Department of Pathology & Medical Biology, Medical Biology Section, Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, University Medical Center Groningen, University of Groningen , Groningen, The Netherlands.
Mol Pharm. 2013 Aug 5;10(8):3033-44. doi: 10.1021/mp4001124. Epub 2013 Jul 12.
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-α activated primary endothelial cells from venous and aortic vascular beds. Both targeted SAINT-O-Somes carrying siRNA against the endothelial gene VE-cadherin specifically downregulated its target mRNA 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 i.v. injection displayed pharmacokinetic comparable to conventional long circulating liposomes. 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.
活化的内皮细胞在炎症性疾病的病理中起着关键作用，并且是内皮细胞特异性递送短干扰 RNA（siRNA）进行治疗干预的合理靶点。本研究证明了基于阳离子两亲物 SAINT-C18（1-甲基-4-（顺-9-二油烯基）甲基-吡啶氯）的新一代脂质体在将 siRNA 递送到炎症性原代内皮细胞中的功能和选择性方面的潜力。为了使内皮细胞具有特异性，这些所谓的 SAINT-O-Somes 与针对血管细胞粘附蛋白 1（VCAM-1）或 E-选择蛋白的抗体结合，并在 TNF-α激活的来自静脉和主动脉血管床的原代内皮细胞中进行了测试。携带针对内皮基因 VE-钙粘蛋白的 siRNA 的靶向 SAINT-O-Somes 特异性地下调了其靶 mRNA 和蛋白质，而没有表现出细胞毒性。用 siRNA 配制的 SAINT-O-Somes 形成了小颗粒（106nm），siRNA 的包封效率为 71%。SAINT-O-Somes 在 37°C 下存在血清时稳定，保护 siRNA 免受血清 RNases 的降解，并且在静脉内注射后显示出与常规长循环脂质体相当的药代动力学特征。因此，这些抗 VCAM-1 和抗 E-选择蛋白的 SAINT-O-Somes 是一种新型的药物递送系统，可将 siRNA 特异性有效地递送到炎症性原代内皮细胞中，并且具有符合体内应用需求的理化特性。
