Development of Liver-Targeting Vasodilator-Encapsulated Nano- Vehicles for Liver Cirrhosis Therapy

[1] Specific Aim: We aim to design and fabricate two kinds of drug nanocarriers: (1)Asialoglycoprotein receptor (ASGPR)-targeted Riociguat-encapsulatedPoly(D,L-lactide-co-glycolide) (PLGA) nanoparticles (ARPNPs); (2) alpha-smooth muscleactin (α-SMA)-targeted Riociguat-loaded PLGA nanoparticles (SRPNPs), and explore theircapabilities for modulation of portal hypertension in mouse model.[2] Background: Portal hypertension is a dangerous complication of liver cirrhosis thatarises from an increase in hepatic vascular resistance and hyperdynamic circulation. Thedevelopment of vascular contractility abnormalities plays a significant role in this process.Within the liver, vascular dysfunction leads to abnormal vasoconstriction, impeding bloodoutflow from the portal system. Conversely, there is systemic and splanchnic vasodilation,which increases the inflow of the portal system and exacerbates portal hypertension.Consequently, systemic vasodilators are not effective in alleviating portal hypertension.Riociguat, a soluble guanylate cyclase stimulator, has been successful in treating pulmonaryhypertension through its vasodilatory effects. Based on the clinical efforts mentioned above,in this study, we aim to develop two kinds of nanoagents which can precisely delivervasodilatory agents to the cirrhotic liver and reduce the portal hypertension consequently.We anticipate that both agents can provide rapid and effective reduction of portalhypertension without systemic side-effects and that is helpful for the therapy performedafterward.[3]Advantages: Both developed nanoagents are anticipated to be able to provide thefollowing characteristics/functions:(1) The nanoagents are handled by intravenous injection that is easy to operate.(2) The encapsulated vasodilatory agents are protected by the nanocarriers and hence thestability as well as the bioavailability of the agents in vivo can be dramatically enhanced.(3) The targeting specificity of the nanoagents may provide precise drug delivery to thecirrhotic liver and confer the therapeutic effectiveness only at the pathogenic spotwithout systemic side-effects.(4) The nanoagents may directly reduce the portal hypertension in the cirrhotic liver andthus enhance the therapeutic efficacy performed afterward.[4] Research Schedule: The following works will be performed in the next one year:(1) Stage 1: Design, fabrication, and optimization of the ARPNPs and SRPNPs.(2) Stage 2: Characterization and property identification of the ARPNPs and SRPNPs.(3) Stage 3: Functional verification of the two nanoagents through in vitro models.