组织因子靶向纳米粒介导CCR2-shRNA抑制动脉粥样硬化斑块的进展

Atherosclerosis is an inflammatory disease, and the high expressed tissue factor can be found in the atherosclerotic plaque location of the each pathological stage. In our previous studies, according to the FVII could specific bind to the TF, we prepared the TF target nanoparticles (EGFP-EGF1-NP) with the fusion protein EGFP-EGF1 and the PEG-PLGA nanoparticles. The studies confirmed the nanoparticles could target to the TF-expressed cells in vitro and in vivo, and play an effective gene silencing as a carrier of the small interference RNA. CCR2 is the chemokine receptor of CCL2, has an important role in inflammation of atherosclerosis. In the same high fat diet, the atherosclerotic plaque of the CCR2 knockout mouse was thinner than the normal mouse. This study plans to utilize the EGFP-EGF1-NP as a targeted carrier, entrapment the CCR2 specific shRNA into it. After intravenous injection, the shRNA could be carried to the area of atherosclerotic plaque by the TF target nanoparticles. Down regulation the expression of CCR2 in the location, then achieving the purpose of the specific inhibition of atherosclerotic plaque.

动脉粥样硬化是一种炎症反应性疾病，其各个阶段在粥样斑块局部都可以检测出异常高表达的组织因子（TF）。前期研究中，本课题组根据FVII因子和TF特异性结合的特点，制备了EGFP-EGF1融合蛋白，并将其连接至PEG-PLGA纳米粒表面制备了组织因子靶向性纳米粒（EGFP-EGF1-NP），证明其在体内外均可靶向到表达TF的细胞，并验证其作为小干扰RNA的载体可以起到高效的基因沉默效应。CCR2作为一种趋化因子受体，在动脉粥样硬化的炎症反应中起到重要的作用，敲除CCR2基因小鼠粥样斑块形成明显减少。本课题利用EGFP-EGF1-NP作为载体，将针对CCR2的shRNA载入纳米粒内部，静脉给药后能靶向到高表达TF的粥样斑块，下调斑块区域CCR2表达水平，进而达到特异性抑制动脉粥样斑块进展的目的。