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- 櫻井 遊
- 北海道大学大学院薬学研究院
書誌事項
- タイトル別名
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- Development of siRNA Delivery Targeting the Tumor Microenvironment with a New Functional Device
- Review for award 機能性素子を用いたがん微小環境を標的とするsiRNA送達技術の開発
- Review for award キノウセイ ソシ オ モチイタ ガン ビショウ カンキョウ オ ヒョウテキ ト スル siRNA ソウタツ ギジュツ ノ カイハツ
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<p>The tumor microenvironment plays a key role in cancer progression, drug resistance, metastasis, etc. To establish a new therapeutic strategy based on control of the tumor microenvironment, I have developed a lipid nanoparticle (LNP)-based in vivo small interfering RNA (siRNA) delivery system equipped with a targeting ligand. First, I established an LNP that induces membrane fusion in response to acidification after internalization by cells using the original pH-sensitive cationic lipid YSK05. A modification of polyethylene glycol to YSK05-containing LNPs allowed significant gene silencing in the human renal cell carcinoma model. Then, I attempted to establish a tumor vasculature-targeting LNP because the vasculature is responsible for the tumor microenvironment. Cyclic RGD peptide is known to be a ligand against integrin αVβ3, which is highly expressed on tumor endothelial cells (TECs). Optimized cyclic RGD peptide-modified LNP (RGD-LNP) suppressed gene expression in TECs to 50%. The inhibition of vascular endothelial cell growth factor receptor 2 (VEGFR2), which is a dominant factor in angiogenesis, by the injection of RGD-LNP significantly delayed tumor growth. Finally, I examined the effect of RGD-LNP on the tumor microenvironment. The suppression of VEGFR2 increased pericyte coverage and endothelial junctions, which indicate maturation of the vasculature. In RGD-LNP-treated mice, systemically administered nanoparticles encapsulating doxorubicin were distributed in a larger area than in untreated mice. Moreover, the therapeutic effect of doxorubicin-loaded liposomes was significantly enhanced by RGD-LNP. In conclusion, I succeeded in developing a new therapy based on regulation of the tumor microenvironment.</p>
収録刊行物
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- 薬学雑誌
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薬学雑誌 139 (11), 1357-1363, 2019-11-01
公益社団法人 日本薬学会
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詳細情報 詳細情報について
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- CRID
- 1390845702310409728
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- NII論文ID
- 130007740064
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- NII書誌ID
- AN00284903
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- ISSN
- 13475231
- 00316903
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- NDL書誌ID
- 030080359
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- PubMed
- 31685731
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- 本文言語コード
- ja
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- データソース種別
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- JaLC
- NDL
- Crossref
- PubMed
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- 使用不可