Hyaluronic acid-decorated reconstituted high density lipoprotein targeting atherosclerotic lesions
Hyaluronic acid-decorated reconstituted high density lipoprotein targeting atherosclerotic lesions
复制标题
透明质酸修饰的重组高密度脂蛋白靶向动脉粥样硬化病变
DOI：
10.1016/j.biomaterials.2014.05.081
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发表时间：
2014-09-01
期刊：
影响因子：
14
通讯作者：
Liu, Jianping
中科院分区：
文献类型：
--
作者：
Liu, Lisha;He, Hongliang;Liu, Jianping
我们当前研究的主要目的是利用透明质酸（HA）修饰含有洛伐他汀（LT）的重构高密度脂蛋白（rHDL），称为HA-LT-rHDL。研究涂层HA是否能有效逃避清道夫受体B类I型（SR-BI）介导的肝脏对LT-rHDL的不良摄取，进而通过HA对动脉粥样硬化病变等炎症部位上调的CD44的强亲和力，在动脉粥样硬化病变中大量积累LT-rHDL，从而增强动脉粥样硬化保护作用。体外表征表明，HA修饰成功地修饰了LT-rHDL的表面，这可以通过HA修饰后的颗粒大小增加、表面负电荷增强和体外药物释放率降低来间接证实。离体成像和组织分布结果证明，与不含HA的rHDL相比，HA修饰使rHDL具有更好的动脉粥样硬化病变靶向效率和更低的肝脏积聚。此外，模型动物的动脉粥样硬化保护效果表明，HA-LT-rHDL比其他LT制剂具有最佳的有效效果，其表现为动脉粥样硬化病变大小最小，平均内膜-中膜厚度（MIT）最小，巨噬细胞浸润最小，基质金属蛋白酶-9 （MMP-9）表达最低。以上结果表明，新设计的HA-LT-rHDL可以减少肝脏的非靶向摄取，并将大量药物递送到动脉粥样硬化病变处，从而有效抑制动脉粥样硬化的进展。(C) 2014 Elsevier Ltd.版权所有。
The primary aim of our current study was to utilize hyaluronic acid (HA) to decorate reconstituted high density lipoprotein (rHDL) loaded with lovastatin (LT), termed as HA-LT-rHDL, in order to investigate whether coating HA could efficiently evade from the undesired uptake of LT-rHDL in liver mediated by scavenger receptor class B type I (SR-BI) and then greatly accumulate LT-rHDL in atherosclerotic lesions via strong HA affinity to CD44 up-regulated at inflammatory sites such as atherosclerotic lesions, thus exerting enhanced atheroprotective efficacy. In vitro characterizations indicated the successful HA decoration onto the surface of LT-rHDL, which could be indirectly verified by the increased particle size, enhanced negative surface charge and reduced in vitro drug release rate after HA decoration. Compared with rHDL without HA, HA decoration endowed rHDL with better atherosclerotic lesions targeting efficiency and lower liver accumulation, proved by results from ex vivo imaging and tissue distribution. Furthermore, atheroprotective efficacy in model animal showed that HA-LT-rHDL had the best potent efficacy than other LT preparations, which was demonstrated by the fewest atherosclerotic lesions sizes, the most minimum mean intima-media thickness (MIT), the lowest macrophage infiltration and expression of matrix metalloproteinase-9 (MMP-9), respectively. Above results demonstrated that the newly designed HA-LT-rHDL could decrease the non-targeted uptake by liver and deliver a large amount of drug into atherosclerotic lesions so as to efficiently suppress the advancement of atherosclerosis. (C) 2014 Elsevier Ltd. All rights reserved.