Integrin-Targeted,Short Interfering RNA Nanocomplexes for Neuroblastoma Tumor-Specific Delivery Achieve MYCN Silencing with Improved Survival |
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| Authors: | Aristides D. Tagalakis Vignesh Jayarajan Ruhina Maeshima Kin H. Ho Farhatullah Syed Lin-Ping Wu Ahmad M. Aldossary Mustafa M. Munye Talisa Mistry Olumide Kayode Ogunbiyi Arturo Sala Joseph F. Standing Seyed M. Moghimi Andrew W. Stoker Stephen L. Hart |
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| Affiliation: | 1. Department of Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH UK;2. Department of Inflammation, Infection and Immunity, UCL Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH UK;3. Centre for Pharmaceutical Nanotechnology and Nanotoxicology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen, 2100 Denmark;4. Department of Histopathology, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, WC1N 3JH UK;5. Department of Life Sciences, Brunel University London, Kingston Lane, Middlesex, UB8 3PH UK;6. Department of Developmental Biology and Cancer, UCL Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH UK |
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| 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. |
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| Keywords: | MYCN neuroblastomas siRNA tumor-specific delivery tumors |
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