Biodegradable synthetic high-density lipoprotein nanoparticles for atherosclerosis
Biodegradable synthetic high-density lipoprotein nanoparticles for atherosclerosis
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DOI：
10.1073/pnas.1301929110
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发表时间：
2013-06-04
影响因子：
11.1
通讯作者：
Dhar, Shanta
中科院分区：
文献类型：
--
作者：
Marrache, Sean;Dhar, Shanta
由于缺乏早期发现，动脉粥样硬化仍然是美国和全世界最常见的死亡原因之一。巨噬细胞凋亡是动脉粥样硬化病变不稳定性的主要因素。开发一种以细胞凋亡为目标的高密度脂蛋白（HDL）模拟纳米颗粒（NP），携带造影剂，用于早期检测易损斑块，并启动利用HDL血管保护作用的预防性治疗，对动脉粥样硬化具有吸引力。在这里，我们报道了一种合成的、可生物降解的HDL-NP平台的构建，该平台通过靶向细胞凋亡过程中发生的线粒体膜电位崩溃来检测易损斑块。该HDL模拟物包含可生物降解聚（乳酸-羟基乙酸），胆固醇油酸酯和磷脂双层涂层的核心，磷脂双层涂层用三苯磷（TPP）阳离子装饰，用于检测线粒体膜的潜在塌陷。脂质层为载脂蛋白（apo） A-I模拟4F肽的吸附提供了表面，核心包含用于光学成像的诊断活性量子点（QDs）。体外摄取、细胞凋亡检测和胆固醇结合研究表明，TPP-HDL-apoA-I-QD NPs具有良好的检测能力和治疗潜力。体外研究表明，这些NPs具有逆转胆固醇转运的潜力。体内生物分布和药代动力学表明，静脉注射TPP-HDL-apoA-I-QD NPs在大鼠体内的组织分布良好，药代动力学参数可控，甘油三酯显著降低。这些高密度脂蛋白NPs表现出良好的生物相容性、稳定性、无毒和非免疫原性，这在早期斑块诊断和预防易损斑块进展方面被证明是有希望的。
Atherosclerosis remains one of the most common causes of death in the United States and throughout the world because of the lack of early detection. Macrophage apoptosis is a major contributor to the instability of atherosclerotic lesions. Development of an apoptosis targeted high-density lipoprotein (HDL)-mimicking nanoparticle (NP) to carry contrast agents for early detection of vulnerable plaques and the initiation of preventative therapies that exploit the vascular protective effects of HDL can be attractive for atherosclerosis. Here, we report the construction of a synthetic, biodegradable HDL-NP platform for detection of vulnerable plaques by targeting the collapse of mitochondrial membrane potential that occurs during apoptosis. This HDL mimic contains a core of biodegradable poly(lactic-co-glycolic acid), cholesteryl oleate, and a phospholipid bilayer coat that is decorated with triphenylphosphonium (TPP) cations for detection of mitochondrial membrane potential collapse. The lipid layer provides the surface for adsorption of apolipoprotein (apo) A-I mimetic 4F peptide, and the core contains diagnostically active quantum dots (QDs) for optical imaging. In vitro uptake, detection of apoptosis, and cholesterol binding studies indicated promising detection ability and therapeutic potential of TPP-HDL-apoA-I-QD NPs. In vitro studies indicated the potential of these NPs in reverse cholesterol transport. In vivo biodistribution and pharmacokinetics indicated favorable tissue distribution, controlled pharmacokinetic parameters, and significant triglyceride reduction for i.v.-injected TPP-HDL-apoA-I-QD NPs in rats. These HDL NPs demonstrate excellent biocompatibility, stability, nontoxic, and nonimmunogenic properties, which prove to be promising for future translation in early plaque diagnosis and might find applications to prevent vulnerable plaque progression.