基于高分辨超声成像系统的心脏移植排斥反应精准诊疗一体化研究

Acute rejection (AR) after heart transplantation is the most common complication and the leading cause of death. Currently the early diagnosis is unavailable due to lack of noninvasive monitor methods with high specificity and sensitivity. According to the fact that CD3+ T Cell invasion is the major pathological process in the early stage of AR, an early integration method to detect and treat AR precisely is proposed based on the development of high-resolution ultrasound imaging and targeted nanometer-microbubble (NB). This project includes the combination of high-resolution ultrasound and targeted drug-loaded NB to establish the sensitive imaging, construction of AR model in mouse using large samples, and effect evaluation of the targeted drug delivery. To be specific, objectives include: (1) establishment of the nonlinear mathematical model of acoustic scattering for NB to achieve NB’s sensitive imaging in tissue or vascular structure;(2) to produce targeted NB probe carrying CD3 (CD3-NB) and multi-function drug-loaded NB carrying both CD3 and FK506 (CD3-NB-FK506); (3) to establish AR model in mouse to implement early diagnosis through high resolution ultrasound combined with CD3-NB, which could be compared with pathological result to optimize the diagnostic strategy;(4) to deliver FK506 into targeted pathological tissue simultaneously through ultrasound exposure to treat AR by the comparison with pathological result. Eventually an integration method to diagnose early and treat precisely for patents with AR would be achieved.

急性排斥反应(AR)是心脏移植术后最常见的并发症和致死原因，目前临床AR缺乏高分辨与敏感的早期无创检测手段。针对AR早期大量CD3+T淋巴细胞浸润的特征，本项目创新性提出基于高分辨率超声成像的AR精准诊疗一体化方法，利用高频超声实现对靶向粘附载药纳米气泡（NB）声探针的敏锐成像，构建小鼠AR模型和开展大样本实验，评估靶向给药的疗效。具体包括：①建立NB非线性声学散射的数学模型，实现对组织/管脉结构中NB的敏锐声成像；②制备靶向NB声探针（CD3-NB），并构建多功能靶向载药NB（CD3-NB-FK506）用于定点给药；③建立小鼠AR模型，利用高分辨超声联合CD3-NB声探针成像评估AR，对比病理金标准，优化高分辨成像诊断AR最佳策略；④超声辐照靶向粘附载药NB探针释放FK506达到对AR靶向治疗，开展病理对照组比对实验。本项目的成功实施将为AR的早期精准诊疗一体化提供新的思路和方法。

急性排斥反应（AR）是心脏移植术后最常见的并发症及主要的致死原因。然而，目前临床上并无高特异与敏感性的无创检测技术用于AR的早期诊断与干预。经颈静脉心内膜心肌活检是诊断AR的“金标准”，但其临床应用中可导致较严重并发症，此外心肌活检存在漏诊可能，严重影响对病情的准确判断。因此，寻找无创、有效、实时动态连续监测心脏移植术后AR指标，并进行早期靶向干预的一体化精确诊疗方法，具有重大意义。.针对AR早期大量T淋巴细胞浸润的病理特征，本项目创新性提出基于高分辨率超声分子成像的AR精准诊疗一体化方法。主要研究成果包括：①成功制备了T细胞靶向纳泡的超声分子成像探针，阐明生物合成纳泡的弹性及非线性声学特性。②构建小鼠/大鼠AR模型，建立了心脏移植急性排斥反应的超声分子成像方法，实现分子水平早期无创诊断心脏移植急性排斥反应。③制备载FK506、antagomir-155微泡，联合超声靶向微泡破坏技术，成功实现超声成像引导药物及基因体内无创靶向递送，显著提高对心脏移植急性排斥反应的治疗效果。.相关研究成果发表学术论文41篇，其中SCI收录论文 36篇。IF>10，2篇；IF>5，11篇；最高IF：22.67；总IF：150.96。三篇代表性论文分别被《Advanced Healthcare Materials》、《Biomaterials Science》、《Transplantation》选为Back Cover和Front Cover。申请发明专利5项，获批实用新型专利6项。本项目部分研究成果获2019年“湖北省科技进步一等奖”，并入选2020年“华中科技大学重大学术进展”。.本项目联合高分辨超声成像与多功能载药纳米气泡超声分子探针，成功实现对心脏移植排斥反应的超声分子成像与靶向治疗，为AR早期精准诊疗提供了一种有效手段。