基于双靶点的新型乳腺癌分子探针的构建及其PET显像研究

Breast cancer has become a sever disease that threats to women's health. Early diagnosis and positive intervention of breast cancer will greatly increase the survival rate of patients. One of the most important breast cancer imaging agent, 18F-fluoroestradio,however is unable to image estrogen receptor (ER) negative breast cancer that accounts for 30~40% of breast cancer patients. Therefore, the development of positron emission tomography (PET) probes that can image both ER(+) and ER(-) breast cancer has important research significance. Based on our preliminary data, we aim to synthesize a small library of dual-targeting inhibitors which are able to specifically interact with both ER and histone deacetylase (HDAC). These inhibitors will then be screened and lead compounds will be selected for labeling with PET radionuclide 18F to generate PET imaging probes for breast cancer. Subsequently, their targeting properties will be studied in vitro and in vivo. By using microPET, the biodistribution and in vivo imaging properties of the probes will be investigated. Compared to single-targeting probes, dual-targeting probes can more accurately reflect and describe the complex phenomenon of life, improve the signal ratio between target and non-target, increase the total number of binding sites, improve the ability of tumor detection and the effect of molecular imaging. Such studies on this important biomarker will hopefully be helpful to move these new dual-targeting probes to the clinic for breast cancer.

乳腺癌已成为危及女性生命健康最常见的恶性肿瘤之一，因此若能实现对乳腺癌的早期诊断并积极干预，会极大提高患者的生存率。目前开发的乳腺癌分子探针18F-氟雌二醇对雌激素受体为阴性的乳腺癌不能显像，而这类患者占乳腺癌总患者的30~40%。因此，开发出对雌激素受体(ER)为阴性和阳性均能显像的PET分子探针具有重要的研究意义。本项目基于前期研究，以雌激素受体和组蛋白去乙酰化酶(HDAC)为双靶点，拟合成一系列氟-18标记的双靶点乳腺癌 PET分子探针，进一步在细胞水平和活体动物研究它们的靶向性。并借助microPET设备，检测合成的分子探针在荷瘤裸鼠的体内分布及PET显像情况。与单靶标分子探针相比，双靶点的分子探针能够更准确地反映和描述复杂的生命现象，提高靶/非靶信号比、增加结合位点总数、提高肿瘤的探测能力、改善分子显像效果。总之，本课题有望研发出具有临床转化潜力的双靶点乳腺癌PET分子探针。

癌症包括乳腺癌是一种发病机制高度复杂、多基因调控的疾病，涉及到多种交叉信号通路。针对单疾病组织细胞中某一种特异性靶分子设计合成的特异单靶分子显像剂，即单靶分子显像，尽管在疾病的诊断和疗效监测等方面发挥了重要的作用，但是单靶分子显像在本质上仍存在不足，它不能够准确地反映和描述出复杂的生命现象。本项目以雌激素受体 (ER)和组蛋白去乙酰化酶 (HDAC)为靶点拟合成双靶点乳腺癌分子探针，并进一步在细胞水平和活体动物研究它们的显像情况。在项目的实施过程中，我们首先对雌激素的靶向配体进行了筛选，确定了炔雌二醇为ER配体，进一步通过荧光分子成像证明了炔雌二醇能够对ER (+)的乳腺癌具有靶向特异性，其相应的荧光探针IRDye800CW-E2能够实现乳腺癌的成像；随后，我们对HDAC进行研究，发现HDAC抑制剂SAHA和SelSA对ER (+)和三阴性乳腺癌均具有靶向特异性，其对应荧光探针IRDye800CW-SAHA、IRDye800CW-SelSA能够实现对ER (+)和三阴性乳腺癌的成像；接着，我们构建了基于ER和HDAC的双靶向缀合物，并用18F进行标记得到了探针7α-18F-MEED-HDACi，PET成像的初步结果表明该探针能用于ER (+)和三阴性乳腺癌的成像。在本项目的支持下，共发表了SCI研究论文5篇，同时还被接收了1篇，并申请了专利1项。