uPAR受体靶向的新型双模态分子探针的研制及显像研究

To maximize tumor excision and minimize collateral damage are the primary goals of cancer surgery. Incomplete excision of tumor tissue however negatively affects the prognosis of the patient. Evidence from numerous experimental and clinical studies has demonstrated significant benefits of molecular imaging in targeted surgery with preoperative molecular diagnostic screening, fluorescence image guided surgery and postoperative imaging. On the basis of our previous research involved in the synthesis of second near-infrared window fluorescence (NIRF-II) emitting organic molecule CH1100 and the development of a novel molecular platform for construction of multimodal imaging probes CHS1, this project aims to synthesize a series of novel NITF-II/PET dual-modality imaging probes such as uPAR targeted 68Ga-CHS with aqueous solubility, high stability and specificity. A powerful synergy will be achieved by combining PET radiotracers for the detection of tumor tissue, and NIRF-II optical tracers for subsequent accurate delineation of tumors such as glioma tumors with significant improvements in spatial resolution and imaging depth. This project will provide a simple, rapid and reliable method for tumor research especially glioma tumors and clinical diagnosis and image guided surgery, and it can help improve intraoperative staging and enable detect ignored tumor lesions in certain organs, highlight tumor margins, and identify important normal structures intraoperatively.

最大限度地切除病变、最大程度地保护正常组织减少损伤、提高患者的存活时间及术后生活质量是肿瘤手术治疗的主要目标。因此如何在术前肿瘤检测、术中手术导航和术后疗效评价已成为重大科研命题。分子成像是一门新兴学科，为解决该问题提供了可能的理想手段。本项目拟在课题组前期工作基础上，发挥正电子发射型计算机断层（PET）非侵入成像的高灵敏度，以及近红外II区有机小分子探针光稳定性好、背景干扰少、生物组织穿透能力强等优势，在生物兼容性好的环辛炔分子平台上（BCN），快速高效地构建一系列尿激酶型纤溶酶原激活物受体(uPAR)靶向的近红外II区/PET双模态有机小分子成像探针，实现肿瘤（如神经胶质瘤）术前PET成像检测肿瘤及动态可视化分析，术中近红外II区成像引导肿瘤切除和术后PET成像评价手术疗效。本研究将为肿瘤尤其是神经胶质瘤的早期诊断、边界确定和手术治疗提供新的研究方法和手段。

最大限度地切除病变、最大程度地保护正常组织减少损伤、提高患者的存活时间及术后生活质量是肿瘤手术治疗的主要目标。因此如何在术前肿瘤检测、术中手术导航和术后疗效评价已成为重大科研命题。项目负责人新开发出一系列近红外二区有机小分子探针如CH1055 、CH1100、CH-4T、H1、HLZ-BTED、H3和 5H5 等，有效突破了现有临床荧光成像背景干扰大、成像深度浅等瓶颈，实现了靶标精准成像、肿瘤精准定位、精准切除以及“可视化”靶向治疗。与其他模态如PET和MRI连用后，可达到精度、深度和组织功能鉴定的有机统一。以通讯作者/共同通讯作者发表SCI论文19篇，原创性成果发表在Nat. Mater.，Nat. Commun.，Chem. Sci.，J. Med. Chem.等国际一流期刊上，其中5篇入选ESI高被引；获得中国和美国授权发明专利各一项（部分成果已转让）。本研究将为肿瘤尤其是神经胶质瘤的早期诊断、边界确定和手术治疗提供新的研究方法和手段。

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