为乳腺癌精准诊治提供多参数影像学信息的分子探针的构建及评价

Molecular imaging plays important roles in not only tumor early detection, but also tumor staging, prognosis evaluation, therapeutic monitoring and guiding individual treatment. However, with the development of medical sciences, single modality or single parameter molecular imaging is unable to meet the threshold for the better understanding of diseases. More sensitive, accurate, and comprehensive molecular imaging strategies are urgently needed. Therefore, multimodality and multiparameter molecular imaging has become the trend of modern medical imaging. Multimodality and multiparameter molecular imaging not only refers to the various parameters provided by imaging instruments, but also refers to the different imaging information provided by molecular probes. According to the different characteristics during the progression of breast cancer, this project focuses on the development of new molecular probes including 99mTc-HYNIC-HXF, 99mTc-HYNIC-CRWY9, and 99mTc-HYNIC-Var7 targeting HER2, integrin α6, and tumor microenvironment. Relying on multimodality molecular imaging, especially nuclear medicine imaging, this study would provide multiparameter imaging information for the early detection of breast cancer, investigations of metastasis and resistance to therapy, monitoring therapy, and guiding personalized therapy.

分子影像在肿瘤诊治中的作用已不仅仅是肿瘤的早期显像诊断，在肿瘤的分期、预后评价、疗效监测以及指导个体化治疗等方面都发挥着不可替代的作用。然而，随着医学的发展，单一模态和单一参数的分子影像技术已经无法满足人们对疾病的认识，临床诊断需要更灵敏、更准确、功能更全面的分子影像手段，因此多模态、多参数分子影像已成为医学影像学发展的趋势。多模态多参数分子影像不仅体现在显像仪器本身提供的各种参数，也体现在不同分子探针给出的各种影像学信息。本课题根据乳腺癌发生、发展过程中的不同特点，针对HER2、integrin α6以及肿瘤微环境构建全新分子探针99mTc-HYNIC-HXF、99mTc-HYNIC-CRWY9和99mTc-HYNIC-Var7，以核医学显像为主，通过多模态显像，获得多参数的有关乳腺癌的影像学信息，为乳腺癌的早期显像诊断、肿瘤转移及耐药机制的研究、疗效监测及指导个体化治疗提供方法和手段。

由于肿瘤HER2表达具有时间和空间异质性，因此目前临床上采用的IHC方法以及FISH方法具有一定的局限性。我们研制出靶向HER2的显像剂99mTc-HP-Ark2，99mTc-HP-Ark2 SPECT/CT显像的灵敏度、特异性和准确率分别为89.5%、88.2%和88.9%。IHC和99mTc-HP-Ark2 SPECT/CT相当等效，从某种程度上可以通过99mTc-HP-Ark2 SPECT/CT判断肿瘤是否是HER2阳性，特别是对于活检不方便或者不可能的情况下，99mTc-HP-Ark2 SPECT/CT有望替代IHC。目前我们已经启动了1类新药的申报，预计2022年申请临床试验批件。.integrin α6的表达与乳腺癌的恶性程度以及转移密切相。我们设计构建了靶向integrin α6的分子探针99mTc-RWY，进行肿瘤患者的在体分子分型。研究结果显示，99mTc-RWY SPECT/CT能对肿瘤进行清晰显像，显像结果与病理检验和IHC检测结果相一致。对92例乳腺癌患者的随访结果显示，integrin α6高表达患者的生存期低于integrin α6低表达患者。.PD-L1的高表达被认为是预测PD-1/PD-L1阻断治疗有效性的生物标志物之一。然而，肿瘤的异质性以及PD-L1表达的动态变化，传统的免疫组化检测方式难以实现对PD-L1的实时定量监测，从而使精准预测PD-1/PD-L1阻断治疗疗效存在困难。我们研制了靶向PD-L1的分子探针99mTc-MY1523，并提出了免疫治疗时间窗的概念， 通过核医学分子影像手段确定PD-L1表达上调的时间窗口，在时间窗内进行PD-L1靶向阻断治疗能够显著提高抗PD-L1治疗的有效性。这项研究工作的临床价值在于，通过放疗或者化疗调控肿瘤PD-L1的表达，在核医学分子影像引导下进行抗PD-L1治疗，能够提高治疗的响应率和疗效。