面向人源异位移植肺癌动物模型的多参数量化光声介观成像先进方法

Molecular targeted therapy has become a significant clinical therapeutics for patients with advanced stage non-small cell lung cancer to improve patient outcomes and low-term survival rates. With the assistance of biomedical imaging technologies, patient-derived xenografts (PDXs) are expected to better develop novel personalized targeted therapeutic strategies, by providing the individualized information of the substantial tumor heterogeneity and its therapeutic responsiveness. Photoacoustic mesoscopy (PAMe) or acoustic-resolution photoacoustic microscopy, combing rich optical contrast and high ultrasonic resolution, is capable of in vivo visualizing tumor angiogenesis, imaging cancer functional heterogeneity and tracing molecular targeted drugs in PDX models through endogenous and exogenous agents. PAMe has shown great potential in directly providing forceful image evidences to study novel personalized targeted therapeutic strategies. However, the currently available PAMe methodologies have the limitations in the image quality, quantitative accuracy and universal applicability, due to insufficiency of high-quality measurements and specific reconstruction methods.. The proposal herein focuses on essential scientific problems existing in the PAMe development for in vivo tumor imaging: 1) a novel multi-spectral PAMe scheme and image system with high sensitivity, high exactness and completeness of measurements, specifically designed to in vivo tumor imaging for PDX models; 2) a robust and high spatial resolution inversion framework for quantitative multi-parameter PAMe image reconstruction, fully considering the impulse response characteristic of ultrasonic transducer and the accurate process of photon migration; 3) studies on the methodology validation and in vivo tumor imaging for PDX models, using prepared high-efficiency photoacoustic agents. The project aims at not only establishing a beneficial guide to the advanced methodology of quantitative multi-parameter PAMe for in vivo functional and molecular tumor imaging in PDX models, but also providing a reliable biomedical imaging tool to explore novel personalized targeted therapeutic strategies involving drug screening and curative effect assessment.

靶向药物治疗已成为改善非小细胞肺癌预后差、生存率低的重要临床手段。通过医学影像技术利用人源性异种移植动物模型(PDX)反映肿瘤特异性及其靶向治疗效果，成为个体化靶向治疗的新型研究策略。光声介观成像(PAMe) 结合分子探针技术可对异位移植PDX模型进行高分辨率的多维度信息肿瘤功能成像和靶向药物分子成像，有望为个体化靶向治疗提供直观的影像学依据。本项目为克服现有PAMe方法在成像质量、定量精度和普遍适用性上的局限性展开深入研究：1)发展适用于PDX模型肿瘤在体成像、高灵敏度和高数据完备性的多光谱PAMe测量方法；2) 研究融合探测器脉冲响应特性和先进光子输运模型的多参数量化PAMe图像反演理论；3) 结合高效光声分子探针，开展方法学验证及在体应用研究，最终建立面向PDX模型肿瘤功能/分子成像的多参数量化PAMe先进成像方法，为探索个体化靶向治疗药物筛选和方案拟定新方法提供可靠的医学影像工具。

利用医学影像技术在人源性异种移植动物模型(PDX)中探究肿瘤特异性及其靶向治疗效果，是个体化靶向治疗的新型研究策略。光声介观成像(PAMe)结合分子探针技术可对异位移植PDX模型进行高分辨率的多维度信息肿瘤功能成像和靶向药物分子成像，有望为个体化靶向治疗提供直观的影像学依据。现有PAMe方法在成像质量、定量精度和普遍适用性上存在局限性。为提高该方法在面向活体小动物肿瘤成像研究中的准确性与适用性，必须有效克服现有PAMe方法的局限性。.本课题以实现小动物肿瘤模型的在体多参数量化PAMe为目标，围绕上述要素涉及的科学问题展开研究：（1）建立了一套面向PDX模型肿瘤功能/分子成像的多参数量化PAMe测量系统，可实现高灵敏度和多维度信息的获取；（2）发展了先进光子输运理论实现近光场区的光子输运精准建模，具有较高的计算效率和普遍适用性；（3）发展了融合探测器脉冲响应特性和有限探测角度成像质量优化的声学量化策略，实现精准初始声压的高效重建；（4）发展了基于非线性混合模型的特征光谱光声成像方法，实现非均匀深层组织中的血氧饱和度定量成像；（5）采用数值模拟、仿体实验、分子探针实验和在体实验对所发展理论、算法及系统的综合特性与实用能力进行评估。本课题研究在传统PAMe局限性上实现突破性创新，为肿瘤恶性生物研究学和靶向药物疗效评估等研究提供了一种合适的成像方法。研究工作将会继续针对不同细胞来源的肿瘤小动物模型进行展开，实现对肿瘤形成机制、生长与转移、药物疗效等的在体观测和定量测量。