纳米脂质体促进柚皮素对弹性蛋白酶诱导的小鼠腹主动脉瘤的抑制作用

Enhanced protective effects of naringenin on elastase-induced mouse abdominal aortic aneurysm through nanoliposome delivery

腹主动脉瘤(AAA)是一种严重的炎症性血管疾病,其特征是基质金属蛋白酶(MMPs)升高、细胞外基质(ECM)降解和血管炎症反应。近年来的研究表明,柚皮素(NGN)作为一种生物活性黄酮,有抑制AAA的作用,但是较低的水溶性及口服吸收特性限制了NGN抑制AAA的有效性。本研究开发了一种NGN纳米脂质体处方(NGN-NL),以增强NGN对弹性蛋白酶诱导的小鼠AAA的抑制作用。首先,我们优化了NGN-NL的处方,发现磷脂和NGN的比例为9:1时为最佳处方。此外,我们观察到,与脂质体处方中的药物及辅料的物理混合物相比,NGN制备成脂质体后具有更强的抑制LPS诱导的巨噬细胞M1极化的作用。在同等剂量下,NGN-NL可比游离NGN展现出更强的抑制巨噬细胞M1极化的作用。此外,脂质体载体本身也呈现一定程度的抑制M1极化的特性,可协同增强NGN抑制巨噬细胞M1极化的效果。体内研究表明,以含有25mg/kg NGN剂量的NGN-NL对小鼠隔日进行腹腔注射,与游离NGN在使用两倍剂量(50mg/kg)下产生的AAA抑制效率相近。具体表现为:改善腹主动脉直径扩张、保持主动脉结构完整性、减缓弹性蛋白降解、减少巨噬细胞浸润和下调腹主动脉MMP-2和MCP-1的表达。但与NGN-NL相比,同等剂量(25mg/kg)的游离NGN并不能有效抑制AAA的发生和发展。综上所述,NGN-NL显著提高了NGN对小鼠AAA的抑制作用,展现出在其未来在AAA临床治疗中的应用潜力。

Abdominal aortic aneurysm(AAA)is a severe inflammatory vascular illness characterized by the increased matrix metalloproteinases(MMPs),degradation of extracellular matrix(ECM),and inflammatory responses.Recent evidence indicates that naringenin(NGN),a bioactive flavanone,can inhibit AAA.However,the poor water solubility and oral absorption of NGN limit its efficacy.In this study,we developed a nanoliposome formulation of NGN(NGN-NL)to enhance the preventive effect of NGN on AAA induced by pancreatic elastase in mice.We investigated the NGN-NL prescription and found that a 9:1 ratio of phospholipids to NGN was the optimized formulation.Additionally,we observed that NGN,when prepared into liposomes,demonstrated a stronger ability to counteract LPS-induced macrophage M1 polarization compared to the physical mixture of NGN with the prescription materials of liposomes.Moreover,at an equal dose,NGN-NL exhibited a better inhibitory effect on macrophage M1 polarization than NGN alone.Furthermore,the liposome carrier itself displayed some extent of anti-M1 polarization properties,synergistically enhancing NGN’s ability to inhibit macrophage M1 polarization.In vivo experiments revealed that intraperitoneal administration of NGN-NL at an NGN dose of 25 mg/kg on alternate days demonstrated a similar effect to a double dose of NGN crude drug(50 mg/kg)in preventing AAA.This was evidenced by an overall improvement in abdominal aorta diameter dilation,preservation of aortic structural integrity,mitigation of elastin degradation,reduction in macrophage infiltration,and downregulation of MMP-2 and MCP-1 in the abdominal aortas.However,an equal dose of NGN crude drug(25 mg/kg)could not efficiently inhibit the occurrence and development of AAA compared with NGN-NL.In conclusion,NGN-NL significantly improved NGN’s efficacy in inhibiting mouse AAA,demonstrating its potential application in clinical AAA treatment in the future.