Dept. 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.
Dept. of Critical Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
PLoS One. 2018 May 15;13(5):e0196976. doi: 10.1371/journal.pone.0196976. eCollection 2018.
Microvascular endothelial cells play a pivotal role in the pathogenesis of sepsis-induced inflammatory responses and multiple organ failure. Therefore, they represent an important target for pharmacological intervention in the treatment of sepsis. Glucocorticosteroids were widely used in the treatment of sepsis but vast evidence to support their systemic use is lacking. The limited effects of glucocorticoids in the treatment of sepsis may be explained by differential effects of drug initiated NF-κB inhibition in different cell types and insufficient drug delivery in target cells. The current study aimed therefore to investigate the effects of an endothelial targeted delivery of dexamethasone in a mouse model of endotoxemia induced by two consecutive i.p. injections of lipopolysaccharide (LPS). To achieve endothelial cell specific delivery of dexamethasone, we modified SAINT-O-Somes, a new generation of liposomes that contain the cationic amphiphile SAINT-C18 (1-methyl-4-(cis-9-dioleyl) methyl-pyridinium chloride, with antibodies against vascular cell adhesion molecule-1 (VCAM-1). In LPS challenged mice, the systemic administration of free dexamethasone had negligible effects on the microvascular inflammatory endothelial responses. Dexamethasone-loaded anti-VCAM-1 SAINT-O-Somes specifically localized at VCAM-1 expressing endothelial cells in the microvasculature of inflamed organs. This was associated with a marginal attenuation of the expression of a few pro-inflammatory genes in kidney and liver, while no effects in the lung were observed. This study reveals that, although local accumulation of the targeted drug was achieved, endothelial targeted dexamethasone containing anti-VCAM-1 SAINT-O-Somes exhibited marginal effects on inflammatory endothelial cell activation in a model of endotoxemia. Studies with more potent drugs encapsulated into anti-VCAM-1 SAINT-O-Somes will in the future reveal whether this delivery system can be further developed for efficacious endothelial directed delivery of drugs in the treatment of sepsis.
微血管内皮细胞在脓毒症诱导的炎症反应和多器官衰竭的发病机制中起着关键作用。因此，它们是治疗脓毒症的药物干预的重要靶点。糖皮质激素在脓毒症的治疗中被广泛应用，但缺乏支持其全身应用的大量证据。糖皮质激素在脓毒症治疗中的有限作用可能是由于药物诱导的 NF-κB 抑制在不同细胞类型中的差异作用以及在靶细胞中药物传递不足所致。因此，本研究旨在探讨在两次腹腔内注射脂多糖（LPS）诱导的内毒素血症的小鼠模型中，将地塞米松内皮靶向递送至内皮细胞的效果。为了实现地塞米松的内皮细胞特异性递送，我们修饰了 SAINT-O-Somes，这是一种包含阳离子两亲物 SAINT-C18（1-甲基-4-（顺式-9-二油烯基）甲基-吡啶氯化物）的新一代脂质体，具有针对血管细胞粘附分子-1（VCAM-1）的抗体。在 LPS 挑战的小鼠中，系统给予游离地塞米松对内毒素血症小鼠的微血管炎症内皮反应几乎没有影响。载有地塞米松的抗-VCAM-1 SAINT-O-Somes 特异性定位于炎症器官微血管中表达 VCAM-1 的内皮细胞。这与肾脏和肝脏中少数促炎基因的表达略有减弱相关，而在肺部则没有观察到效果。本研究表明，尽管实现了靶向药物的局部积累，但内皮靶向含有抗-VCAM-1 的 SAINT-O-Somes 的地塞米松对内毒素血症模型中炎症内皮细胞激活的作用仅为边际。未来，用更有效的药物包封到抗-VCAM-1 SAINT-O-Somes 中的研究将揭示该递药系统是否可以进一步开发用于脓毒症的有效内皮定向药物递送。
