Switchable Molecular Nanoprobes for Fast and Specific Intraoperative Diagnosis of Brain Tumors

用于快速、特异性脑肿瘤术中诊断的可切换分子纳米探针

• 批准号: 9222010
• 负责人: Peter Nakaji
• 金额: $ 17.75万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9222010
• 关键词: Address; Admission activity; Affect; Affinity; Alpha Cell; American; Animal Model; Arizona; Astrocytes; Astrocytoma; B-Cell Lymphomas; B-Lymphocytes; Binding; Biomimetics; Biopsy; Blinded; Brain; Brain Neoplasms; Cancer Detection; Cancer Patient; Caring; Cell membrane; Cells; Central Nervous System Lymphoma; Clinical; Clinical Trials; Collaborations; Contrast Media; Coupled; Craniotomy; DNA; Data; Decision Making; Development; Diagnosis; Diagnostic; Engineering; Excision; Fluorescence; Frozen Sections; Future; Glial Fibrillary Acidic Protein; Health Care Costs; Histologic; Hospitals; Hour; Human; Hybrids; Imaging Device; Immunohistochemistry; Incisional Biopsy; Institutes; Intervention; Intracellular Space; Label; Lead; Left; Lesion; Lymphoma; MS4A1 gene; Malignant Neoplasms; Membrane; Methods; Microscope; Molecular; Molecular Conformation; Molecular Nanotechnology; Molecular Target; Morbidity - disease rate; Morphology; Nanostructures; Nanotechnology; Neuraxis; Neurologic; Neurosurgeon; North America; One-Step dentin bonding system; Operative Surgical Procedures; Optics; Paraffin Embedding; Pathologic; Pathologist; Pathology; Patient Care; Patient risk; Patients; Permeability; Physicians; Polynucleotides; Postoperative Period; Protocols documentation; Research; Residencies; Savings; Scientist; Specificity; Staining method; Stains; Structure; Surgeon; Techniques; Testing; Time; Tissue Embedding; Tissues; Translating; Tumor Volume; United States; Universities; Xenograft procedure; aptamer; base; brain volume; cancer care; cancer imaging; cancer therapy; chemotherapy; clinical care; clinically relevant; contrast imaging; design; experimental study; extracellular; fluorescence imaging; fluorophore; improved; innovation; nanoprobe; neurosurgery; novel; novel diagnostics; programs; public health relevance; rapid diagnosis; rapid technique; tool; treatment planning; tumor

 DESCRIPTION (provided by applicant): Physicians need rapid and specific histopathologic diagnoses for their cancer patients. For example, open surgical biopsies may contain diagnostic information bearing on intraoperative decisions such as surgical resection vs conservative treatment. But standard rapid diagnosis by frozen section may not discriminate between relevant pathologies. Standard specific diagnosis by immunohistochemistry (IHC) can take days to provide these data. This situation may deny information critical for good decision making at open biopsy. For example, small cell astrocytomas and central nervous system lymphomas are difficult to distinguish on frozen section. Astrocytomas require aggressive resection, but lymphomas are best left unresected. Misdiagnosis could lead to unnecessary resection of eloquent brain or missed aggressive resection of an invasive malignant tumor. A method that rapidly provides relevant diagnostic information will improve clinical care. This project develops nanoprobes that rapidly provide diagnostic histopathologic information from fresh tumor biopsies. Aptamers are an emerging class of polynucleotides easily engineered to identify specific molecular targets. Recent methods let aptamers switch conformation when they bind a target, and this change can provide imaging contrast. Our project aims to generate switchable aptamer contrast agents that detect clinically relevant extracellular and intracellular IHC targets Aim 1 develops a switchable aptamer that rapidly detects the extracellular marker for human central nervous system lymphoma in fresh xenograft tissue biopsies. Aim 2 develops a switchable aptamer against the intracellular astrocytoma marker glial fibrillary acid protein (GFAP). We plan to rapidly deliver the GFAP-specific aptamer to intracellular space using a DNA tetrahedron nanostructure. Both aims optimize rapid aptamer-based labeling of xenograft biopsies. This project develops switchable aptamers as contrast agents for rapid IHC-quality labeling. Our future plan is to develop a clinical trial evaluating aptamer-based diagnostics on intraoperative decision-making during initial craniotomy for brain diagnosis and/or resection. This proposal brings together physicians and scientists from the Barrow Neurological Institute (BNI) and Arizona State University's (ASU) Biodesign Institute. BNI is the largest Neurosurgery residency program in North America and cares for one of the largest volumes of brain tumor patients in the United States. BNI has been a leader in advancing fluorescence imaging tools for brain tumor imaging, and is the only North American center with an advanced Zeiss LSM710/5LiveDUO confocal microscope situated in the pathology department. The Biodesign Institute has been a leader in developing DNA nanotechnology, and its Center for Molecular Design and Biomimetics is innovating the use of DNA as structural material. This collaboration between BNI and the Biodesign Institute will develop an innovative class of nanomolecules for the rapid diagnosis, and improved care of cancer patients.

