Anti-VCAM-1 and Anti-E-selectin SAINT-O-Somes for Selective Delivery of siRNA into Inflammation-Activated Primary Endothelial Cells

Activated endothelial cells play a pivotal role in the pathology of inflammatory diseases and present a rational target for therapeutic intervention by endothelial specific delivery of short interfering RNAs (siRNA). This study demonstrates the potential of the recently developed new generation of liposomes based on cationic amphiphile SAINT C18 (1-methyl-4-(cis-9-dioleyl)methyl-pyridinium-chloride) for functional and selective delivery of siRNA into inflamed primary endothelial cells. To create specificity for inflamed endothelial cells, these so-called SAINT-O-Somes were harnessed with antibodies against vascular cell adhesion protein 1 (VCAM-1) or respectively E-selectin and tested in TNF-alpha activated primary endothelial cells from venous and aortic vascular beds. Both targeted SAINT-O-Sornes carrying siRNA against the endothelial gene VE-cadherin specifically downregulated its target rnRNA and protein without exerting cellular toxicity. SAINT-O-Somes formulated with siRNA formed small particles (106 nm) with a 71% siRNA encapsulation efficiency. SAINT-O-Somes were stable in the presence of serum at 37 C, protected siRNA from degradation by serum RNases, and after iv injection displayed pharmacokinetic comparable to conventional long circulating liposornes. These anti-VCAM-1 and anti-E-selectin SAINT-O-Somes are thus a novel drug delivery system that can achieve specific and effective delivery of siRNA into inflamed primary endothelial cells and have physicochemical features that comply with in vivo application demands.