Development of folate-modified siRNA lipoplexes for tumor-targeting by intravenous injection

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07142
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Hoshi University
• Principal Investigator: Hattori Yoshiyuki 星薬科大学, 薬学部, 教授 (90350222)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: siRNA / 葉酸 / 葉酸受容体 / がん / リポソーム / リポプレックス

Outline of Final Research Achievements

In this study, we prepared small interfering RNA (siRNA)/cationic liposome complexes (lipoplexes) modified with folate (FA)-polyethylene glycol-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) to facilitate their uptake into tumor cells via folate receptor (FR), and with PEG1600-cholesterol (PEG1600-Chol) or PEG2000-chondroitin sulfate conjugate (PEG2000-CS), to enhance their systemic stability. Among the FA-PEG-modified siRNA lipoplexes, 0.5 mol% FA-PEG5000-DSPE-modified lipoplexes with 2.5 mol% PEG2000-CS or PEG1600-Chol (LP-0.5F5/2.5P2-CS and LP-0.5F5/2.5P1.6-CL, respectively) exhibited selective growth inhibition of human nasopharyngeal carcinoma KB cells through transduction with polo-like kinase 1 (PLK1) siRNA. Furthermore, their lipoplexes markedly decreased the accumulation of siRNA in murine lungs after systemic injection. Finally, systemic injection of LP-0.5F5/2.5P2-CS lipoplexes increased accumulation of siRNA in KB tumor xenografts and induced anti-tumor effect.

Free Research Field

薬剤学

Academic Significance and Societal Importance of the Research Achievements

siRNAは、配列特異的に遺伝子の発現を抑制できることから、がんに対する創薬開発が期待されているが、静脈内投与でsiRNAをがんに送達することが困難であった。本研究課題で開発した葉酸修飾リポプレックスは、静脈内投与でがん組織にsiRNAを送達できることから、今後、siRNAを用いた新しいがんの治療のためのリポソーム製剤の開発につながるものと期待される。