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: 9111703
• 负责人: Peter Nakaji
• 金额: $ 23.25万
• 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 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9111703
• 关键词: Address; Admission activity; Affect; Affinity; American; Animal Model; Arizona; 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; Nanostructures; Nanotechnology; Neuraxis; Neurologic; Neurosurgeon; North America; One-Step dentin bonding system; Operative Surgical Procedures; Paraffin Embedding; Pathologist; Pathology; Patient Care; Patient risk; Patients; Physicians; Polynucleotides; Protocols documentation; Research; Residencies; Scientist; Specificity; Staining method; Stains; Structure; Surgeon; Techniques; Testing; Time; Tissues; Translating; United States; Universities; Xenograft procedure; aptamer; base; cancer imaging; chemotherapy; clinical care; clinically relevant; contrast imaging; design; extracellular; fluorescence imaging; fluorophore; human tissue; improved; innovation; meetings; nanoprobe; neurosurgery; novel; novel diagnostics; programs; public health relevance; rapid diagnosis; research study; 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）：医生需要对癌症患者进行快速和特异性的组织病理学诊断。例如，开放手术活检可能包含与术中决策有关的诊断信息，例如手术切除与保守治疗。但标准的快速诊断冷冻切片可能无法区分相关的病理。通过免疫组织化学（IHC）进行标准特异性诊断可能需要数天时间才能提供这些数据。这种情况可能会否定在开放活检时做出正确决策的关键信息。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的切除，但淋巴瘤最好不切除。误诊可能导致不必要的功能脑切除或错过侵袭性恶性肿瘤的积极切除。快速提供相关诊断信息的方法将改善临床护理。该项目开发了纳米探针，可以快速提供来自新鲜肿瘤活检的诊断组织病理学信息。适体是一类新兴的多核苷酸，易于工程化以鉴定特异性分子靶标。最近的方法让适体在结合目标时转换构象，这种变化可以提供成像对比度。我们的项目旨在产生可转换的适体造影剂，检测临床相关的细胞外和细胞内的IHC目标1开发了一种可转换的适体，快速检测新鲜异种移植组织活检中人类中枢神经系统淋巴瘤的细胞外标志物。目的2开发针对星形细胞瘤细胞内标志物胶质细胞酸性蛋白（GFAP）的可转换适体。我们计划使用DNA四面体纳米结构将GFAP特异性适体快速递送到细胞内空间。这两个目标都优化了异种移植活检的快速适体标记。该项目开发了可转换适体作为快速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，评估基于适体的诊断在最初的开颅手术中的决策，脑诊断和/或切除。 这项提案汇集了来自巴罗神经研究所（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，也是美国最大的脑肿瘤患者之一。BNI一直是推进脑肿瘤成像荧光成像工具的领导者，是北美唯一一家拥有先进蔡司LSM 710/5LiveDUO共聚焦显微镜的病理学中心。生物设计研究所一直是开发DNA纳米技术的领导者，其分子设计和仿生学中心正在创新DNA作为结构材料的使用。BNI和Biodesign Institute之间的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。