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: 10215378
• 负责人: Kenneth Scott Hettie
• 金额: $ 5.06万
• 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 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10215378
• 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; Imaging Device; In Vitro; 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; Oncology; 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; Visualization; 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 facilities; imaging probe; imaging study; imaging system; in vitro Assay; in vivo; in vivo imaging; inhibitor/antagonist; innovation; interest; member; microPET; migration; molecular imaging; mouse model; multimodality; novel; optical imaging; overexpression; personalized medicine; preclinical imaging; 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 星形胶质细胞瘤是最常见的恶性脑肿瘤。即使接受治疗，平均 恶性程度最高者的预期寿命只有15个月。高级别胶质瘤尤其复杂 由于它们的渗透性质和低可及性（即，血脑屏障、颅骨）。由 当它被意识到时，肿瘤已经相当晚期了。标准治疗是手术切除肿瘤， 化疗/放疗，最确定的预后因素是切除程度。一种更伟大理解 为了开发更有效和个性化的治疗方法，分子景观是必要的。在 此外，靶向高对比剂将用于外科切除，其中精确去除所有且仅 癌组织至关重要 研究人员已经确定了许多可以区分癌组织和健康组织的生物标志物 并作为预后标志物。如果掺入可活化探针中，这些生物标志物可用于 荧光引导手术，使癌组织的可视化更加明显。这样的话，外科医生 更容易去除所有的癌症，从而延长寿命并降低缓解率。其中一种生物标志物是 组织蛋白酶B，一种参与细胞蛋白质周转的溶酶体半胱氨酸蛋白酶，在高表达的细胞中过表达。 恶性脑胶质瘤，并显示参与肿瘤的侵袭和迁移。因此，我们的目标是 合成一种新分子探针以成像星形胶质细胞瘤中的组织蛋白酶B活性。 探针有几个关键组成部分：荧光团，放射性正电子发射体，肽载体 使其能够穿过血脑屏障，以及组织蛋白酶B特异性识别的底物， 劈开该探针将使用有机化学、化学生物学和放射化学合成， 将使用标准技术（例如，NMR和质谱法）。评价其 细胞和鼠癌症模型中的生物物理学和药理学性质将随后进行。 一旦组装好探针，将对其进行放射性标记，并静脉注射到受试者体内。的 探针将行进到大脑，伴随着穿过血脑屏障，并进入组织蛋白酶 B将裂解特定底物。一旦被切割，探针自分解（分解）并发出荧光。的 探针还具有可以使用正电子发射断层扫描检测的放射性标记。这允许 探针将在以后用于人类，因为它的信号可以更好地穿透人体的组织，骨骼和器官 身体探针具有模块化设计，这意味着底物可以交换以靶向不同的酶， 兴趣这种可推广的策略是重要的，并且适用于各种人类疾病和癌症， 特别是在人类基因组计划后的时代，现在已经确定了数百种生物标志物。

项目成果

Thickness-Sensing Sandwiched Plasmonic Biosensors Enable Label-Free Naked-Eye Antibody Quantification.

• DOI: 10.1021/acs.nanolett.2c03732
• 发表时间: 2022-12-14
• 期刊: NANO LETTERS
• 影响因子: 10.8
• 作者: Nan, Jingjie;Sun, Weihong;Liu, Xin;Che, Yuanyuan;Shan, Hongli;Yue, Ying;Liu, Jiaxin;Wang, Lei;Liu, Kun;Xu, Wei;Zhang, Wenyan;Zhang, Songling;Liu, Bin;Hettie, Kenneth S.;Zhu, Shoujun;Zhang, Junhu;Yang, Bai
• 通讯作者: Yang, Bai

Targeting intracranial patient-derived glioblastoma (GBM) with a NIR-I fluorescent immunoconjugate for facilitating its image-guided resection.

用NIR-I荧光免疫偶联物靶向颅内患者衍生的胶质母细胞瘤（GBM），以促进其图像引导的切除。

• DOI: 10.1039/d0ra07245a
• 发表时间: 2020-11-22
• 期刊: RSC advances
• 影响因子: 3.9
• 作者: Hettie KS;Teraphongphom NT;Ertsey RD;Rosenthal EL;Chin FT
• 通讯作者: Chin FT

Off-Peak Near-Infrared-II (NIR-II) Bioimaging of an Immunoconjugate Having Peak Fluorescence Emission in the NIR-I Spectral Region for Improving Tumor Margin Delineation.

• DOI: 10.1021/acsabm.0c01050
• 发表时间: 2020-12-21
• 期刊: ACS APPLIED BIO MATERIALS
• 影响因子: 4.7
• 作者: Hettie, Kenneth S;Teraphongphom, Nutte Tarn;Ertsey, Robert;Chin, Frederick T
• 通讯作者: Chin, Frederick T