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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要星形细胞胶质瘤是最常见的恶性脑肿瘤类型。即使接受治疗，平均最恶性的预期寿命仅为15个月。高级别胶质瘤尤其复杂由于其浸润性和可及性较低（即血脑屏障、颅骨），无法进行诊断和治疗。由当人们意识到时，肿瘤已经相当晚期了。标准护理是手术切除肿瘤，然后进行化疗/放疗，最决定性的预后因素是切除程度。更深入的了解为了开发更有效和个性化的治疗方法，对分子景观的研究是必要的。在此外，有针对性的高对比度试剂将用于手术切除，其中精确切除所有且仅癌组织至关重要。研究人员已经发现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。如果合并到可激活探针中，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，外科医生就可以更容易消除所有癌症，从而延长寿命并降低缓解率。一种这样的生物标志物是组织蛋白酶 B 是一种参与细胞蛋白质周转的溶酶体半胱氨酸蛋白酶，在高度恶性脑胶质瘤，并被证明参与肿瘤的侵袭和迁移。因此，我们的目标是合成一种新型分子探针，对星形胶质细胞瘤中的组织蛋白酶 B 活性进行成像。该探针有几个关键组件：荧光团、放射性正电子发射器、肽载体使其能够穿过血脑屏障，并且是组织蛋白酶 B 能够特异性识别和识别的底物劈开。该探针将利用有机化学、化学生物学和放射化学合成及其结构将使用标准技术（例如核磁共振和质谱）进行验证。对其评价细胞和小鼠癌症模型的光物理和药理学特性也将随之而来。探针组装完毕后，将进行放射性标记，并静脉注射到测试对象体内。这探针将到达大脑，在陪伴下穿过血脑屏障，进入组织蛋白酶所在的肿瘤 B将切割特定的底物。一旦被切割，探针就会自毁（分解）并发出荧光。这探针还具有放射性标记，可以使用正电子发射断层扫描进行检测。这允许探针后来用于人体，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。该探针采用模块化设计，这意味着可以更换底物以针对不同的酶兴趣。这种普遍化的策略意义重大，适用于多种人类疾病和癌症，特别是在后人类基因组计划时代，现已鉴定出数百种生物标志物。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Near-infrared Fluorophores for Thrombosis Diagnosis and Therapy.

用于血栓诊断和治疗的近红外荧光团。

DOI：
发表时间：
2021-05
期刊：
影响因子：
4.6
作者：
Sun, Bin;Hettie, Kenneth S;Zhu, Shoujun
通讯作者：
Zhu, Shoujun

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

使用 NIR-I 荧光免疫偶联物靶向颅内患者来源的胶质母细胞瘤 (GBM)，以促进其图像引导切除。

DOI：
发表时间：
2020-11-22
期刊：
影响因子：
3.9
作者：
Hettie, Kenneth S;Teraphongphom, Nutte Tarn;Ertsey, Robert D;Rosenthal, Eben L;Chin, Frederick T
通讯作者：
Chin, Frederick T

Near-Infrared Fluorescent Rosol Dye Tailored toward Lymphatic Mapping Applications.

DOI：
10.1021/acs.analchem.8b05709
发表时间：
2019-01-23
期刊：
Analytical chemistry
影响因子：
7.4
作者：
Kenneth S. Hettie;Jessica L. Klockow;T. Glass;F. Chin
通讯作者：
F. Chin

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.

对在 NIR-I 光谱区域具有峰值荧光发射的免疫缀合物进行非峰值近红外-II (NIR-II) 生物成像，以改善肿瘤边缘描绘。

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

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

厚度传感夹层等离子体生物传感器可实现无标记肉眼抗体定量。

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