Development of self-assembly prodrug: Application to the cancer therapy by reset of immune-cycle

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H00657
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 90:Biomedical engineering and related fields
• Research Institution: Tohoku University (2022); Chiba University (2020-2021)
• Principal Investigator: Akita Hidetaka 東北大学, 薬学研究科, 教授 (80344472)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 脂質様材料 / 癌免役 / プロドラッグ

Outline of Final Research Achievements

Liposomes have been identified as a technique for controlling the dynamics of poorly water-soluble drugs. A high degree of hydrophobicity is required to retain drugs in the lipid membrane in the bloodstream. Coincidentally, we have developed lipid-like materials (ssPalm) that respond to the intracellular environment, penetrate the biological membrane barrier, and are destabilized for nucleic acid drug discovery. In this study, we developed a system that integrates prodrugs compatible with lipid nanoparticles formed from this material, and (1) spontaneously forms nano particles from drugs, (2) controls in vivo and intracellular trafficking and (3) release drugs by self-degradation in responds to the intracellular environment. We demonstrated the therapeutic effect on cancer when administering these drugs, and also verified their potential as nucleic acid delivery systems.

Free Research Field

薬剤学

Academic Significance and Societal Importance of the Research Achievements

本研究の基盤となるssPalmは、『電荷的に中性なナノ粒子の形成能』と『エンドソーム脱出促進能（第三級アミン）』、『自己崩壊能（ジスルフィド結合）』を一分子内に集約した脂質様材料である。本材料から形成されるナノ粒子を低分子に応用することで、負に制御された癌免疫サイクルを矯正することで癌を治療するという、抗癌剤を用いない治療原理を提唱するものである。
エステラーゼ等に依存する従来のプロドラッグにおいては、その分解効率が化学構造により大きく影響をうけるために、適用できる薬物に制限があった。今回開発するナノ粒子はどの細胞においても普遍的な還元環境に応答して、薬物放出を可能とする点で高い汎用性がある。