Introduction

Atherosclerosis (ATH), the build up of fat in the arteries, is a principal cause of heart attack and stroke. Drug instability and lack of target specificity are major drawbacks of current clinical therapeutics. These undesirable effects can be eliminated by site-specific drug delivery. The endothelial surface over ATH lesions has been shown to overexpress vascular cell adhesion molecule1 (VCAM1), which can be used for targeted therapy.

Methods

Here, we report the synthesis, characterization, and development of anti VCAM1-functionalized liposomes to target cells overexpressing VCAM1 under static and flow conditions. Liposomes were composed of dioleoyl-phosphatidylcholine, sphingomyelin, cholesterol, and distearoyl-phosphatidylethanolamine-polyethylene glycol-cyanur (31.67:31.67:31.67:5 mol%). VCAM1 expression in endothelial cells was induced by lipopolysaccharide (LPS) treatment.

Results

Characterization study revealed that liposomes were negatively charged (− 7.7 ± 2.6 mV) with an average diameter of 201.3 ± 3.3 nm. Liposomes showed no toxicity toward THP-1 derived macrophages and endothelial cells. Liposomes were able to target both fixed and non-fixed endothelial cells, in vitro, with significantly higher localization observed in non-fixed conditions. To mimic biological and physiologically-relevant conditions, liposome targeting was also examined under flow (4 dyn/cm²) with or without erythrocytes (40% v/v hematocrit). Liposomes were able to target LPS-treated endothelial cells under dynamic culture, in the presence or absence of erythrocytes, although targeting efficiency was five-fold lower in flow compared to static conditions.

Conclusions

This liposomal delivery system showed a significant improvement in localization on dysfunctional endothelium after surface functionalization. We conclude that VCAM1-functionalized liposomes can target and potentially deliver therapeutic compounds to ATH regions.

中文翻译：

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在流动条件下使用免疫脂质体靶向功能失调的血管内皮细胞。

介绍

动脉粥样硬化 (ATH) 是动脉中脂肪的堆积，是心脏病发作和中风的主要原因。药物不稳定性和缺乏靶点特异性是目前临床治疗的主要缺点。这些不良影响可以通过特定部位的药物输送来消除。已显示 ATH 病变上的内皮表面过度表达血管细胞粘附分子 1 (VCAM1)，可用于靶向治疗。

方法

在这里，我们报告了抗 VCAM1 功能化脂质体的合成、表征和开发，以靶向在静态和流动条件下过表达 VCAM1 的细胞。脂质体由二油酰-磷脂酰胆碱、鞘磷脂、胆固醇和二硬脂酰-磷脂酰乙醇胺-聚乙二醇-氰尿 (31.67:31.67:31.67:5 mol%) 组成。通过脂多糖（LPS）处理诱导内皮细胞中的VCAM1表达。

结果

表征研究表明，脂质体带负电荷 (− 7.7 ± 2.6 mV)，平均直径为 201.3 ± 3.3 nm。脂质体对 THP-1 衍生的巨噬细胞和内皮细胞没有毒性。脂质体能够在体外靶向固定和非固定内皮细胞，在非固定条件下观察到显着更高的定位。为了模拟生物学和生理学相关条件，还在有或没有红细胞（40% v/v 血细胞比容）的流动（4 dyn/cm ^{2 ）下检查脂质体靶向。}脂质体能够在动态培养下，在存在或不存在红细胞的情况下靶向 LPS 处理的内皮细胞，尽管与静态条件相比，靶向效率在流动中低五倍。

结论

这种脂质体递送系统在表面功能化后对功能失调的内皮的定位有显着改善。我们得出结论，VCAM1 功能化脂质体可以靶向并潜在地将治疗化合物递送至 ATH 区域。