Nanotechnology Research Center, Bu-Ali Research Institute, Mashhad University of MedicalSciences, Mashhad, Iran; Department of Medical Biotechnology, Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Immunology Research Center, Department of Immunology, Medical School, Mashhad University of Medical Sciences. Mashhad, Iran.
Biomed Pharmacother. 2019 Jan;109:2305-2308. doi: 10.1016/j.biopha.2018.11.125. Epub 2018 Nov 29.
C-reactive protein (CRP) is an acute-phase protein which can bind to and aggregate oxidized low-density lipoprotein (ox-LDL) particles, thereby enhancing the uptake of oxLDL by macrophages. This finally leads to the formation of foam cells that are a typical characteristic of atherosclerotic plaques. Serum CRP has been shown to bind to phospholipids such as phophatidylcholine (PC), phosphatidylglycerol (PG) and phosphatidylserine (PS). Owing to the rapid and efficient clearance of nanoliposomes from the circulation by the liver, we hypothesized that nanoliposomes composed of the mentioned phospholipids can serve as a potential tool to lower elevated serum CRP levels following acute inflammation. To evaluate this hypothesis, nanoliposomal formulations containing hydrogenated soy phosphatidylcholine (HSPC), a combination of HSPC and 1,2-distearoyl-sn-glycero-3-phosphoglycerol (DSPG), and a combination of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 1,2-dioleoyl-sn-glycero-3-phospho-l-serine (DOPS) were prepared using lipid film hydration method followed by extrusion at the final concentration of 20 mM. To elevate circulating CRP levels in mice, 0.1 ml of Freund's complete adjuvant (CFA) containing 5 mg/ml heat-killed Mycobacterium tuberculosis was subcutaneously injected into the hind paw of the mice. CFA-challenged mice were intravenously treated with nanoliposomal formulations at the dose of 250 μmol/kg 16 h after CFA challenge that is coincided with peak serum CRP level. After 2 h, the blood was collected and serum level of CRP was measured using a quantitative sandwich enzyme-linked immunosorbent assay. All nanoliposomal formulations showed a size range from 100 to 150 nm in diameter and a polydispersity index of < 0.1. Results showed that all nanoliposomal formulations including DOPC/DOPS, HSPC and HSPC/DSPG could significantly decrease serum levels of CRP by 82.76% (74.44-86.92%, p = 0.0001), 44.41% (35.79-50.21%, p = 0.0001) and 38.47% (17.21-43.52%, p=0.0002) [Median (interquartile range)], respectively, when compared with the control group. Dexamethasone as a standard could decrease serum CRP level by 27.47% (16.32-31.63%, p = 0.0025) which was a smaller effect compared with the nanoliposomal preparations. In conclusion, negatively charged nanoliposomes could efficiently reduce the elevated serum levels of CRP in CFA-challenged mice.
C-反应蛋白（CRP）是一种急性期蛋白，可与氧化型低密度脂蛋白（ox-LDL）颗粒结合并聚集，从而增强巨噬细胞对 oxLDL 的摄取。这最终导致泡沫细胞的形成，这是动脉粥样硬化斑块的典型特征。已经表明，血清 CRP 可以与磷脂如磷脂酰胆碱（PC）、磷脂酰甘油（PG）和磷脂酰丝氨酸（PS）结合。由于纳米脂质体通过肝脏被迅速有效地从循环中清除，因此我们假设由所述磷脂组成的纳米脂质体可以作为降低急性炎症后升高的血清 CRP 水平的潜在工具。为了评估这一假设，使用脂质体薄膜水化法制备了含有氢化大豆磷脂酰胆碱（HSPC）、HSPC 与 1,2-二硬脂酰基-sn-甘油-3-磷酸甘油（DSPG）的组合以及 1,2-二油酰基-sn-甘油-3-磷酸胆碱（DOPC）和 1,2-二油酰基-sn-甘油-3-磷酸-L-丝氨酸（DOPS）的纳米脂质体制剂，最终浓度为 20mM。为了提高小鼠循环中的 CRP 水平，将含有 5mg/ml 热灭活结核分枝杆菌的弗氏完全佐剂（CFA）0.1ml 皮下注射到小鼠的后爪中。在 CFA 挑战后 16 小时，即与血清 CRP 水平峰值同时，用纳米脂质体制剂以 250μmol/kg 的剂量对 CFA 挑战的小鼠进行静脉内治疗。2 小时后，采集血液并使用定量夹心酶联免疫吸附测定法测量 CRP 血清水平。所有纳米脂质体制剂的粒径均在 100 至 150nm 之间，多分散指数<0.1。结果表明，所有纳米脂质体制剂，包括 DOPC/DOPS、HSPC 和 HSPC/DSPG，均可使 CRP 血清水平分别降低 82.76%（74.44-86.92%，p=0.0001）、44.41%（35.79-50.21%，p=0.0001）和 38.47%（17.21-43.52%，p=0.0002）[中位数（四分位距）]，与对照组相比。地塞米松作为标准品可使 CRP 血清水平降低 27.47%（16.32-31.63%，p=0.0025），与纳米脂质体制剂相比，效果较小。总之，带负电荷的纳米脂质体可以有效地降低 CFA challenged 小鼠中升高的血清 CRP 水平。
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