一氧化氮 (Nitric oxide，NO) 為一已知的生物信號分子，在生物體中擁有許多功能，可以藉由生物體內之一氧化氮合成酶 (Nitric oxide synthases) 進行合成，根據先前的研究，NO同時因其自由基的特性而能造成細胞相當的毒性，並與血管新生 (angiogenesis) 息息相關，進而具有作為抗癌分子之能力。由於NO為氣態分子，需藉由其他化合物的輔助，方能進行傳遞，市面上既有之一氧化氮供體 (NO donor) 分子均有半衰期短的問題，難以應用於臨床治療。本篇研究中，利用以鐵離子為核心之NO donor，即雙亞硝基鐵錯合物 (dinitrosyl iron complexes，簡稱為DNIC)，其分子擁有較高之穩定性及較緩慢NO釋放速率。為了能在生物體內更加有效率的傳遞NO，我們利用聚乳酸聚乙醇酸 (PLGA) 將此化合物包覆形成奈米粒子，再將其外圍包覆多種脂質 (lipid)，增加體內循環之穩定性。
蕾莎瓦 (Sorafenib) 為目前臨床肝癌唯一用藥，但本身狹窄的治療窗口和較差的藥物動力學限制其在臨床上的應用以及治療功效，本研究進一步以NO為輔劑結合sorafenib，針對肝癌進行複合性治療，為了更加有效率並專一的傳遞這兩種化合物，我們利用PLGA同時包覆兩化合物，並包裹多種lipid，且修飾SP94肝癌標靶胜肽增加靶向性，在體外測試 (in vitro) 中，觀察到NO可敏化 (sensitize) 肝癌細胞對Sorafenib的反應，進而達到加乘的毒殺效果，並利用西方點墨法，觀察細胞內Akt蛋白質磷酸化的變化，以及下游mTor相關蛋白之改變，研究藥物影響之生化機制，冀望因此解決雷沙瓦所遇到之治療困境，進而增加治療效率。

Sorafenib is a multikinase inhibitor approved for several cancers, including hepatocellular carcinoma (HCC). Sorafenib is also used as anti-agiogenesis therapy in many study. However, sorafenib still faces several problems such as poor pharmacokinetics and resistance mechamism. Due to limited efficacy of Sorafenib, we introduced an adjuvant to overcome the ressistant mechanisms and thus synergistically elevate the therapeutic effect.
Nitric oxide (NO) is a well-known endogenous signaling molecule. NO could regulate many biological functionl, including agiogenesis, proliferation, apopoptosis and immune responses. According to the previous study, NO is also a highly reactive molecule which has potential to serve as an anti-cancer drug. In this study, we used dinitrosyl iron complexes (SEt) as a NO donor to deliver NO into the cancer cells. We successfully inhibited the liver cancer cell growth by treatment of combined SEt and sorafenib in vitro. The protein expression of pAkt was also down-regulated by the combication treatment. Futhermore, we developed a tumor-targeted PLGA nanoparticles to co-deliver SEt and sorafneib into hepatocellular carcinoma (HCC). We showed the nanoscale combination therapy could efficiently inhibit the tumor growth in vivo.

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