Intratumor RNA interference of cell cycle genes slows down tumor progression

Abstract

Small interfering RNAs (siRNAs) are emerging as promising therapeutic tools. However, the widespread clinical application of such molecules as modulators of gene expression is still dependent on several aspects that limit their bioavailability. One of the most promising strategies to overcome the barriers faced by gene silencing molecules involves the use of lipid-based nanoparticles (LNPs) and viral vectors, such as adenoviruses (Ads). The primary obstacle for translating gene silencing technology from an effective research tool into a feasible therapeutic strategy remains its efficient delivery to the targeted cell type in vivo. In this study, we tested the capability of LNPs and Ad to transduce and treat locally tumors in vivo. Efficient knockdown of a surrogate reporter (luciferase) and therapeutic target genes such as the kinesin spindle protein (KIF11) and polo-like kinase 1 were observed. Most importantly, this activity led to a cell cycle block as a consequence and slowed down tumor progression in tumor-bearing animals. Our data indicate that it is possible to achieve tumor transduction with si/short hairpin RNAs and further improve the delivery strategy that likely in the future will lead to the ideal non-viral particle for targeted cancer gene silencing.

Kinesin-5: Cross-bridging mechanism to targeted clinical therapy

“…As a result, many proteomic screens have been done to try to identify novel protein partners and intricate signaling pathways in which Kinesin-5 is involved (Table 2). Kinesin-5 knock-down by siRNA or chemical inhibition has afforded researchers insights into cellular phenotypes that can occur (Goshima and Vale, 2003), its role in diseases (Formstecher et al, 2006; Liu et al, 2008a; Dharmapuri et al, 2011; Groth-Pedersen et al, 2012; Marra et al, 2013; Martens-de Kemp et al, 2013; Tabernero et al, 2013), and proteins that are either up-regulated or down-regulated as a result (Tsui et al, 2009). While screens that identify protein networks that are affected by Kinesin-5 have been informative in describing potential regulatory networks for this motor, the challenge of elucidating the specific players and biochemical interactions linking these networks remains a goal of future research.…”

Technologies for Investigating the Physiological Barriers to Efficient Lipid Nanoparticle–siRNA Delivery

“…1): (1) a cationic lipid that contains a cationic head group, a lipophilic tail group, and a connecting linker; (2) a PEGylated lipid; (3) cholesterol; and (4) a helper lipid. One such lipid nanoparticle, LNP201, has been extensively investigated Pei et al 2010;Tao et al 2010;Bartz et al 2011;Dharmapuri et al 2011;Shi et al 2011;Tadin-Strapps et al 2011;Wei et al 2011). Fig.…”

Systemic siRNA Delivery via Peptide-Tagged Polymeric Nanoparticles, Targeting PLK1 Gene in a Mouse Xenograft Model of Colorectal Cancer

“…In our study, we used a small peptide sequence to make the nanoparticle target specific because of their small size and ease of being used in organic solvents for conjugations. Another recent study uses liponanoparticles to deliver siRNA via intratumoral injections [48]. Lipid-based nanoparticles have been widely used in various therapeutic studies; however, their nonspecificity is a limitation when intended to deliver drugs/genes systemically.…”