Hypoxia-injured pulmonary vascular targeting and microenvironment-responsive nanoparticle to treat hypoxic pulmonary hypertension

Hypoxic pulmonary hypertension (HPH) is characterized by sustained pulmonary vasoconstriction and vascular remodeling caused by chronic hypoxia. The vicious cycle between hypoxia-inducible factor-1α (HIF-1α) activation and reactive oxygen species (ROS) burst release plays a central role in disease progression. P-selectin is overexpressed on hypoxia-injured pulmonary vascular endothelial cells and pulmonary smooth muscle cells. Fucoidan (Fuco) is a high-affinity ligand for P-selectin. Based on this, a hypoxia-injured pulmonary vascular targeting drug delivery system siHIF-1α/PSS31@Fuco (HPF) was developed. HPF was able to target for hypoxia-injured pulmonary vascular endothelial cells and pulmonary smooth muscle cells via the P-selectin, then HPF was taken up by those cells via caveolin-1-dependent endocytosis. Subsequently, the ROS-triggered depolymerization of PSS31 ensured efficient cytosolic release of siHIF-1α and SS31 to efficiently inhibit the expression of HIF-1α and the production of ROS, respectively. In HPH rats, HPF alleviated pulmonary vascular remodeling and improved the hemodynamics and right ventricular function by breaking the vicious cycle between HIF-1α activation and ROS production. Therefore, HPF is a promising nanotherapeutic strategy for HPH.