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Integrin-Targeted, Short Interfering RNA Nanocomplexes for Neuroblastoma Tumor-Specific Delivery Achieve MYCN
Aristides D Tagalakis1,2, Vignesh Jayarajan1, Ruhina Maeshima1
1Department of Genetics and Genomic Medicine UCL Great Ormond Street Institute of Child Health University College London 30 Guilford Street London WC1N 1EH UK.
Abstract:
The authors aim to develop siRNA therapeutics for cancer that can be administered systemically to target tumors and retard their growth. The efficacy of systemic delivery of siRNA to tumors with nanoparticles based on lipids or polymers is often compromised by their rapid clearance from the circulation by the liver. Here, multifunctional cationic and anionic siRNA nanoparticle formulations are described, termed receptor-targeted nanocomplexes (RTNs), that comprise peptides for siRNA packaging into nanoparticles and receptor-mediated cell uptake, together with lipids that confer nanoparticles with stealth properties to enhance stability in the circulation, and fusogenic properties to enhance endosomal release within the cell. Intravenous administration of RTNs in mice leads to predominant accumulation in xenograft tumors, with very little detected in the liver, lung, or spleen. Although non-targeted RTNs also enter the tumor, cell uptake appears to be RGD peptide-dependent indicating integrin-mediated uptake. RTNs with siRNA against MYCN (a member of the Myc family of transcription factors) in mice with MYCN-amplified neuroblastoma tumors show significant retardation of xenograft tumor growth and enhanced survival. This study shows that RTN formulations can achieve specific tumor-targeting, with minimal clearance by the liver and so enable delivery of tumor-targeted siRNA therapeutics.
Insights
New receptor-targeted nanocomplexes (RTNs) effectively deliver siRNA cancer therapeutics systemically to tumors. This approach enhances stability, targets tumors specifically, and retards growth with minimal liver clearance.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapeutics
Background:
- Systemic delivery of small interfering RNA (siRNA) for cancer treatment is challenging due to rapid clearance by the liver.
- Existing nanoparticle formulations often struggle with stability and targeted delivery to tumor sites.
Purpose of the Study:
- To develop novel multifunctional nanoparticles for systemic siRNA delivery to tumors.
- To overcome limitations of current nanoparticle-based siRNA delivery systems.
Main Methods:
- Development of receptor-targeted nanocomplexes (RTNs) incorporating peptides for targeting and lipids for stability and cell uptake.
- Intravenous administration of RTNs in mice bearing xenograft tumors.
- Evaluation of RTN biodistribution, tumor accumulation, and therapeutic efficacy using siRNA against MYCN in neuroblastoma models.
Main Results:
- RTNs demonstrated predominant accumulation in xenograft tumors with minimal uptake in the liver, lung, or spleen.
- Tumor cell uptake was shown to be RGD peptide-dependent, indicating integrin-mediated internalization.
- RTN delivery of MYCN siRNA significantly retarded neuroblastoma xenograft tumor growth and improved survival in mice.
Conclusions:
- RTN formulations enable specific tumor targeting and effective systemic delivery of siRNA therapeutics.
- The multifunctional design of RTNs enhances circulation stability and endosomal release, improving therapeutic outcomes.
- This technology holds promise for developing advanced, targeted cancer therapies with reduced systemic toxicity.
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