Photo-Activated Verteporfin-Loaded Polymeric Nanocarrier-Thermogel Hybrid System for Preventing Venous Neointimal Hyperplasia and Stenosis in Murine Arteriovenous Fistulas

Background: The patency of the Arteriovenous Fistula (AVF) is a prerequisite for the smooth operation of hemodialysis patients, while the dysfunction of vascular access due to endothelial hyperplasia and stenosis is an important factor in the increase of mortality in patients, and the transformation of VSMCs and their migration is an important factor in the endothelialization of AVFs. The Hippo-YAP signaling pathway regulates the proliferation and migration of VSMCs, which are involved in the process of vascular injury and remodeling. Verteporfin (VER) has great potential as a YAP inhibitor to ameliorate AVF intimal hyperplasia, but how to deliver VER to the stenosis site effectively and release VER in a controlled manner is a challenge. Methods: 1.Expression of YAP in the neointima of arteriovenous fistula and its role in the proliferation of vascular smooth muscle cells; 2.Construction and characterization of nanoparticle/hydrogel system loaded with verteporfin; 3.The effect of blocking YAP signal by TKhbPPE/VER@PPP system on VSMCs proliferation; 4.Exploration of TKhbPPE/VER@PPP system in AVF of CKD mice. Results: 1.The high expression of YAP in the neointima of arteriovenous fistula was associated with the migration and proliferation of vascular smooth muscle cells. 2.TKhbPPE/VER@PPP nanoparticle/hydrogel system loaded with verteporfin was successfully constructed. 3.The effect of blocking YAP signal by TKhbPPE/VER@PPP system on VSMCs proliferation. 4.Application of drug-loaded nanoparticle/hydrogel TKhbPPE/VER@PPP system in mouse blood vessels. Conclusion: 1. There was high expression of YAP protein in the neointima of the arteriovenous fistula of mice, and YAP was involved in the proliferation and migration of vascular smooth muscle cells. 2. The drug-loading nanoparticles TKhbPPE/VER were successfully prepared and characterized, and the drug-loading nanoparticle/hydrogel system TKhbPPE/VER@PPP was constructed. 3. The system can promote the self-degradation of drug-loaded nanoparticles through red light irradiation, release VER, inhibit cell proliferation and migration by acting on VSMCs, and downregulate the expression of YAP protein in cells. 4.The gTKhbPPE/VER is capable of perivascular retention and photoregulated release of VER to ameliorate AVF endothelial stenosis. Funding: Government Support – Non-U.S.