An 18F PET/NIRF Smart Probe for Identifying, Grading, and Visualizing Astrocytic Gliomas

用于识别、分级和可视化星形胶质细胞瘤的 18F PET/NIRF 智能探头

• 批准号: 9255899
• 负责人: Kenneth Scott Hettie
• 金额: $ 5.71万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9255899
• 关键词: Academia; Address; Animals; Astrocytoma; Autoradiography; Biochemical; Biodistribution; Biological Markers; Biology; Biopsy; Blood - brain barrier anatomy; Brain; Cancer Model; Cancerous; Caspase; Cathepsins; Cathepsins B; Cell Culture Techniques; Cells; Chemicals; Cleaved cell; Clinical; Confocal Microscopy; Contrast Media; Coumarins; Development; Diagnosis; Disease Progression; Disease remission; Enzyme Activation; Enzyme Kinetics; Enzymes; Evaluation; Excision; Fluorescence; Glioma; Goals; Growth; Human; Human Genome Project; Human body; Image; Image Analysis; Imagery; Imaging Device; In Vitro; Injectable; Intravenous; Label; Learning; Life Expectancy; Ligands; Logic; Longevity; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Mass Spectrum Analysis; Measures; Methods; Modality; Molecular; Molecular Chaperones; Molecular Probes; Monitor; Multimodal Imaging; Mus; Nature; Neurologic; Operative Surgical Procedures; Optics; Organ; Organic Chemistry; Organic Synthesis; Peptide Hydrolases; Peptides; Permeability; Pharmacology; Physiological Processes; Positron; Positron-Emission Tomography; Prognostic Factor; Prognostic Marker; Property; Radiation therapy; Radioactive; Radiochemistry; Radiolabeled; Randomized; Recurrence; Research Personnel; Research Training; Role; Signal Transduction; Structure; Surgeon; Techniques; Testing; Time; Tissues; Training; Translations; Travel; Tumor Cell Invasion; Validation; Western Blotting; Work; animal imaging; base; bone; carboxypeptidase C; career; clinical application; cranium; design; effective therapy; enzyme activity; experience; experimental study; fluorescence-guided surgery; fluorophore; human disease; image guided; imaging agent; imaging probe; imaging study; imaging system; in vitro Assay; in vivo; in vivo imaging; inhibitor/antagonist; innovation; interest; member; migration; molecular imaging; mouse model; multimodality; novel; oncology; optical imaging; overexpression; personalized medicine; pre-clinical; protein degradation; response; scaffold; skills; standard of care; targeted imaging; tumor; tumor progression; vector

PROJECT SUMMARY Astrocytic gliomas are the most common type of malignant brain tumor. Even with treatment, the average life expectancy for the most malignant grade is only 15 months. High grade gliomas are especially complicated to diagnose and treat due to their infiltrative nature and low accessibility (i.e., blood brain-barrier, skull). By the time it is realized, the tumor is quite advanced. The standard of care is surgical removal of the tumor followed by chemo/radiotherapy, with the most conclusive prognostic factor being extent of removal. A greater understanding of the molecular landscape is necessary in order to develop more effective and personalized treatments. In addition, targeted high-contrast agents would find use for surgical resections where exact removal of all and only cancerous tissue is vital. Researchers have identified numerous biomarkers that can differentiate cancerous from healthy tissues and serve as prognostic markers. If incorporated into an activatable probe, these biomarkers could be used for fluorescence-guided surgery to make visualization of cancerous tissues more evident. That way, the surgeon is more apt to remove all the cancer which increases lifespan and reduces remission rates. One such biomarker is cathepsin B, a lysosomal cysteine protease that is involved in cellular protein turnover, overexpressed in highly malignant brain gliomas, and shown to be involved in tumor invasion and migration. Therefore, we aim to synthesize a novel molecular probe to image cathepsin B activity in astrocytic gliomas. The probe has several key components: a fluorophore, a radioactive positron emitter, a peptide vector that allows it to cross the blood-brain barrier, and a substrate that cathepsin B will specifically recognize and cleave. The probe will be synthesized using organic chemistry, chemical biology, and radiochemistry and its structure will be verified using standard techniques (e.g., NMR and mass spectrometry). Evaluation of its photophysical and pharmacological properties in cells and murine cancer models will follow. Once the probe is assembled, it will be radiolabeled, and injected intravenously into the test subject. The probe will travel to the brain, be chaperoned across the blood-brain barrier, and enter the tumor where cathepsin B will cleave the specific substrate. Once cleaved, the probe self-immolates (disassembles) and fluoresces. The probe also has a radioactive label that can be detected using positron emission tomography. This allows the probe to be later used in humans as its signal can better penetrate the tissues, bones, and organs of the human body. The probe has a modular design meaning the substrate can be exchanged to target a different enzyme of interest. This generalizable strategy is significant and applicable to a variety of human diseases and cancers, especially in the post-Human Genome Project era when hundreds of biomarkers have now been identified.

项目摘要 星形细胞神经胶质瘤是最常见的恶性脑肿瘤类型。即使接受治疗，平均 最恶性等级的预期寿命仅为15个月。高级神经胶质瘤特别复杂 诊断和治疗由于其渗透性和低可及性（即血液脑障碍物，头骨）。由 它已经实现了，肿瘤非常先进。护理标准是手术切除肿瘤，然后是 化学/放射疗法，最终的预后因素是去除程度。更大的理解 为了开发更有效和个性化的治疗，必须进行分子景观。在 此外，有针对性的高对比剂可以找到用于手术切除术的用途 癌组织至关重要。 研究人员已经确定了许多可以区分癌性与健康组织的生物标志物 并用作预后标记。如果将这些生物标志物纳入可激活的探测器中 荧光引导的手术使癌组织的可视化更为明显。这样，外科医生就是 更容易去除所有癌症，从而增加寿命并降低缓解率。一个这样的生物标志物是 组织蛋白酶B，一种参与细胞蛋白更新的溶酶体半胱氨酸蛋白酶，高度表达高度 恶性脑胶质瘤，并显示与肿瘤侵袭和迁移有关。因此，我们的目标是 在星形细胞神经胶质瘤中合成一个新型分子探针，以形象组织蛋白酶B活性。 该探针具有多个关键成分：荧光团，放射性正电子发射极，肽载体 这使其可以越过血脑屏障，并且是组织蛋白酶B会明确识别和 劈开。该探针将使用有机化学，化学生物学和放射化学及其合成 结构将使用标准技术（例如NMR和质谱法）进行验证。评估它 细胞和鼠类癌模型的光物理和药理特性将随后发生。 一旦组装探针，它将被放射标记，并静脉注射到测试对象中。这 探针将前往大脑，在血脑屏障上伴侣，然后进入肿瘤 B将切割特定的底物。一旦裂开，探测器会自免除（分解）和荧光。这 探针还具有放射性标签，可以使用正电子发射断层扫描检测。这允许 探针以后在人类中使用，因为其信号可以更好地穿透人类的组织，骨骼和器官 身体。探针具有模块化设计，这意味着可以交换底物以靶向不同的酶 兴趣。这种可推广的策略很重要，适用于各种人类疾病和癌症， 特别是在人类后基因组项目时代，现在已经确定了数百种生物标志物。