Development of siRNA therapy for liver-metastasized tumor by sequential intravenous injection of chondroitin sulfate and siRNA lipoplex

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08251
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Physical pharmacy
• Research Institution: Hoshi University
• Principal Investigator: Hattori Yoshiyuki 星薬科大学, 薬学部, 教授 (90350222)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: siRNA / 正電荷リポソーム / がん治療 / 肝転移がん / コンドロイチン硫酸

Outline of Final Research Achievements

Previously, we found that intravenous injection of chondroitin sulfate (CS), followed by intravenous injection of cationic liposome/siRNA complex (siRNA lipoplex) could deliver siRNA into the liver metastasis. In this study, we examined the effects of the type of cationic lipid in the liposome on siRNA delivery into the liver and liver metastasis. We prepared 17 types of cationic liposomes to evaluate the gene-silencing effect of siRNA in mouse liver following sequential injection of CS plus siRNA lipoplex. In 14 types of cationic liposomes, siRNA was accumulated in the liver when siRNA lipoplexes were injected immediately after CS. However, suppression of targeted mRNA expression in the liver after sequential injection of CS plus siRNA lipoplex were observed in only 3 types of cationic liposomes. Furthermore, sequential injection of PKL1 siRNA or HSF1 siRNA lipoplexes into mice with liver HeLa metastasis could suppress tumor growth.

Free Research Field

薬剤学

Academic Significance and Societal Importance of the Research Achievements

短鎖二本鎖RNA (siRNA)は、配列特異的に遺伝子の発現を抑制できることから、siRNAを利用した肝転移がんなどの難治性疾患に対する創薬開発が期待されているが、標的組織にsiRNAを送達することが困難であった。そこで肝転移がんに対するsiRNAの送達法として、siRNAと正電荷リポソームの複合体（siRNAリポプレックス）投与直前にコンドロイチン硫酸を投与する連続投与法を開発し、連続投与に用いる正電荷リポソーム製剤の正電荷脂質の違いによりsiRNAの効果が異なることを明らかにした。