基于XCT/FMT成像技术的肿瘤组织荧光剂药代动力学关键技术研究

The imaging technology of fluorophore pharmacokinetic parameters based on the fluorescence molecular tomography (FMT) has some potential applications in the fields of early tumor detection, staging, efficient evaluation and dynamic monitoring of biology and pathology information. At present, the research is at the initial stage at home and abroad, and there are some major problems to be solved. The performances strongly rely on the three fundamental factors: the sensitivity, rapidity of the measurement system, the accuracy of the modeling and the robustness of the image reconstruction. For these purposes, we implement a highly synergistic scheme of XCT and FMT based on photon counting technology and the prototype system with high-sensitivity, high temporally-and spatially-resolutions, develop an accurate model of the photon migration in heterogeneous tissue and compartmental modeling, and research the highly efficient numerical solutions. Based on these, we build a quantitative and robust inversion framework for FMT image reconstruction with the support of XCT structural a-priori and inversion technology of pharmacokinetic parameters based Expended Kalman Filter. In addition, we further research the methods to improve the quantitativeness, resolution and stability of image reconstruction and investigate the proposed methods based on prototype system. The ultimate goal of the research is to obtain the fluorophore pharmacokinetic multi-parameters and develop a quantitative and dynamic tool for small-animal based tumor malignant biology applications.

基于荧光分子层析（FMT）成像技术的荧光剂药代动力学参数重建技术在肿瘤早期检测、肿瘤分期、药效评价、动态生物学和病理信息监测等领域具有重要应用价值。目前该技术研究在国内外处于初始阶段，还有大量关键问题亟待解决。本课题针对肿瘤组织体荧光剂药代动力学研究对测量系统灵敏性、快速性、建模精确性以及图像重建技术鲁棒性等关键技术的要求，发展XCT系统与扫描式光子计数型动态FMT系统协同测量方法，建立非均匀组织精确光子传输模型和药代动力学分室模型，并研究其高效数值求解方法。在此基础上，探索基于XCT先验信息支持的FMT先进反演理论以及基于扩展卡尔曼滤波的药代动力学参数重建技术，并研究有效改善图像重建精度、分辨率和稳定性的方法，结合测量系统进行模拟组织体和小动物实验验证，实现小动物模型肿瘤组织的荧光剂药代动力学多参数动态、定量监测。

荧光剂药代动力学参数重建技术在肿瘤早期检测、肿瘤分期、药效评价等领域具有重要应用价值。本研究在精确建模的基础上实现了一个理论缜密、技术可行的荧光药代动力学多参数图像重建方案，并在此基础上探索出有效改善图像重建精度、分辨率和鲁棒性的方法，并开展了相关验证性实验。主要包括：①将基于光纤耦合的多通道光子计数测量技术与扫描、非接触式测量方案相结合，建立了高灵敏、高分辨的动态XCT/FMT测量系统。该系统可在一分钟内获取荧光层析图像，并获得组织体的结构和功能信息；②使荧光分子层析成像方法得到进一步延伸和发展，在得到荧光相关参数图像的同时，通过分室模型的非线性滤波方法得到荧光剂药代动力学多参数图像，有效估计了荧光剂药代动力学渗透率等参数，并获得了各个室内荧光剂浓度的丰富信息；③基于XCT解剖信息和辐射传输高阶近似方程的非均匀组织精确光子输运模型和分室模型及其基础上的优化重建方法，提高了成像质量的精确性和鲁棒性；④目前已对所提方法和技术进行了动态仿体、活体健康小鼠和活体肿瘤小鼠实验。其中，动态仿体实验有效模拟了荧光剂在组织体内的代谢过程，系统最高分辨率和灵敏度可达5r/min，最高量化度可达98.08%；活体健康小鼠肝部ICG代谢研究，以及ICG和ICG负载纳米药物在肿瘤小鼠中的代谢研究成果充分证明了本项目发展的基于XCT/FMT荧光剂药代动力学研究的有效性。