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[Development of siRNA Delivery Targeting the Tumor Microenvironment with a New Functional Device]
1Graduate School of Pharmaceutical Sciences, Hokkaido University.
Abstract:
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.
Insights
Researchers developed a novel lipid nanoparticle (LNP) system for targeted delivery of small interfering RNA (siRNA) to control the tumor microenvironment and enhance cancer therapy. This RGD-LNP system effectively targets tumor vasculature, leading to improved drug delivery and therapeutic outcomes.
Area of Science:
- Oncology
- Nanotechnology
- Molecular Biology
Background:
- The tumor microenvironment significantly influences cancer progression, drug resistance, and metastasis.
- Targeting the tumor microenvironment presents a promising strategy for novel cancer therapeutics.
- Lipid nanoparticles (LNPs) offer a versatile platform for in vivo delivery of therapeutic agents.
Purpose of the Study:
- To develop a lipid nanoparticle (LNP)-based delivery system for in vivo small interfering RNA (siRNA) targeting the tumor microenvironment.
- To engineer LNPs with a targeting ligand for enhanced accumulation and efficacy within tumor vasculature.
- To evaluate the therapeutic potential of the developed LNP system in a preclinical cancer model.
Main Methods:
- Development of pH-sensitive cationic LNPs using YSK05 for efficient cellular uptake and membrane fusion.
- Modification of LNPs with cyclic RGD peptide (RGD-LNP) to target integrin αVβ3 on tumor endothelial cells (TECs).
- Assessment of gene silencing efficacy, impact on tumor vasculature (VEGFR2 inhibition), and therapeutic effects of doxorubicin-loaded liposomes in a renal cell carcinoma model.
Main Results:
- YSK05-containing LNPs demonstrated significant gene silencing in a human renal cell carcinoma model.
- RGD-LNPs effectively suppressed gene expression in TECs and inhibited VEGFR2, delaying tumor growth.
- RGD-LNP treatment promoted tumor vasculature maturation and significantly enhanced the therapeutic efficacy of doxorubicin.
Conclusions:
- A novel RGD-LNP delivery system was successfully developed for targeting and regulating the tumor microenvironment.
- This LNP system demonstrates potential for improving cancer therapy by enhancing drug delivery and efficacy.
- Targeting tumor vasculature with RGD-LNPs represents a promising strategy for developing new cancer therapeutics.
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