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

项目总结 星形细胞胶质瘤是最常见的恶性脑肿瘤类型。即使经过治疗，平均来说 最恶性级别的预期寿命只有15个月。高级别胶质瘤尤其复杂。 由于其浸润性和低可及性(即血脑屏障、头骨)而难以诊断和治疗。由 一旦意识到这一点，肿瘤就相当晚期了。护理的标准是手术切除肿瘤，然后是 化疗/放疗，最有说服力的预后因素是切除的程度。更好的理解 为了开发更有效和个性化的治疗方法，分子景观的研究是必要的。在……里面 此外，靶向高对比剂将用于手术切除，准确地切除所有和仅 癌组织是至关重要的。 研究人员已经确定了许多可以区分癌症组织和健康组织的生物标志物 并可作为预后标志物。如果结合到可激活的探针中，这些生物标记物可以用于 荧光引导手术，使癌症组织的可视化更加明显。那样的话，外科医生 更容易切除所有可延长寿命和降低缓解率的癌症。其中一个生物标志物是 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 恶性脑胶质瘤，并被证明与肿瘤的侵袭和转移有关。因此，我们的目标是 合成一种新的分子探针以显示星形细胞胶质瘤中组织蛋白酶B的活性。 该探测器有几个关键组件：一个荧光团，一个放射性正电子发射器，一个多肽载体 这使得它能够穿过血脑屏障，组织蛋白酶B将专门识别和 克利夫。该探针将使用有机化学、化学生物学和放射化学合成，并将其 将使用标准技术(例如，核磁共振和质谱学)来验证结构。智能交通系统的评价 接下来将研究细胞和小鼠癌症模型中的光物理和药理学特性。 一旦探针组装完成，它将被放射性标记，并被静脉注射到受试者体内。这个 探针将到达大脑，被陪伴着穿过血脑屏障，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，探针就会自焚(解体)并发出荧光。这个 探测器也有一个放射性标签，可以使用正电子发射断层扫描进行检测。这允许 稍后在人类身上使用的探头，其信号可以更好地穿透人体的组织、骨骼和器官 尸体。该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 利息。这一可概括的策略是重要的并且适用于各种人类疾病和癌症， 尤其是在后人类基因组计划时代，现在已经识别了数百个生物标记物。

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.