Cholesteryl Oligoarginine Delivering Vascular Endothelial Growth Factor siRNA Effectively Inhibits Tumor Growth in Colon Adenocarcinoma

Abstract

Vascular endothelial growth factor (VEGF) is a multifunctional angiogenic growth factor that is a primary stimulant of the development and maintenance of a vascular network in the vascularization of solid tumors. It has been reported that a blockade of VEGF-mediated angiogenesis is a powerful method for tumor regression. RNA interference represents a naturally occurring biological strategy for inhibition of gene expression. In mammalian systems, however, the in vivo application of small interfering RNA (siRNA) is severely limited by the instability and poor bioavailability of unmodified siRNA molecules. In this study, we tested the hypothesis that a hydrophobically modified protein transduction domain, cholesteryl oligo-d-arginine (Chol-R9), may stabilize and enhance tumor regression efficacy of the VEGF-targeting siRNA. The noncovalent complexation of a synthetic siRNA with Chol-R9 efficiently delivered siRNA into cells in vitro. Moreover, in a mouse model bearing a subcutaneous tumor, the local administration of complexed VEGF-targeting siRNA, but not of scrambled siRNA, led to the regression of the tumor. Hence, we propose a novel and simple system for the local in vivo application of siRNA through Chol-R9 for cancer therapy.

Transvascular delivery of small interfering RNA to the central nervous system

“…A nona(Larginine) peptide was reported to be highly efficient in facilitating the cellular uptake of nucleic acids, and replacement of L-arginine with D-arginine (to form 9dR) enhanced the uptake even further 17 . Moreover, a cholesterol-conjugated oligo(D-arginine) has been used to deliver siRNA to a transplanted tumour in mice 18 . Thus, we tested whether RVG fused to 9dR could bind and deliver siRNAs to neuronal cells.…”

Evaluation of Cell-Penetrating Peptide/Adenovirus Particles for Transduction of CAR-Negative Cells

“…Nonetheless polyarginine has facilitated efficient intercellular delivery of siRNA (Kim, Christensen et al 2006), plasmid (Kish, Tsume et al 2007) and different proteins (Futaki, Suzuki et al 2001;Wright, Rothbard et al 2003). …”

Polymers in Small-Interfering RNA Delivery

“…Kim group conjugated the cholesterol moiety and cationic cell-penetrating peptides oligo-D-arginine to develop hydrophobically modified protein transduction domain, cholesteryl oligo-D-arginine (Chol-R9) (Kim et al, 2006b). The efficient regression of a subcutaneous tumor in a mouse model upon local administration of complexed VEGF-targeting siRNA could be attributed to the enhanced cellular uptake and stability of Chol-R9/siRNA complexes as induced by the cationic cell-penetrating peptides and the cholesterol moiety, respectively.…”