MRI fluorescence tomography for quantifying tumor receptor concentration in vivo

MRI 荧光断层扫描用于量化体内肿瘤受体浓度

• 批准号: 8828624
• 负责人: Scott C Davis
• 金额: $ 50.64万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8828624
• 关键词: Accounting; Adjuvant; Algorithms; Animal Experiments; Animal Model; Animals; Antibody Therapy; Binding; Blood Vessels; Brain Neoplasms; Cell Proliferation; Cell Surface Receptors; Cessation of life; Clinical; Clinical Treatment; Complex; Contrast Media; Coupled; Data; Development; Drug Kinetics; Drug Targeting; Enhancing Antibodies; Extravasation; Fluorescence; Glioblastoma; Glioma; Gold; Health; Image; Imagery; Imaging technology; Immunoblotting; Individual; Kinetics; Magnetic Resonance Imaging; Manuals; Measurement; Measures; Methodology; Modality; Modeling; Molecular; Molecular Profiling; Monitor; One-Step dentin bonding system; Peptides; Performance; Pharmaceutical Preparations; Process; Recovery; Reporting; Research; Resolution; Slice; Solid Neoplasm; Structure; Surface; System; Techniques; Technology; Testing; Therapeutic; Time; Tissues; Tracer; U251; Up-Regulation; Validation; Work; animal imaging; base; cancer therapy; clinical practice; cost; cost effective; density; design; drug development; experience; fluorescence imaging; fluorescence molecular tomography; gliosarcoma; image processing; image reconstruction; imaging Segmentation; imaging agent; imaging software; improved; in vivo; instrument; interest; molecular imaging; neoplastic cell; next generation; non-invasive imaging; novel; open source; optical imaging; personalized cancer therapy; pharmacokinetic model; pre-clinical; programs; quantitative imaging; receptor; receptor density; receptor expression; response; targeted imaging; targeted treatment; tomography; tool; tumor; tumor growth

DESCRIPTION (provided by applicant): The abnormal expression of cell surface receptors on tumor cells has become a major focus of efforts to individualize cancer therapy. Receptors involved in cell proliferation and programmed death are commonly targeted with antibody therapies, and new treatment modalities seek to exploit this abnormality to preferentially deliver toxic payloads to tumor cells. However, because of the complexity of tumor vasculature and leakage, the ability to noninvasively quantify the availability of these receptors remains elusive, precluding quantitative characterization and longitudinal monitoring of tumor receptor concentration. This project aims to advance a novel noninvasive MRI-coupled optical imaging approach that accounts for contrast agent pharmacokinetics and thus is capable of quantifying receptor concentration and availability in sub-surface tumors. This capability is enabled by imaging the kinetics of two fluorescent tracers injected simultaneously, one targeted to the receptor of interest, and the other to a non-targeted counterpart. Fitting the time course data to a dual-tracer compartmental model allows the recovery the density of cellular receptors available for binding. Accessing this parameter noninvasively could have a profound impact on drug development programs and even clinical practice, enabling characterization and tracking of drug targets in tumors. The aims in this project are designed to advance and validate all aspects of this technology. Specifically, a novel, low cost multispectral fluorescence tomography system dedicated to MRI-guided dual tracer fluorescence tomography (MRg-DTFT) in preclinical MRI research scanners will be developed, validated and used to explore the molecular response to new cancer therapies. Imaging performance of the instrument will be assessed using multi-tracer phantoms and by comparing in vivo animal images to co-registered fluorescence imaging of ex-vivo tissue slices. Significant development effort will also be directed towards optimizing the image processing and reconstruction algorithms required for fully integrated MRI-optical image recovery and analysis for the dual-tracer approach, with the ultimate aim of enabling one-click parameter recovery and visualization. These tools will be deployed to further validate the dual-tracer approach through extensive animal experiments which examine receptor density in multiple orthotopic glioblastoma tumors known to have varying receptor expression profiles and vascular structure. Finally, this unique capability will be deployed to investigate the effect an emerging tumor- penetrating therapeutic adjuvant has on available receptor density.

描述（由申请人提供）：肿瘤细胞上细胞表面受体的异常表达已成为个性化癌症治疗的主要努力。与细胞增殖和程序性死亡有关的受体通常采用抗体疗法的靶向，而新的治疗方式试图利用这种异常，以优先将有毒的有效载荷递送到肿瘤细胞中。但是，由于肿瘤脉管系统和泄漏的复杂性，无创量化这些受体的可用性的能力仍然难以捉摸， 排除肿瘤受体浓度的定量表征和纵向监测。该项目旨在推进一种新型的非侵入性MRI耦合光学成像方法，该方法解释了对比剂药代动力学，因此能够量化地下表面肿瘤中受体浓度和可用性。通过对两个同时注入的荧光示踪剂的动力学进行成像，一个靶向感兴趣的受体，而另一个则源于非目标对应物，可以实现此能力。将时间过程数据拟合到双轨道隔室模型中，可以恢复可用于结合的细胞受体的密度。非侵入性访问此参数可能会对药物开发计划甚至临床实践产生深远的影响，从而使肿瘤中药物靶标的表征和跟踪。该项目的目标旨在推进和验证该技术的所有方面。具体而言，将在临床前MRI研究扫描仪中使用专门用于MRI引导的双示踪荧光断层扫描（MRG-DTFT）的新型低成本多光谱荧光断层扫描系统，并将经过验证，验证并用于探索分子对新癌症治疗的反应。该仪器的成像性能将使用多跟踪器幻象进行评估，并通过比较体内动物图像与Ex-Vivo组织切片的共注册荧光成像进行比较。重大开发工作还将用于优化对双追踪方法完全集成的MRI光学图像恢复和分析所需的图像处理和重建算法，以实现一键式参数恢复和可视化的最终目的。这些工具将通过广泛的动物实验来进一步验证双跟踪方法，该实验检查了多种原位胶质母细胞瘤肿瘤中的受体密度，已知具有变化的受体表达谱和血管结构。最后，将部署这种独特的能力来研究新兴的肿瘤穿透性治疗辅助对可用受体密度的影响。