超声介导携氧DDFP相变纳米微泡靶向溶栓治疗冠状动脉微循环栓塞

After the onset of acute myocardial infarction (AMI), the key of therapy is for immediate elimination of micro-thrombus and recanalization of micro-circulation at culprit coronary territory. However, effective thrombolytic therapy of coronary micro-embolization has always been an unsolved issue clinically. New tactic provided as ultrasound mediated targeted AMI micro-thrombolysis would be feasible with novel oxygen-carrying DDFP phase-change nano-scale agent. With ultrasonic irradiated targeting transport, DDFP nano-scale agent is capable of phase-changing into gas-core bubbles and activating to sustaining and stable cavitation effects, as it is sensitive to low acoustic energy. For its functions of thrombolysis and oxygen diffusion, recanalization of coronary micro-circulation and recovery of AMI can be achievable. Contents of our study are as below: Preparation and qualification of low-acoustic-energy sensitive DDFP phase-change nano-scale agent is the first step; With ultrasonic irradiation and models of in-vitro thrombus occlusion of artificial vessel and in-vivo coronary micro-embolism of AMI pigs, its therapeutic functions of thrombus dissolution and oxygen diffusion are to be evaluated as well as the improvements of coronary micro-circulation and cardiac function. By carrying out this study, a novel therapy of AMI coronary micro-embolization is to be established non-invasively with safety and high efficiency.

急性心肌梗死（AMI）后及时清除冠脉微血栓、疏通微循环是AMI治疗关键。但冠脉微循环血栓治疗一直是临床上未能解决的难题。携氧DDFP相变纳米微泡的超声靶向溶栓疗法为AMI 冠脉微循环栓塞治疗提供新策略。在超声辐照介导下，携氧DDFP相变纳米微泡高效靶向输送同时，超声能量敏感型相变微泡将实现气液相变并产生持续、稳定的空化效应， 通过溶栓及携氧功能促冠脉微循环血运重建，达到治疗AMI目的。本研究主要研究内容为：制备超声能量敏感型DDFP相变纳米微泡及鉴定；应用超声辐照介导DDFP相变纳米微泡作用于人工血管血栓栓塞模型及猪冠脉微循环栓塞型急性心肌梗死模型，检测相变微泡溶栓、携氧功能、溶解冠脉微血栓及心功能改善情况。藉此建立一种安全、高效、无创的AMI冠脉微循环栓塞治疗方式。

随着人们生活水平的日益提高，血栓栓塞性疾病成为严重威胁人类生命健康的重大疾病，特别是冠状动脉和脑血管栓塞所引起的心肌梗死和脑梗塞的发病率和死亡率均高居各种疾病之首，且近年来还有渐增之势，是目前临床亟待解决的重点和难点。急性动脉栓塞发生时，病变动脉局部闭塞，血管管腔内形成广泛血栓及高凝状态，受支配的组织由于持续缺氧最终导致坏死。若不能得到及时缓解，局部组织坏死将会不可逆转，严重影响患者的预后。为了避免这一情况发生，必须及时重建血运，改善及促进微循环，满足局部组织氧耗需求。对于急性心肌梗死冠状动脉血栓栓塞，目前临床普遍通过急诊溶栓或介入治疗恢复动脉供血，但由于急诊治疗时间窗较短，在错过抢救时机后栓塞将难以溶解，缺血区亦难再恢复。此外，研究表明通过急诊介入治疗的患者中，仍有65%存在永久性的微循环栓塞。要扭转这一状态，需要促进溶栓药物与微血管内血栓迅速充分作用，提高微循环血运重建的效率。因此及时疏通冠状动脉微循环栓塞，是治疗急性心肌梗死的关键。.本项目创新性地通过制备一种载H2O2液态氟碳脂质纳米造影剂与超声联合作用达到溶解血栓，疏通冠状动脉，恢复心肌组织灌注的目的。本项目实验证实，超声微泡联合进行冠状动脉急诊溶栓的方法能够有效清除血管内的血栓栓塞，通过产生稳定、持续的空化作用，在短时间内快速实现冠状动脉血管再通，有效缓解心肌缺血缺氧，挽救濒死心肌。同时，超声微泡冠状动脉溶栓是安全性高、普遍适用并迅速起效的急诊治疗方法。.因此，本项目制备的H2O2/DDFP相变纳米微泡，依据急性心梗治疗的“时间-生命原则”，综合应用相变微泡的溶栓及携氧功能并联合超声辐照的物理效应，具有靶向、安全、高效的优势，能够针对性的解决冠状动脉微循环急性栓塞导致心肌不可逆转性坏死的难题。本项目可显著提高心肌梗死的治疗疗效并扩大急诊救治的安全适用范围，将对患者的预后产生积极的影响，具有十分广阔的临床应用前景。