In Vivo Delivery of RNAi by Reducible Interfering Nanoparticles (iNOPs)

Abstract

RNA interference (RNAi) has considerable potential as a therapeutic strategy, but the development of efficient in vivo RNA delivery methods remains challenging. To this end, we designed and synthesized chemically modified interfering nanoparticles (iNOPs) composed of functionalized poly-l-lysine dendrimers modified with reducible spacers to facilitate release of small interfering RNAs (siRNAs) in vivo. We show that the novel siRNA–iNOP complexes mediate efficient gene-specific RNAi in cultured cells and in mice, where they display enhanced tissue-targeting capabilities. At a clinically feasible dose of 1 mg kg–1, apolipoprotein B (apoB) siRNA–iNOP complexes achieved ∼40–45% reduction of liver apoB mRNA and plasma apoB protein levels within 48 h of administration to mice, without apparent toxicity. Collectively, these findings demonstrate that siRNA delivery by the modified reducible iNOPs can provide a clinically significant and potentially tissue-specific new approach for RNAi therapy.

Therapeutic targeting of polo-like kinase 1 using RNA-interfering nanoparticles (iNOPs) for the treatment of non-small cell lung cancer

“…Finally, the surface of iNOP-7 can be easily functionalized to contain a number of different moieties to improve drug release or target specific cell types. Recently, we developed a next-generation iNOP nanoparticle which contains a reducible (disulfide bond) spacer on its surface to improve the release kinetics of siRNA once in contact with a cellular microenvironment [ 33 ]. Future studies designed to modify the surface of iNOP-7 to contain tumor cell-targeting moieties in an effort to improve the amount of siRNA specifically delivered to lung tumor cells are being undertaken in our laboratory.…”

Gene regulation by non-coding RNAs

“…Hepatic tumor-bearing mice treated with such SNALPs showed significant improvement in survival (Judge et al, 2009). Other strategies employed synthesis of cholesterol-modified lipids (Ghosh et al, 2010), interfering nanoparticles (iNOPs) (Baigude and Rana, 2012, Su et al, 2011, Baigude and Rana, 2009, Baigude et al, 2007, Baigude et al, 2013), and functionalized nanotubes (McCarroll et al, 2010) as new siRNA delivery agents. iNOPs can be quickly assembled by mixing siRNA with functionalized poly-L-lysine dendrimers without the need for complex liposomal formulation procedures or harsh covalent reaction to label RNA with lipids or other delivery agents.…”

“…iNOPs can be quickly assembled by mixing siRNA with functionalized poly-L-lysine dendrimers without the need for complex liposomal formulation procedures or harsh covalent reaction to label RNA with lipids or other delivery agents. At a clinically feasible dose of 1 mg kg −1 , apolipoprotein B (apoB) siRNA–iNOP complexes achieved ~40–45% reduction of liver apoB mRNA and plasma apoB protein levels within 48 h of administration to mice, without apparent toxicity (Baigude et al, 2013). …”

Efficient delivery of small interfering RNA into cancer cells using dodecylated dendrimers

“…25 The incorporation of hydrophobic chains such as lipids into most polymers generates amphiphilic materials. [36][37][38][39][40] Functionalization of PAMAM dendrimers with hydrophobic chains such as dodecyl chains can significantly improve the DNA delivery efficacy of unmodified dendrimers in mesenchymal stem cells. The lipid-polymer conjugates such as PAMAM dendron-bearing lipids can assemble into micelles and show high affinity to cell membranes due to the fusogenic lipids.…”