靶向载小檗碱纳米颗粒经声控释放活化巨噬细胞TFEB核转位介导自噬稳定动脉粥样硬化斑块作用及机制研究

At present, the morbidity of cardiovascular disease induced by atherosclerosis (AS) is becoming higher and higher. Besides expensive intervention and bypass surgery, it is extremely urgent to look for a popularized and effective method for the treatment of AS. Our previous study firstly applied noninvasive targeting sonodynamic therapy (SDT) mediated by Chinese herb sonosensitizer to AS and confirmed that it could significantly reduce and stabilize AS plaques. But it was noted that the dosage of intravenous injection of Chinese herb sonosensitizer and the side effects were large in research in vivo. So we come up with a sono-control drug carrier nano-system to release Berberine based on our earlier work. We put forward on constructing “singlet oxygen sensitive switch” connecting with nanoparticles and hyaluronic acid which could be recognized by macrophages to form a target drug carrier system loaded with Berberine. Use specific ultrasound intensity to active Berberine that produce singlet oxygen to open the “singlet oxygen sensitive switch” in order to release Berberine into plaques. And it is further researched whether Berberine-mediated SDT could active the nuclear translocation of transcriptional factor EB to induce the autophagy increase via gene regulation, promote cholesterol efflux and stabilize AS plaques. This study involves in the chemistry, physics and medicine, which has theoretical significance, clinical values and the prospects for industrialization.

目前，动脉粥样硬化（AS）引起的心血管疾病发生率越来越高，除昂贵的介入和搭桥治疗术外，寻求一种简单、有效且经济的方法治疗AS至关重要。本课题组率先将无创的声动力（SDT） 应用于AS治疗，体内研究发现中药声敏剂介导的SDT能显著缩小和稳定 AS 斑块，降低脂质含量，但仍然存在直接静脉注射剂量大、副作用大的问题，因此在前期工作基础上提出靶向载小檗碱纳米颗粒经“声控”释放体系。拟材料上，构建“单线态氧敏感开关”键连纳米颗粒和可被巨噬细胞靶向识别的透明质酸，装载小檗碱形成靶向载药系统，使用特定强度的超声激活纳米颗粒内小檗碱产生单线态氧，打开“单线态氧敏感开关”，释放小檗碱到斑块巨噬细胞内。理论上，研究释放后的小檗碱介导的 SDT能否活化巨噬细胞新型转录因子EB 核转位，并通过基因调控诱导自噬增强，促胆固醇流出，稳定AS斑块。本项目为交叉学科研究，有重要的理论意义、广阔的临床价值和产业化前景。

随着人口老龄化加剧，心血管疾病成为一种严重威胁人类健康的常见疾病，具有高患病率、高致残率和高死亡率的特点。其中动脉粥样硬化(AS)作为心血管疾病中的常见致病因素，其患者日趋增多，除昂贵的介入和搭桥术治疗AS外，寻求一种简单、有效和易于推广的方法势在必行。声动力治疗是利用超声的物理能量激活特定药物发生化学反应，产生活性氧，从而发挥生物学效应的一种治疗方法。构建“单线态氧敏感开关”键连纳米颗粒和可被巨噬细胞靶向识别的透明质酸，装载小檗碱形成载药系统，使用特定强度的超声激活纳米颗粒内小檗碱产生单线态氧，打开“单线态氧敏感开关”，释放小檗碱到巨噬细胞内，并筛选出了适合声敏剂。证明了小檗碱介导的声动力疗法对巨噬细胞、泡沫细胞有治疗作用，能够通过诱导巨噬细胞和泡沫细胞发生自噬、抑制炎症、增强了斑块内促胆固醇流出清除功能。小檗碱诱导巨噬细胞细胞TFEB促进自噬抑制凋亡，促进不稳定斑块变成稳定斑块。本项目涉及化学、物理学、医学等多学科交叉研究，有理论意义、临床价值和产业化前景。.申请国家专利2项，已授权发明专利1项。发表SCI和国内外文章16篇（SCI文章10篇、中文核心6篇），其中IF≥5.0SCI文章5篇，5.0≥IF≥4.0SCI文章2篇。培养博士后出站1名，博士毕业2名，硕士毕业6名。参加国际学术会议1次，国内专题报告5次。遴选为博士研究生导师1名，获龙江学者青年学者、黑龙江省青年科技奖、ISHR Travel Award、哈尔滨医科大学优秀教师、哈尔滨医科大学青年科技人才奖等。获2019年度黑龙江省医药卫生科学技术奖（自然科学奖）一等奖。