靶向动脉粥样硬化易损斑块的金纳米棒光声成像研究

Atherosclerosis (AS) is the main cause of increasing morbidity and mortality of cardiovascular and cerebrovascular diseases. AS patients often have vulnerable plaques. The atherosclerotic plaque rupture can lead to acute myocardial infarction, sudden cardiac death, ischemic stroke and other serious consequences, so the existence of vulnerable plaque is dangerous to cardiovascular and cerebrovascular disease patients. The existing imaging methods are difficult to identify and evaluate the stability of vulnerable plaques. This project intends to design and construct a gold nanorod photoacoustic imaging contrast agent targeting vulnerable plaque of AS. According to the characteristics of high expression of urokinase receptor in atherosclerotic plaque and high expression of matrix metalloproteinase (MMP-9) in vulnerable plaque, gelatin and urokinase (uPA) were modified on the surface of gold nanorods. As uPA was used as specific target probe, the gold nanorods are enriched in AS plaque. With the gelatin layer on the surface of gold nanorods removed by MMP-9 degradation, the optical properties of gold nanorods can change and produce different photoacoustic signals. This project will provide new techniques and methods for the clinical evaluation and diagnosis of atherosclerotic plaques, and will be helpful to further understand the vulnerability mechanism of atherosclerotic plaques. It is very important for research and application.

动脉粥样硬化（AS）是导致心脑血管疾病发病率及死亡率逐年攀升最主要的病因。AS病人多存在易损斑块，斑块一旦破裂可导致急性心肌梗死、心源性猝死和缺血性卒中等严重后果，对心脑血管疾病患者的生命具有极大的危险性。现诊断所依赖的影像学方法尚难以识别易损斑块及对其稳定性进行评估。本项目拟设计构建一种靶向AS易损斑块的金纳米棒光声成像造影剂，根据AS斑块中高表达尿激酶受体和易损斑块中高表达的基质金属蛋白酶（MMP-9）的特点，在金纳米棒表面修饰明胶和尿激酶（uPA）分子，以uPA为特异性靶向探针，实现金纳米棒在AS斑块中的富集；通过MMP-9对明胶的降解脱去金纳米棒表面的明胶层，由此实现金纳米棒光学性质的改变，产生不同光声信号，从而对易损斑块进行识别和定位。该项目将为动脉粥样硬化易损斑块的临床评估和诊断提供新技术和方法，也有助于深入了解动脉粥样硬化斑块的易损机制，具有非常重要的科学研究价值和应用前景。

动脉粥样硬化病人多存在易损斑块，斑块破裂对患者具有极大的危险性。为了满足临床中各种需求，纳米材料的性质和作用受到越来越多研究人员的关注。本项目通过设计构建一种光声成像造影剂，制备了多肽连接金纳米棒和金纳米颗粒的组装体，表面修饰尿激酶分子可靶向斑块，由于易损斑块中高表达的基质金属蛋白酶（MMP9）可特异性剪切多肽，该组装体实现了紫外可见近红外光谱和光声信号对MMP9的浓度依赖性响应，验证了体内易损斑块识别的可行性。与此同时，设计制备了新型纳米材料并研究其性能，比较研究多种纳米颗粒对内皮细胞影响规律，重点研究氧化铁纳米颗粒对内皮间质转分化影响和在MRI成像应用中对肾组织的影响；发现了金核/银壳纳米颗粒可促进多巴胺在非神经组织的生成及金核/铂壳纳米颗粒促进白血病细胞巨核细胞分化作用，表明纳米颗粒在临床中具有重要的应用潜能。