Photon-counting X-ray and Optical Tomography for Preclinical Cancer Research

用于临床前癌症研究的光子计数X射线和光学断层扫描 摘要 临床前成像是癌症研究中的关键工具。由于癌症在时空上表现出非常复杂的 因此，迫切需要开发新的成像技术来表征癌症的特征。 组织及其微环境。为此目的，多模态成像具有提供最佳的潜力。 解剖、功能和分子信息同时在活的和完整的动物。我们最感兴趣的， 人表皮生长因子受体2（HER 2）表达在乳腺癌中具有预后和预测价值 癌目前，抑制受体二聚化的治疗性单克隆抗-HER 2抗体是FDA- 参阅会议过程然而，关于HER 2在乳腺癌中的作用的观点越来越复杂 基因组测序强调了肿瘤间和肿瘤内异质性在治疗中的重要性， 阻力因此，显然需要一种非侵入性临床前成像模式，其能够 监测HER 2受体表达水平、靶向药物递送和肿瘤反应之间的相互作用。 该项目的总体目标是开发一个混合X射线和光学原型的高维光学 断层扫描（HOT）由能量分辨微型CT（GEM）引导，对乳腺肿瘤进行可视化和定量 异质性、HER 2表达和二聚化以及临床前模型中的治疗反应。在x- 射线侧，光子计数微CT记录单个X射线光子及其能级，并使 化学物质分解。因此，小鼠的解剖结构可以用 水、脂质、骨、钙、碘和钆。在光学方面，光学分子断层扫描图 功能性生物标志物和分子探针的分布。对于靶向治疗非常重要， 体内宏观荧光寿命Förster共振能量转移（MFLI-FRET）成像，我们最近 结果表明，定量MFLI-FRET信号与细胞内药物递送强烈相关， 通过离体免疫组织化学分析验证的病理部位。协同作用，基础材料 解决与光子计数显微CT可以与独特的光学性质，并用于纠正 用于定量光学分子层析成像非均匀光学背景。此外，对比- 增强的微CT可以识别感兴趣的区域以使光学分子断层摄影术规则化。具体 目的是（1）原型的混合HOTGEM系统的全面和协同的x射线和光学 成像，（2）开发联合方法，用于从多对比度收集的数据集重建图像， HOTGEM系统，和（3）在具有不同水平的HER 2和HER 3的异种移植系统中表征乳腺癌。 使用HOTGEM系统检测HER 2激活突变。完成后，拟议的HOTGEM系统将 经验证，可为材料分解提供50µm X射线分辨率，为材料分解提供100µm光学分辨率。 对于每个混合体内扫描，在30分钟内共配准靶定位，证明是一种 这是HER 2断层成像的突破，并准备进行技术转让和商业转化。

Photon-counting X-ray and Optical Tomography for Preclinical Cancer Research ABSTRACT Preclinical imaging is a critical tool in cancer research. Since cancer exhibits very complex spatiotemporal features, there is a strong need for the development of novel imaging technologies to characterize cancerous tissues and their microenvironments. For this purpose, multimodal imaging has the best potential to provide anatomical, functional and molecular information concurrently in live and intact animals. Of our primary interest, human epidermal growth factor receptor 2 (HER2) expression has prognostic and predictive values in breast cancer. Currently, therapeutic monoclonal anti-HER2 antibodies that inhibit receptor dimerization are FDA- approved. However, an increasingly more complex view of the role of HER2 in breast cancer has emerged from genome sequencing that highlights the importance of inter- and intra-tumor heterogeneity in therapy resistance. Thus, there is a clear need for a non-invasive preclinical imaging modality that is capable of monitoring the interplay between HER2 receptor expression level, targeted drug delivery, and tumor response. The overall goal of this project is to develop a hybrid x-ray and optical prototype for High-dimensional Optical Tomography (HOT) Guided-by Energy-resolved Micro-CT (GEM), visualize and quantitate breast tumor heterogeneity, HER2 expression and dimerization, and therapeutic response in preclinical models. On the x- ray side, photon-counting micro-CT records individual x-ray photons and their energy levels, and enables chemically-specific material decomposition. As a result, a mouse anatomy can be represented in terms of water, lipid, bone, Calcium, Iodine, and Gadolinium. On the optical side, optical molecular tomography maps the distribution of functional biomarkers and molecular probes. Of great importance to targeted therapy, with in vivo Macroscopy Fluorescence Lifetime Förster Resonance Energy Transfer (MFLI-FRET) imaging, our recent results demonstrate that quantitative MFLI-FRET signals correlate strongly with intracellular drug delivery at the pathological site as validated via ex vivo immunohistochemistry analysis. Synergistically, basis materials resolved with photon-counting micro-CT can be related to unique optical properties, and used to correct a heterogeneous optical background for quantitative optical molecular tomography. Furthermore, contrast- enhanced micro-CT can identify regions of interest to regularize optical molecular tomography. The specific aims are to (1) prototype a hybrid HOTGEM system for comprehensive and synergistic x-ray and optical imaging, (2) develop joint methods for image reconstruction from datasets in multi-contrasts collected with the HOTGEM system, and (3) characterize breast cancer in xenograft systems with varying levels of HER2 and HER2-activating mutations using the HOTGEM system. Upon completion, the proposed HOTGEM system will have been validated to offer 50µm x-ray resolution for material decomposition and 100µm optical resolution for target localization in co-registration within 30 minutes for each hybrid in vivo scan, demonstrated to be a breakthrough for tomographic HER2 imaging, and ready for technology transfer and commercial translation.