 描述(由申请人提供)：医生需要为他们的癌症患者提供快速和具体的组织病理学诊断。例如，开放的手术活检可能包含与术中决定有关的诊断信息，例如手术切除还是保守治疗。但标准的冰冻切片快速诊断可能不能区分相关病理。标准的免疫组织化学特异性诊断(IHC)可能需要几天时间才能提供这些数据。这种情况可能会否定对开腹活检做出良好决策至关重要的信息。例如，小细胞星形细胞瘤和中枢神经系统淋巴瘤在冰冻切片上很难区分。星形细胞瘤需要积极切除，但淋巴瘤最好不要切除。误诊可能导致不必要的能言善辩的脑切除，或错过侵袭性恶性肿瘤的积极切除。一种快速提供相关诊断信息的方法将改善临床护理。这个项目开发了纳米探针，可以从新鲜的肿瘤活检组织中快速提供诊断组织病理学信息。适配子是一类新兴的多核苷酸，很容易被设计成识别特定的分子靶标。最近的方法是让适配子在结合靶标时改变构象，这种改变可以提供成像对比度。我们的项目旨在产生检测临床相关细胞外和细胞内IHC靶点的可切换适配子造影剂。目标1开发一种可切换适配子，在新鲜的异种移植组织活检中快速检测人类中枢神经系统淋巴瘤的细胞外标记。目的2开发一种针对星形细胞瘤细胞内标志胶质纤维酸性蛋白(GFAP)的可切换适配子。我们计划使用DNA四面体纳米结构将GFAP特异性适配子快速输送到细胞内空间。这两个目标都旨在优化异种移植活检的基于适体的快速标记。该项目开发可切换适配子作为快速IHC质量标记的造影剂。我们未来的计划是开发一项临床试验，评估基于适配子的诊断对脑诊断和/或切除的初始开颅术中决策的影响。这项提案汇集了来自巴罗神经学研究所(BNI)和亚利桑那州立大学(ASU)生物设计研究所的医生和科学家。BNI是北美最大的神经外科住院医师计划，也是美国数量最多的脑瘤患者之一。BNI在先进的脑肿瘤成像荧光成像工具方面一直处于领先地位，也是唯一一家在病理科配备先进蔡司LSM710/5LiveDUO共焦显微镜的北美中心。生物设计研究所在开发DNA纳米技术方面一直处于领先地位，其分子设计和生物仿生中心正在创新使用DNA作为结构材料。BNI和生物设计研究所的这项合作将开发一种创新的纳米分子，用于快速诊断和改善癌症患者的护理。

项目成果

Provision of rapid and specific ex vivo diagnosis of central nervous system lymphoma from rodent xenograft biopsies by a fluorescent aptamer.

通过荧光适体对啮齿动物异种移植活检中的中枢神经系统淋巴瘤进行快速、特异性的离体诊断。

• DOI: 10.3171/2020.4.jns192476
• 发表时间: 2020
• 期刊: Journal of neurosurgery
• 影响因子: 4.1
• 作者: Georges,Joseph;Qi,Xiaodong;Liu,Xiaowei;Zhou,Yu;Woolf,EricC;Valeri,Amber;Al-Atrache,Zein;Belykh,Evgenii;Feuerstein,BurtG;Preul,Mark;Scheck,AdrienneC;Reiser,Mark;Anderson,Trent;Gopez,Jonas;Appelt,Denah;Yocom,Steven;Eschbac
• 通讯作者: Eschbac