以甘氨酸脱羧酶为靶点的癌症早期诊断分子探针的研究

Non-invasive detection of cancer stem cells (CSC) is of great importance for cancer treatment, nevertheless is still a long-standing challenge in clinics. PET is a cutting-edge imaging technique that produces a 3-D image of functional processes in the body, and can distinguish diseased region from health tissue with great sensitivity. The most broadly used PET tracer is 18F-2-fluorodeoxyglucose (FDG). It is now the gold standard for PET neuroimaging and cancer patient management. However, [18F]FDG is not able to detect CSC as glucose metabolism is inactive in CSC. To discover a CSC specific PET tracer, here we describe a new glycine mimics—boron derived glycine (B-Gly), that is designed to serve as a specific imaging probe for Glycine Decarboxylase (GLDC). GLDC is recently reported as a specific marker for CSC. It is required for CSC growth and plays an essential role of promoting cellular transformation and tumorigenesis. GLDC catalyzes a chemical reaction, of which the two substrates are glycine and H-protein-lipoyllysine, whereas its two products are H-protein-S-aminomethyldihydro lipoyllysine and CO2. The structure of B-Gly is identical to that of glycine, except for a replacement of the carboxylate with trifluoroborate, which is an isostereo of carboxylate. According to our hypothesis, B-Gly can participate the decarboxylation progress but would not finish the complete reaction. Consequently, 18F-labelled B-Gly is metabolically trapped within GLDC and therefore highlight GLDC by using the radioactive signal from 18F isotope. In our previous study, B-Gly exhibits strong stability under both in vitro and in vivo conditions. The cellular uptake of B-Gly follows the similar pathway as Gly, suggesting that B-Gly holds great promise for the development of new imaging probe for targeting GLDC under in vivo conditions. In this proposal, a novel PET imaging probe is expected to be discovered for CSC and guiding corresponding treatments.

癌症的早期诊断是癌症治疗的关键，也是临床中面临的一个重大难题。本课题拟借助于放射性分子成像技术，以三氟化硼和羧酸根的生物相似性为基础，发展针对肿瘤干细胞（CSC）的放射性分子探针。作为CSC的特异性靶点，甘氨酸脱羧酶（GLDC）在CSC上有着特异性的高表达。为了实现对GLDC的特异性识别，我们将甘氨酸中的羧基替换为三氟化硼，得到的硼甘氨酸（B-Gly）与甘氨酸（Gly）具有相似的化学结构，其可以做为GLDC的底物进入脱羧过程。本项目将通过建立GLDC高表达的细胞株以及活体动物成像实验，研究B-Gly与Gly的生物相似性，并通过放射性标记在活体上验证B-Gly的成像能力及其组织摄取与GLDC表达的定量关系。本课题将证实我们提出的“18F标记的B-Gly可特异性地识别CSC中的GLDC，并可通过放射性成像对CSC完成特异性识别”的假说, 为CSC的活体侦测以及癌症的早期诊断提供新思路。

糖尿病已成为我国三大慢性流行性疾病之一，严重影响我国国民健康建设，同时，传统的糖尿病防治手段存在确诊时间滞后，缺乏直接诊断手段的严重问题。因此，新型的精确、长时程的糖尿病指标检测手段的研发，是糖尿病医疗领域亟待解决的问题。近年来，新型硼氨酸PET分子探针为简单氨基酸的放射性标记带来了福音。针对甘氨酸在血糖调节中的重要作用，本课题利用硼氨酸分子基础开发新型甘氨酸衍生物PET探针——[18F]FBG，并用于胰岛的体内示踪与定量研究，[18F]FBG在小鼠胰腺中的摄取量与活性胰岛β细胞数量呈线性相关。该方法具有无创性、简便安全以及普适性等重要优势。与经典的血糖检测手段相比，该技术可以对正常胰岛的早期损伤病变进行检测，适用于早期的糖尿病高危人群筛查；同时可以避免胰岛移植过程中外源修饰胰岛带来的潜在风险，对糖尿病防治具有重要意义，对我国糖尿病医疗领域的发展有着重大的推动作用。在该项目的支持和启发下，团队提出了“探测/激活一体化”的理念，在国际上首次报道了基于脱硅反应的活体化学。该策略赋予了18F-硼氨酸等影像探针激活功能，实现了放射性分子影像引导的肿瘤靶向的前药可控释放和蛋白功能靶向激活，揭示了细胞焦亡的抗肿瘤免疫功能 (Nature, 2020, 579, 421–426；J Am Chem Soc, 2021, 143, 2250–2255；Angew Chem Int Ed, 2021, 133, 19903–19911)。该工作基于化学、生命科学与核科学的交叉融合，探索了放射性药物研究的新方向，显示出放射化学工具解决生命科学难题的优势。