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.
Highlights
Neuroblastoma is the most common solid tumor of childhood, accounting for 8–10% of all childhood cancers and 15% of cancerrelated deaths in children.[1]
We propose that a tumor-specific, MYCN-targeted short interfering RNA (siRNA) treatment for disseminated neuroblastoma may be achieved by systemic administration of the siRNA encapsulated in a suitable nanoparticle formulation
We have previously described a nanocomplex formulation that enabled tumor-specific plasmid DNA transfection, with very little transfection of liver or other organs[13] and demonstrated pDNA-expressed cytokine adjuvant immunotherapy;[13b] but siRNA therapeutics offer alternative targets and strategies in cancer therapies, such as ectopically expressed oncogenes
Summary
Neuroblastoma is the most common solid tumor of childhood, accounting for 8–10% of all childhood cancers and 15% of cancerrelated deaths in children.[1]. Standing Department of Inflammation Infection and Immunity UCL Great Ormond Street Institute of Child Health University College London 30 Guilford Street, London WC1N 1EH, UK Dr L.-P. Neuroblastoma tumors are highly vascularized with a leaky endothelium that may enable extravasation of nanoparticles into the tumor from the circulation,[11] or by endothelial transcytosis.[12] We have previously described a nanocomplex formulation that enabled tumor-specific plasmid DNA (pDNA) transfection, with very little transfection of liver or other organs[13] and demonstrated pDNA-expressed cytokine adjuvant immunotherapy;[13b] but siRNA therapeutics offer alternative targets and strategies in cancer therapies, such as ectopically expressed oncogenes. W. Stoker Department of Developmental Biology and Cancer UCL Great Ormond Street Institute of Child Health University College London 30 Guilford Street, London WC1N 1EH, UK their in vivo biodistribution, therapeutic effects, and toxicity. RTNs were assessed for systemic delivery of siMYCN formulations to neuroblastoma tumor xenografts and we describe a pharmacokinetic/ pharmacodynamic model of the effects of treatment on tumor growth
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