JIANG
2
;
Chenshi LIN
2
;
Zongmin ZHAO
3
;
Ruifeng ZHANG
4
;
Wei HE
2
Author Information
1. Department of Anesthesiology, Affiliated Drum Tower of Nanjing University, Nanjing 210008, China.
2. School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
3. Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA.
4. Department of Respiratory Medicine, Zhongda Hospital of Southeast University, Nanjing 210009, China.
- Publication Type:Journal Article
- Keywords:
Caspase 3;
Co-delivery;
Fork-head box transcriptional factor O1;
Pulmonary artery smooth muscle cells;
Pulmonary hypertension
- From:
Acta Pharmaceutica Sinica B
2023;13(6):2369-2382
- CountryChina
- Language:English
-
Abstract:
Pulmonary hypertension (PH) is an insidious pulmonary vasculopathy with high mortality and morbidity and its underlying pathogenesis is still poorly delineated. The hyperproliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs) contributes to pulmonary vascular remodeling in pulmonary hypertension, which is closely linked to the downregulation of fork-head box transcriptional factor O1 (FoxO1) and apoptotic protein caspase 3 (Cas-3). Here, PA-targeted co-delivery of a FoxO1 stimulus (paclitaxel, PTX) and Cas-3 was exploited to alleviate monocrotaline-induced pulmonary hypertension. The co-delivery system is prepared by loading the active protein on paclitaxel-crystal nanoparticles, followed by a glucuronic acid coating to target the glucose transporter-1 on the PASMCs. The co-loaded system (170 nm) circulates in the blood over time, accumulates in the lung, effectively targets the PAs, and profoundly regresses the remodeling of pulmonary arteries and improves hemodynamics, leading to a decrease in pulmonary arterial pressure and Fulton's index. Our mechanistic studies suggest that the targeted co-delivery system alleviates experimental pulmonary hypertension primarily via the regression of PASMC proliferation by inhibiting cell cycle progression and promoting apoptosis. Taken together, this targeted co-delivery approach offers a promising avenue to target PAs and cure the intractable vasculopathy in pulmonary hypertension.
