基于金纳米棒携载报告基因心脏组织工程治疗心肌梗死及PET/MR/PAI多模分子影像监测

Cardiomyocytes are terminal cells which can’t regenerate. Cardiac tissue engineering is a promising strategy for repairing injured myocardium. However, there is no proper vector that facilitate functional tissue formation and noninvasive monitoring currently. Studies reported gold nanoparticles have efficacy against myocardial injury, and a variety of gold nanostructures have been used in cardiac tissue engineering and demonstrated promoting formation of functional cardiac tissue and electrophysiology, and we have demonstrated gold nanorod is a good theranostic platform since the ease of surface modification. Under the support of National Natural Science Foundation of China, our team has successfully established a variety of reporter gene imaging systems, in which multimodal imaging based on tyrosinase (TYR) reporter gene carried by lentivirus can monitor stem cell therapy of myocardium infarction to 28 days. Therefore, this project intends to establish gold nanorods carrying reporter gene TYR based engineering functionalized cardiac patch and injectable hydrogel as the support material for the treatment of myocardial infarction. On one hand, it can better promote functional myocardial tissue maturation and fuse with host myocardium, to achieve the purpose of repairing injured myocardium. On the other hand, make use of melanin-the product of TYR single reporter gene, multi-modality imaging is used to monitor the survival and distribution of transplanted tissue in vivo by means of PET / MR / photoacoustic imaging , providing new strategies for the treatment of myocardial infarction and multidimensional noninvasive monitoring.

心肌细胞是终末细胞，不能再生，心脏组织工程是有前景的修复受损心肌的方法，但目前尚缺促进功能组织形成及无创监测的载体。研究证实金纳米粒具有抗心肌损伤作用，且多种金纳米结构有助于功能化心脏组织贴片及电生理的形成，我们前期亦证实金纳米棒表面易于修饰，是一种良好的诊疗一体化平台。课题组在多项国家自然基金项目资助下，先后成功建立多种报告基因显像系统，其中基于慢病毒携载酪氨酸酶（TYR）单报告基因进行多模态显像可以监测干细胞治疗心肌梗死至28天。因此，本项目构想建立基于金纳米棒为载体携载报告基因TYR的组织工程心脏贴片结合可注射水凝胶作为支撑材料治疗心肌梗死，一方面可更好促进功能化心肌组织成熟及与宿主心肌融合，达到修复受损心肌的目的；另一方面通过TYR表达产物黑色素行PET/MR/光声显像，实现单一报告基因多模态显像无创监测移植组织在体内的存活及分布的目的，为心肌梗死的治疗和多维度无创监测提供新策略。

心肌梗死是严重危害人类健康的重大疾病，本项目围绕心肌梗死有效治疗和无创监测的临床难题，成功研究了多种具有潜力的生物治疗新策略对心梗模型鼠进行治疗，并应用多模态分子影像学方法进行无创监测：一是成功构建了体外人生长激素释放肽缓释系统，通过体外细胞实验和心肌梗死模型及组织学验证证实了人生长激素释放肽结合温敏性水凝胶对心肌梗死的治疗作用，可以改善心肌活力和心功能；二是成功构建了基于金纳米颗粒的温敏导电水凝胶（GNR@SN/Gel），联合间充质干细胞（MSCs）对心梗大鼠进行治疗，并应用68Ga、18F-FDG PET显像和超声心动图对治疗过程及治疗效果进行无创监测，体内外实验证明MSC联合GNR@SN/Gel可以保护心梗大鼠的心功能、抑制心梗心肌的胶原沉积、改变瘢痕构成成分、改善机电耦合、促进血管生成、减轻心脏代偿的负荷，对心梗具有联合治疗作用，是一种有潜力的心梗治疗方法；三是基于仿生纳米技术与高分子技术，制备了靶向梗死心肌的仿生血小板膜包覆小檗碱缓释高分子纳米药物，用于治疗心肌梗死，并对其机制进行了研究，以期解决小檗碱静脉给药的一过性副作用问题，同时从改善梗死心肌微环境角度出发，利用调控巨噬细胞表型实现了梗死心肌的无创修复；此外，还尝试了心脏电极贴片和药物缓释微针贴片的新型策略治疗心肌梗死，研究尚需进一步完善。在心肌梗死的监测中，还研究了68Ga-FAPI动态监测心梗后活化成纤维细胞的可行性，为心梗后纤维化及其他纤维化疾病的无创监测提供了一种具有临床前景的方法。综上，本项目的实施为心肌梗死的治疗与无创监测提供了多种具有潜力的新策略。