Atherosclerosis remains one of the leading causes of morbidity and mortality globally. Recently, reconstituted high-density lipoprotein (rHDL), the synthetic form of endogenous plasma HDL, has been utilized as a therapeutic delivery system for statins, a class of lipid-lowering drugs, to treat atherosclerosis. Accumulating evidence suggests that ganglioside GM1 modification can induce an increased stability, a prolonged circulation time, and a decreased reticuloendothelial system uptake of liposomes. Therefore, we hypothesized that GM1 modification probably has similar effects on statin-loaded rHDL and finally enhances its inhibitory effect on atherogenesis. To test this hypothesis, we prepared GM1-modified lovastatin (LT)-loaded rHDL (LT-GM1-rHDL), as well as LT-loaded rHDL (LT-rHDL) and LT-loaded nanostructured lipid carriers (LT-NLC) for comparison, via thin film dispersion followed by physicochemical characterization, in vitro LT release assay, and in vitro cellular experiments. Subsequently, the pharmacokinetic behavior, tissue distribution, and in vivo antiatherosclerotic effect of all LT-loaded nanocarriers were evaluated by using ApoE^–/– mice fed with a high-fat diet. We found that LT-GM1-rHDL has a more efficient LT sustained-release, a longer circulation time, a lower liver uptake, a better atherosclerotic plaque targeting efficiency, and a stronger inhibitory effect on atherogenesis compared with LT-NLC and LT-rHDL. The data verified our hypothesis that GM1 modification of statin-loaded rHDL can induce an enhanced inhibitory effect on atherogenesis and imply that statin-GM1-rHDL can potentially be recruited as a promising drug delivery system for the treatment of atherosclerosis.

中文翻译：

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通过神经节苷脂GM1修饰增强他汀负载的重组高密度脂蛋白的抗动脉粥样硬化功效。

动脉粥样硬化仍然是全球发病率和死亡率的主要原因之一。最近，重构的高密度脂蛋白（rHDL）（内源性血浆HDL的合成形式）已被用作他汀类药物（一种降脂药物）的治疗性递送系统，用于治疗动脉粥样硬化。越来越多的证据表明，神经节苷脂GM1修饰可以诱导增加的稳定性，延长的循环时间和减少的脂质体对网状内皮系统的吸收。因此，我们假设GM1修饰可能对载有他汀的rHDL具有相似的作用，并最终增强了其对动脉粥样硬化的抑制作用。为了验证这一假设，我们准备了载有GM1的洛伐他汀（LT）的rHDL（LT-GM1-rHDL），以及负载LT的rHDL（LT-rHDL）和负载LT的纳米结构脂质载体（LT-NLC）进行比较，通过薄膜分散，物理化学表征，体外LT释放测定和体外细胞实验进行比较。随后，使用ApoE评估了所有载有LT的纳米载体的药代动力学行为，组织分布和体内抗动脉粥样硬化作用^{– / –}高脂饮食喂养的小鼠。我们发现LT-GM1-rHDL与LT-NLC和LT-rHDL相比，具有更有效的LT持续释放，更长的循环时间，更低的肝脏摄取，更好的动脉粥样硬化斑块靶向效率以及对动脉粥样硬化的更强抑制作用。数据证实了我们的假设，即载有他汀的rHDL的GM1修饰可以诱导对动脉粥样硬化的增强抑制作用，并暗示他汀-GM1-rHDL可能被招募为治疗动脉粥样硬化的有希望的药物递送系统。