Abstract:
Elevated brain angiotensin II activity plays a key role in the development of neurogenic hypertension. While blood pressure (BP) control in neurogenic hypertension has been successfully demonstrated by regulating central angiotensin II activity, current techniques involving cerebrovascular injections of potential therapeutic agents are not suitable for clinical translation. To address this gap, we present the synthesis of dual-functionalized liposomes functionalized with targeting ligand and cell-penetrating peptide. Functionalized liposomes were synthesized using the thin film hydration technique and loaded with plasmid DNA encoding short hairpin RNA targeted toward angiotensin II receptors (PEAS), via the post-insertion method. The synthesized liposomes had a cationic surface charge, an average size of 150 nm, and effectively entrapped more than 89% of loaded PEAS. These liposomes loaded with PEAS demonstrated biocompatibility and efficient delivery to brain-derived cell lines, resulting in a remarkable reduction of more than 70% in receptor expression within 7 days. To assess the therapeutic potential, spontaneously hypertensive rats were administered intravenous injections of functionalized liposomes loaded with PEAS, and the changes in mean arterial pressure were monitored for 45 days. Remarkably, this treatment led to a significant (p < 0.001) decrease in BP of more than 30 mm Hg compared with saline-treated rats.
摘要:
脑血管紧张素II活性升高在神经源性高血压的发展中起关键作用。虽然神经源性高血压的血压(BP)控制已通过调节中枢血管紧张素II活性得到成功证明,目前涉及脑血管注射潜在治疗药物的技术不适合临床翻译。为了解决这个差距,我们介绍了用靶向配体和细胞穿透肽官能化的双官能化脂质体的合成。使用薄膜水合技术合成了功能化的脂质体,并装载了编码靶向血管紧张素II受体(PEAS)的短发夹RNA的质粒DNA,通过后插入方法。合成的脂质体具有阳离子表面电荷,平均尺寸为150nm,并有效捕获了89%以上的负载PEAS。这些负载有PEAS的脂质体表现出生物相容性和有效递送到脑源性细胞系,导致受体表达在7天内显著减少超过70%。为了评估治疗潜力,自发性高血压大鼠静脉注射载有PEAS的功能化脂质体,监测平均动脉压的变化45天。值得注意的是,与盐水处理的大鼠相比,这种处理导致BP显著降低(p<0.001)超过30mmHg.