Petersen Latrisha K, York Adam W, Lewis Daniel R, Ahuja Sonali, Uhrich Kathryn E, Prud'homme Robert K, Moghe Prabhas V
Department of Biomedical Engineering, Rutgers University , 599 Taylor Road, Piscataway, New Jersey 08854, United States.
Mol Pharm. 2014 Aug 4;11(8):2815-24. doi: 10.1021/mp500188g. Epub 2014 Jul 9.
Atherosclerosis, an inflammatory lipid-rich plaque disease is perpetuated by the unregulated scavenger-receptor-mediated uptake of oxidized lipoproteins (oxLDL) in macrophages. Current treatments lack the ability to directly inhibit oxLDL accumulation and foam cell conversion within diseased arteries. In this work, we harness nanotechnology to design and fabricate a new class of nanoparticles (NPs) based on hydrophobic mucic acid cores and amphiphilic shells with the ability to inhibit the uncontrolled uptake of modified lipids in human macrophages. Our results indicate that tailored NP core and shell formulations repress oxLDL internalization via dual complementary mechanisms. Specifically, the most atheroprotective molecules in the NP cores competitively reduced NP-mediated uptake to scavenger receptor A (SRA) and also down-regulated the surface expression of SRA and CD36. Thus, nanoparticles can be designed to switch activated, lipid-scavenging macrophages to antiatherogenic phenotypes, which could be the basis for future antiatherosclerotic therapeutics.
动脉粥样硬化是一种富含炎症脂质的斑块疾病，巨噬细胞中不受调控的清道夫受体介导的氧化脂蛋白（oxLDL）摄取使其持续存在。目前的治疗方法缺乏直接抑制病变动脉内oxLDL积累和泡沫细胞转化的能力。在这项工作中，我们利用纳米技术设计并制造了一类新型纳米颗粒（NPs），其基于疏水粘酸核心和两亲性外壳，能够抑制人类巨噬细胞中修饰脂质的不受控制的摄取。我们的结果表明，定制的NP核心和外壳配方通过双重互补机制抑制oxLDL内化。具体而言，NP核心中最具抗动脉粥样硬化保护作用的分子竞争性地减少了NP介导的对清道夫受体A（SRA）的摄取，并且还下调了SRA和CD36的表面表达。因此，可以设计纳米颗粒将活化的、脂质清除巨噬细胞转变为抗动脉粥样硬化表型，这可能是未来抗动脉粥样硬化治疗的基础。
