MRI fluorescence tomography for quantifying tumor receptor concentration in vivo

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体化癌症治疗努力的主要焦点。参与细胞增殖和程序性死亡的受体通常是抗体疗法的靶点，新的治疗方式试图利用这种异常来优先向肿瘤细胞递送毒性有效载荷。然而，由于肿瘤脉管系统和渗漏的复杂性，非侵入性地量化这些受体的可用性的能力仍然是难以捉摸的， 排除了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的非侵入性MRI耦合光学成像方法，该方法可解释造影剂的药代动力学，从而能够量化表面下肿瘤中的受体浓度和可用性。这种能力是通过对同时注射的两种荧光示踪剂的动力学进行成像来实现的，一种荧光示踪剂靶向感兴趣的受体，另一种荧光示踪剂靶向非靶向的对应物。将时程数据拟合到双示踪剂房室模型允许恢复可用于结合的细胞受体的密度。非侵入性地检测这一参数可能对药物开发计划甚至临床实践产生深远的影响，从而能够表征和跟踪肿瘤中的药物靶点。该项目的目的是推进和验证该技术的各个方面。具体而言，将开发、验证一种新型、低成本的多光谱荧光断层扫描系统，专门用于临床前MRI研究扫描仪中的MRI引导双示踪剂荧光断层扫描（MRg-DTFT），并用于探索对新癌症疗法的分子反应。将使用多示踪剂体模并通过比较体内动物图像与离体组织切片的共配准荧光成像来评估仪器的成像性能。重要的开发工作也将针对优化图像处理和重建算法所需的完全集成的磁共振成像光学图像恢复和分析的双示踪剂的方法，最终目标是实现一键参数恢复和可视化。这些工具将被部署，以进一步验证双示踪剂的方法，通过广泛的动物实验，检查受体密度在多个原位胶质母细胞瘤肿瘤已知具有不同的受体表达谱和血管结构。最后，这种独特的能力将被用来研究一种新兴的肿瘤穿透治疗佐剂对可用受体密度的影响。

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.