Molecular Fluorescence-Guided Surgery Platform

分子荧光引导手术平台

• 批准号: 8649029
• 负责人: KEITH D. PAULSEN
• 金额: $ 55.02万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-08 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8649029
• 关键词: Advanced Development; Aminolevulinic Acid; Animal Model; Animals; Binding; Biological; Biological Assay; Biological Markers; Biomedical Engineering; Cell Surface Receptors; Clinical; Clinical Trials; Contrast Media; Detection; Development; Development Plans; Discipline of Nuclear Medicine; Disease; Dose; Drug Kinetics; Engineering; Epidermal Growth Factor Receptor; Excision; Fluorescence; Fluorescent Dyes; Glioma; Human; Image; Injection of therapeutic agent; Institution; Intellectual Property; Investigational Drugs; Malignant Neoplasms; Methods; Microscope; Modality; Molecular; Molecular Probes; New Drug Approvals; North America; Nuclear; Operative Surgical Procedures; Oral; Outcome; Pathway interactions; Patients; Peptide Synthesis; Peptides; Pharmaceutical Preparations; Phase; Positioning Attribute; Positron-Emission Tomography; Procedures; Process; Production; Proteins; Recurrence; Research Infrastructure; Resected; Risk; Series; Signal Transduction; Specificity; Specimen; Strategic Planning; Surgical Oncology; Technology; Testing; Time; Toxicity Tests; Tracer; Translations; Xenograft procedure; absorption; base; brain tumor resection; cost; cost effective; efficacy testing; experience; fluorescence imaging; fluorophore; in vivo; industry partner; medical schools; molecular imaging; neurosurgery; novel; oncology; pre-clinical; primary outcome; protoporphyrin IX; public health relevance; single photon emission computed tomography; success; tumor

DESCRIPTION (provided by applicant): This Academic-Industrial Partnership (AIP) for the development and translation of molecularly-targeted optically-fluorescent imaging agents, GMP-produced for guiding surgical resection in phase 0 clinical trials. While recent advances in the technology for guiding surgical oncology will establish an efficient pipeline have been impressive, significant limitations remain in determining, intraoperatively, the biological margins of disease. Fluorescence-guided surgical resection based on protoporphyrin IX production in high-grade gliomas has highlighted the potential promise of the approach to the extent that intraoperative fluorescence imaging, with both red and infrared channels, is now available on state-of-the-art surgical microscopes manufactured by Leica and Zeiss. Despite these rapid advances, development of the molecular tracers that are required to guide surgical procedures has been lacking. The basis of this application and the underlying tenet of the proposed AIP are that a cost-effective, risk-diluted approach to and cost-effective testing contrast agent development and are needed in order to realize the promise of fluorescence-guidance during surgery. The testing will be carried out with end-points of surgical testing in phase 0 micro dosing studies signal detection and binding specificity being the primary outcomes from the phase 0 trials. Rapid testing is critical because most agents will not be successful, and we need a strategy to reduce the time, cost and risk required to quickly assess targeting efficacy in early human surgical trials. Creation of such a pipeline process stands to accelerate dramatically the paradigm shift to molecular-guided surgical oncology that will revolutionize both the procedures that are possible and the surgical outcomes that will result. The proposed AIP between Dartmouth (Engineering and Medical Schools), Affibody AB, and LI-COR brings together 3 partners who have the intellectual property (IP), expertise and infrastructure to develop, test and advance molecularly-targeted fluorescent tracers for surgical guidance. The first agent we will advance will be an affibody molecule (created and extensively characterized in animals by Affibody, AB, and currently undergoing nuclear imaging studies in humans) targeted to the epidermal growth factor receptor (EGFR) conjugated with a fluorescent dye (systematically developed by LI-COR for human use) with absorption and emission spectra in the near infrared. The compound will be developed and produced through peptide synthesis under GMP conditions, single administration toxicity testing in requisite animal models will be completed, and a first-in-human phase 0 dose escalation study will be pursued at Dartmouth under exploratory investigational new drug (eIND) approval from the FDA.

描述（由申请人提供）：这种学术工业合作伙伴关系（AIP）用于开发和翻译分子靶向光荧光成像剂，GMP生产用于指导0阶段临床试验中的指导外科手术切除。尽管指导外科肿瘤学技术的最新进展将建立有效的管道令人印象深刻，但在术中确定生物学边缘仍然存在重大局限性 疾病。荧光引导的基于原生态IX在高级神经胶质瘤中产生的外科手术切除，突显了该方法的潜在希望，即术中荧光成像（均具有红色和红外通道）的术中荧光成像，现在可以在由Leica和Zeiss制造的先进的手术显微镜上获得。尽管有这些快速的进步，但仍缺乏指导外科手术所需的分子示踪剂的发展。该应用程序的基础和拟议的AIP的基本宗旨是，采用成本效益，风险降低的方法和具有成本效益的测试对比剂开发，以实现手术期间荧光引导的承诺。该测试将在0阶段的微量剂量研究信号检测和结合特异性中以手术测试的终点进行，这是0阶段试验的主要结果。快速测试至关重要，因为大多数代理商都不会成功，我们需要一项策略来减少快速评估早期定位疗效所需的时间，成本和风险 人类手术试验。这样的管道过程的创建可以显着加速范式向分子引导的手术肿瘤学转变，这将彻底改变可能的过程和将会导致的手术结果。达特茅斯（工程和医学院），Affibododody AB和Li-Cor之间的AIP汇集了3个具有知识产权（IP），专业知识和基础设施的合作伙伴，以开发，测试和 提前分子靶向荧光示踪剂，用于手术指导。我们将提出的第一个代理将是一种杂骨分子（在动物中创建和广泛特征是通过Abs，AB和目前在人类中进行核成像研究的），其针对表皮生长因子受体（EGFR），与荧光染料（由Li-Cor进行人使用的人类使用）与吸收和发射光谱相结合。该化合物将在GMP条件下通过肽合成开发和生产，将在必要的动物模型中完成单个给药毒性测试，并且将在Dartmouth进行第一阶段0剂量升级研究，并在FDA获得探索性研究新药（EIND）批准。