Hong Kristen, Yu Minzhi, Crowther Julia, Mei Ling, Olsen Karl, Luo Yonghong, Chen Yuqing Eugene, Guo Yanhong, Schwendeman Anna
Department of Pharmaceutical Sciences and the Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA.
Pharmaceutics. 2022 Jul 28;14(8):1570. doi: 10.3390/pharmaceutics14081570.
Atherosclerosis progression is driven by an imbalance of cholesterol and unresolved local inflammation in the arteries. The administration of recombinant apolipoprotein A-I (ApoA-I)-based high-density lipoprotein (HDL) nanoparticles has been used to reduce the size of atheroma and rescue inflammatory response in clinical studies. Because of the difficulty in producing large quantities of recombinant ApoA-I, here, we describe the preparation of phospholipid-based, ApoA-I-free micelles that structurally and functionally resemble HDL nanoparticles. Micelles were prepared using various phosphatidylcholine (PC) lipids combined with 1,2-distearoyl--glycero-3-phosphoethanolamine-N-[azido(polyethylene glycol)-2000] (DSPE-PEG2k) to form nanoparticles of 15-30 nm in diameter. The impacts of PC composition and PEGylation on the anti-inflammatory activity, cholesterol efflux capacity, and cholesterol crystal dissolution potential of micelles were investigated in vitro. The effects of micelle composition on pharmacokinetics and cholesterol mobilization ability were evaluated in vivo in Sprague Dawley rats. The study shows that the composition of HDL-mimicking micelles impacts their overall atheroprotective properties and supports further investigation of micelles as a therapeutic for the treatment of atherosclerosis.
动脉粥样硬化的进展是由胆固醇失衡和动脉中未解决的局部炎症驱动的。在临床研究中，基于重组载脂蛋白A-I（ApoA-I）的高密度脂蛋白（HDL）纳米颗粒的给药已被用于减小动脉粥样硬化斑块的大小并挽救炎症反应。由于难以大量生产重组ApoA-I，在此，我们描述了基于磷脂的、不含ApoA-I的胶束的制备，其在结构和功能上类似于HDL纳米颗粒。使用各种磷脂酰胆碱（PC）脂质与1,2-二硬脂酰-sn-甘油-3-磷酸乙醇胺-N-[叠氮基（聚乙二醇）-2000]（DSPE-PEG2k）组合制备胶束，以形成直径为15-30nm的纳米颗粒。在体外研究了PC组成和聚乙二醇化对胶束的抗炎活性、胆固醇流出能力和胆固醇晶体溶解潜力的影响。在Sprague Dawley大鼠体内评估了胶束组成对药代动力学和胆固醇动员能力的影响。该研究表明，模拟HDL的胶束组成影响其整体抗动脉粥样硬化特性，并支持进一步研究胶束作为治疗动脉粥样硬化的疗法。
