Integrin‐Targeted, Short Interfering RNA Nanocomplexes for Neuroblastoma Tumor‐Specific Delivery Achieve MYCN Silencing with Improved Survival

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.

Unprotonatable and ROS‐Sensitive Nanocarrier for NIR Spatially Activated siRNA Therapy with Synergistic Drug Effect

“…several strategies including targeting ligand modification, [5][6][7][8] size engineering, [9,10] tunable surface charge, [11][12][13] and sheddable polyethylene glycol (PEG) strategies, [14][15][16] which substantially enhance siRNA therapy effect. However, non-specific gene inhibition in normal tissues remains a limitation for siRNA therapy, which is due to the uncontrolled distribution of siRNA in vivo.…”

“…Small interfering RNA (siRNA) molecules have been extensively explored to treat many diseases including cancer and liver diseases due to their highly efficient target gene silencing. [ 1–4 ] siRNA delivery efficiency has been greatly improved through several strategies including targeting ligand modification, [ 5–8 ] size engineering, [ 9,10 ] tunable surface charge, [ 11–13 ] and sheddable polyethylene glycol (PEG) strategies, [ 14–16 ] which substantially enhance siRNA therapy effect. However, non‐specific gene inhibition in normal tissues remains a limitation for siRNA therapy, which is due to the uncontrolled distribution of siRNA in vivo.…”

New Applications of Lipid and Polymer-Based Nanoparticles for Nucleic Acids Delivery

“…The newly developed structures demonstrated improved tissue penetration, enhanced dispersal, and more widespread cellular transfection than cationic systems. Similar anionic targeting hybrid nanocarriers have also shown promising results for siRNA delivery to neuroblastoma tumors with reduced systemic and cellular toxicity [129].…”

A systematic review of circulating-free MYCN amplification status as a noninvasive and prominent prognostic and recurrence monitoring indicator for neuroblastoma

“…There are several mechanisms by whichMYCN is overexpressed in tumors, ranging from induction ofMYCN transcriptional activation, increased MYCN protein stability due to dysregulated MYCN phosphorylation, and reduced proteasomal degradation to MYCN gene amplification [62][63][64][65][66][67]. Additionally, the aberrant expression of MYCN induces a unique cancer stem cell-like phenotype by enabling infinite self-renewal, apoptotic resistance, and metabolic reprogramming characterized by increased glycolysis with active oxidative phosphorylation [67][68][69][70][71].MYCN is one of the earliest genetic markers discovered in neuroblastoma, and MYCN amplification status is one of the strongest predictors of poor prognosis [72][73][74][75][76][77]. In high-risk neuroblastoma patients, MYCN amplification, if present, will always be present at diagnosis.…”