Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle

Area of Science:

• Biotechnology
• Nanomedicine
• Molecular Biology

Background:

• Small interfering RNA (siRNA) therapeutics offer precise gene inhibition but face challenges in delivery, stability, and immune response.
• Targeted delivery systems are needed to overcome siRNA's limitations for effective therapeutic applications.

Purpose of the Study:

• To develop ligand-targeted, sterically stabilized nanoparticles for enhanced siRNA delivery and gene inhibition.
• To investigate the targeting efficiency and therapeutic efficacy of RGD-peptide-functionalized nanoparticles carrying VEGF R2-targeting siRNA in tumor models.

Main Methods:

• Construction of self-assembling nanoparticles using PEGylated polyethyleneimine (PEI) with RGD peptide ligands for targeting integrin-rich tumor neovasculature.
• Delivery of siRNA targeting vascular endothelial growth factor receptor-2 (VEGF R2) to inhibit tumor angiogenesis.
• Evaluation of cellular uptake, siRNA sequence specificity, and therapeutic effects in tumor-bearing mice following intravenous administration.

Main Results:

• PEGylated PEI nanoparticles demonstrated siRNA sequence-specific delivery and activity, dependent on the RGD peptide ligand.
• Intravenous administration resulted in selective tumor uptake and siRNA-mediated inhibition of VEGF R2 protein expression within the tumor.
• Significant inhibition of tumor angiogenesis and tumor growth rate was observed in treated mice.

Conclusions:

• The developed nanoparticle system achieves dual targeting: tissue-selective delivery via RGD ligands and gene-selective inhibition via siRNA.
• This approach holds promise for developing advanced targeted therapeutics with improved tissue and gene selectivity.
• Potential to enhance targeted therapies, particularly for targets with suboptimal therapeutic profiles.