MRI fluorescence tomography for quantifying tumor receptor concentration in vivo

项目总结/摘要 肿瘤细胞表面受体的异常表达已成为肿瘤治疗的主要焦点。 个性化癌症治疗的努力。参与细胞增殖和程序化的受体 死亡通常是抗体治疗的目标，新的治疗方式寻求 利用这种异常来优先向肿瘤细胞递送毒性有效载荷。但由于 由于肿瘤血管系统和渗漏的复杂性， 这些受体的可用性仍然难以捉摸，排除了定量表征， 肿瘤受体浓度的纵向监测。这个项目旨在推进一部小说 考虑造影剂的无创MRI耦合光学成像方法 因此能够定量受体浓度和在体内的可用性。 皮下肿瘤通过对两种荧光示踪剂的动力学进行成像， 同时注射，一种靶向感兴趣的受体，另一种靶向非靶向受体。 对应物。将时间过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。删除此参数 非侵入性地可能对药物开发计划甚至临床 实践，使表征和跟踪肿瘤中的药物靶点。这其中的目的 项目旨在推进和验证这项技术的各个方面。特别是 新型低成本多光谱荧光断层扫描系统，专用于MRI引导的双 临床前MRI研究扫描仪中的示踪剂荧光断层扫描（MRg-DTFT）将在 开发、验证并用于探索对新癌症疗法的分子反应。 仪器的成像性能将使用多示踪剂体模进行评估， 将体内动物图像与离体组织切片的共配准荧光成像进行比较。 重要的开发工作也将致力于优化图像处理， 完全集成的MRI-光学图像恢复和分析所需的重建算法 对于双示踪剂方法，最终目标是实现一键参数恢复， 视觉化将部署这些工具，通过以下方式进一步验证双重跟踪方法： 广泛的动物实验，检查受体密度在多个原位 已知成胶质细胞瘤肿瘤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部署来研究新出现的肿瘤的影响- 穿透性治疗佐剂没有可用的受体密度。

Project Summary/Abstract 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.