Zhang Xue-Qing, Even-Or Orli, Xu Xiaoyang, van Rosmalen Mariska, Lim Lucas, Gadde Suresh, Farokhzad Omid C, Fisher Edward A
Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Adv Healthc Mater. 2015 Jan 28;4(2):228-36. doi: 10.1002/adhm.201400337. Epub 2014 Aug 22.
Liver X receptor (LXR) signaling pathways regulate lipid metabolism and inflammation, which has generated widespread interest in developing synthetic LXR agonists as potential therapeutics for the management of atherosclerosis. In this study, it is demonstrated that nanoparticles (NPs) containing the synthetic LXR agonist GW3965 (NP-LXR) exert anti-inflammatory effects and inhibit the development of atherosclerosis without causing hepatic steatosis. These NPs are engineered through self-assembly of a biodegradable diblock poly(lactide-co-glycolide)-b-poly(ethylene glycol) (PLGA-b-PEG) copolymer. NP-LXR is significantly more effective than free GW3965 at inducing LXR-target gene expression and suppressing inflammatory factors in macrophages in vitro and in vivo. Additionally, the NPs elicit negligible lipogenic gene stimulation in the liver. Using the Ldlr (-/-) mouse model of atherosclerosis, abundant colocalization of fluorescently labeled NPs within plaque macrophages following systemic administration is seen. Notably, six intravenous injections of NP-LXR over 2 weeks markedly reduce the CD68-positive cell (macrophage) content of plaques (by 50%) without increasing total cholesterol or triglycerides in the liver and plasma. Together, these findings identify GW3965-encapsulated PLGA-b-PEG NPs as a promising nanotherapeutic approach to combat atherosclerosis, providing the benefits of LXR agonists without their adverse effects on hepatic and plasma lipid metabolism.
肝X受体（LXR）信号通路调节脂质代谢和炎症反应，这使得开发合成LXR激动剂作为动脉粥样硬化治疗的潜在药物引起了广泛关注。在本研究中，已证明含有合成LXR激动剂GW3965的纳米颗粒（NP-LXR）具有抗炎作用，并能抑制动脉粥样硬化的发展，且不会引起肝脂肪变性。这些纳米颗粒是通过可生物降解的双嵌段聚（丙交酯-共-乙交酯）-b-聚（乙二醇）（PLGA-b-PEG）共聚物的自组装工程化制备的。在体外和体内，NP-LXR在诱导LXR靶基因表达和抑制巨噬细胞炎症因子方面比游离GW3965显著更有效。此外，这些纳米颗粒在肝脏中引起的脂肪生成基因刺激可忽略不计。使用动脉粥样硬化的Ldlr（-/-）小鼠模型，全身给药后可见荧光标记的纳米颗粒在斑块巨噬细胞内大量共定位。值得注意的是，在2周内静脉注射6次NP-LXR可显著降低斑块中CD68阳性细胞（巨噬细胞）的含量（降低50%），而不会增加肝脏和血浆中的总胆固醇或甘油三酯。总之，这些发现确定了包裹GW3965的PLGA-b-PEG纳米颗粒是一种有前景的抗动脉粥样硬化纳米治疗方法，它具有LXR激动剂的益处，而对肝脏和血浆脂质代谢没有不良影响。
