由於台灣過去的B型肝炎與C型肝炎病毒感染率高，加上飲酒、肥胖及環境毒素等因素，使肝病成為許多人健康的隱形殺手。肝臟本身缺乏痛覺神經，因此早期的肝病通常不易察覺，患者往往在疾病進展至嚴重階段時才發現。隨著病情惡化，可能導致肝硬化，最終發展為肝癌。而不管是肝纖維化、肝硬化都會造成肝臟周邊血管很大的壓力。常見的肝門靜脈高壓症狀包括持續疲倦、皮膚和眼白變黃（黃疸），以及腹部腫脹（腹水）、脾腫大，嚴重可以能會造成肝性腦病變、甚至昏迷。尤其，肝硬化和肝纖維化均是不可逆的，若沒有及早治療，後續也不好控制病情。因此本研究想透過我們奈米粒子，製備出能包覆藥物且在身體內能穩定相容的標靶載體，來嘗試降低肝硬化造成的門脈高壓，為肝臟門脈高壓這個疾病的治療帶來一點貢獻。我們的目標是開發出具標靶性包覆藥Asialoglycoprotein receptor 1 (ASGPR1)受體，並負載促血管舒張藥物利奧西呱之(Riociguat)之聚乳酸聚甘醇酸高分子奈米粒子。預期此粒子能提升藥物抵達肝臟的效率，，達到精準治療的效果。預期作用在小鼠肝臟細胞FL83B或是人類肝臟星狀細胞LX2細胞，使cGMP上升，促使血管平滑肌放鬆並降低血壓。目前此具標靶性ASGPR1受體負載利奧西呱(Riociguat)奈米粒子已製備完成，測量粒子粒徑大小約254.78 ± 13.53nm、電位-17.54± 1.89mV、包覆率為82.6 ± 6.8，載藥率為0.324±0.104，37度24小時作用下藥物釋放量率為30.27%。細胞實驗結果顯示具標靶性ASGPR1受體負載利奧西呱之(Riociguat)奈米粒子會使cGMP上升。 本研究主要為研製促血管舒張之標靶奈米藥物載體於調控肝硬化中門脈壓力標靶奈米藥物載體，目前在功能性之試管實驗中，具標靶性ASGPR1受體負載利奧西呱(Riociguat)奈米粒子證實可以讓正常小鼠的肝細胞(FL83B)和人類肝臟星狀細胞(LX2)產生cGMP，進而使血管的門脈壓力下降。;In Taiwan， liver disease is often referred to as the "national disease，" with liver cancer being one of the top three cancer-related causes of death. High prevalence rates of hepatitis B and C virus infections， along with factors such as alcohol consumption， obesity， and environmental toxins， have made liver disease a silent threat to many people′s health. Since the liver lacks pain nerves， early-stage liver diseases often go unnoticed， with patients typically diagnosed only at advanced stages. As the condition worsens， it may lead to cirrhosis and eventually liver cancer. Whether it is liver fibrosis or liver cirrhosis， it will cause great pressure on the blood vessels around the liver. Common symptoms of portal hypertension include persistent fatigue， yellowing of the skin and whites of the eyes (jaundice)， abdominal swelling (ascites)， and an enlarged spleen. Severe cases may result in hepatic encephalopathy or even coma. In particular， both cirrhosis and liver fibrosis are irreversible. If not treated early， it will be difficult to control the disease . This study aims to develop nanoparticle-based targeted drug carriers that can encapsulate drugs and achieve biocompatibility within the body， thereby attempting to reduce portal hypertension caused by cirrhosis and contribute to the treatment of this disease.Nanoparticles made of poly(lactic-co-glycolic acid) (PLGA) were developed to target the asialoglycoprotein receptor 1 (ASGPR1) and encapsulate the vasodilatory drug Riociguat. These nanoparticles are designed to enhance the drug′s delivery efficiency to the liver， achieving precise therapeutic effects. The nanoparticles were tested on mouse liver cells (FL83B) and human hepatic stellate cells (LX2) to evaluate their ability to increase cGMP levels， thereby promoting vascular smooth muscle relaxation and reducing blood pressure.Targeted ASGPR1 receptor-loaded Riociguat nanoparticles were successfully synthesized， with particle size measuring approximately 254.78 ± 13.53 nm， zeta potential of -23.63 ± 1.8 mV，and an encapsulation efficiency of 82.6 ± 6.8%. Drug release at 37°C over 24 hours was 30.27%. Cell experiments showed that the ASGPR1-targeted Riociguat nanoparticles increased cGMP levels. This study primarily focused on developing targeted vasodilatory nanoparticle drug carriers to regulate portal hypertension in cirrhosis. Functional in vitro experiments demonstrated that the ASGPR1-targeted Riociguat nanoparticles increased cGMP levels in normal mouse liver cells (FL83B) and human hepatic stellate cells (LX2)， effectively reducing portal pressure.
