Molecular Photoacoustic Imaging using Multitargeted Contrast Agents

描述(申请人提供)：这项拟议的研究寻求使用集成的光声成像和超声，结合分子靶向造影剂，获得肿瘤细胞受体表达的非侵入性体内分子图像。虽然分子成像方法已经发展，但在空间分辨率、景深、时间分辨率和灵敏度方面仍然存在挑战。多模式光声和超声成像结合了光学和超声成像的优点，能够在活体内以几厘米深的高分辨率进行对比度的光学探测。这项拟议的研究试图证明肿瘤受体表达的光声分子成像。假说是，具有多种靶向造影剂的光声成像与高分辨率超声成像相结合，将提供必要的灵敏度和分辨率，以检测和区分体内肿瘤表达不同受体的区域。该项目的第一个目标是在体外展示多重靶向造影剂的光声成像，这些造影剂已经内吞到表达相关受体的细胞中。然后，将含有靶细胞的包裹体注射到体外动物组织中，并使用多光谱光声成像，以便建立统计相关性，以区分具有不同光学性质的造影剂和天然组织发色团。第二个目标是通过注射复合靶向造影剂，在体内展示复合肿瘤受体在小鼠肿瘤移植瘤模型中表达的光声和超声成像。第三个目标是在小鼠模型中对肿瘤生长和药物治疗反应进行纵向研究，使用光声和超声成像技术组合成像肿瘤内摄取的靶向造影剂。为实现这些目标而提出的培训计划旨在建立具有特定技术专长的见习导师。入选的导师分别是超声波和光声成像、生物医学应用的血浆纳米颗粒的合成和应用以及癌症的细胞表达和调控方面的专家。PI将参加研究道德行为的正式培训和针对其研究领域的培训，为独立研究做好准备。 公共卫生相关性：能够提供疾病组织详细信息的非侵入性分子成像方法的发展将使疾病的早期诊断、制定量身定制的治疗计划和改进对疾病进展的监测成为可能。为了实现这一目标，这项研究建议使用光声和超声成像的组合，使用细胞靶向的金纳米棒作为唯一可区分的成像对比剂。

DESCRIPTION (provided by applicant): The proposed research seeks to use integrated photoacoustic imaging and ultrasound, combined with molecularly targeted contrast agents, to acquire non-invasive in vivo molecular images of tumor cell receptor expression. While methods of molecular imaging have been developed, challenges with spatial resolution, depth of field, temporal resolution and sensitivity remain. Multimodal photoacoustic and ultrasound imaging combines advantageous features of optical and ultrasound imaging, enabling optical probing of contrast at a high resolution at a depth of several centimeters in vivo. The proposed research seeks to demonstrate photoacoustic molecular imaging of tumor receptor expression. The hypothesis is that photoacoustic imaging with multiplex targeted contrast agents, combined with high resolution ultrasound imaging, will provide the necessary sensitivity and resolution to detect and distinguish between regions of in vivo tumors which are expressing different receptors. The first aim of the project is to demonstrate in vitro photoacoustic imaging of multiplex targeted contrast agents which have been endocytosed in cells expressing the relevant receptor. Inclusions containing targeted cells will then be injected in ex vivo animal tissue and imaged using multispectral photoacoustics in order to develop statistical correlations to distinguish between contrast agents with varying optical properties, and native tissue chromophores. The second aim will demonstrate in vivo photoacoustic and ultrasound imaging of complex tumor receptor expression within cancer tumor xenografts in murine animal models using injections of the multiplex targeted contrast agents. The third aim will perform longitudinal studies on tumor growth and response to drug treatment within the murine model, using the combined photoacoustic and ultrasound imaging techniques to image targeted contrast agents uptaken within the tumor. The training plan proposed to accomplish these goals has been designed to establish trainee mentors with specific technical expertise. The selected mentors are experts in ultrasound and photoacoustic imaging; the synthesis and applications of plasmonic nanoparticles for biomedical applications; and the cell expression and regulation of cancer; respectively. The PI will enroll in formal training in the ethical conduct of research and in training specific to her research field, to prepare her for independent research. PUBLIC HEALTH RELEVANCE: The development of non-invasive molecular imaging methods capable of providing detailed information on diseased tissues would enable the earlier diagnosis of disease, the development of tailored treatment plans, and improved monitoring of disease progression. To achieve this goal, this research proposes the use of a combination of photoacoustic and ultrasound imaging using cellularly-targeted gold nanorods as uniquely distinguishable imaging contrast agents.