Molecular Photoacoustic Imaging using Multitargeted Contrast Agents

描述（由申请人提供）：拟议的研究旨在使用集成的光声成像和超声，结合分子靶向造影剂，以获取肿瘤细胞受体表达的非侵入性体内分子图像。虽然已经开发了分子成像的方法，但空间分辨率、景深、时间分辨率和灵敏度方面的挑战仍然存在。多模态光声和超声成像结合了光学和超声成像的有利特征，使得能够在体内以高分辨率在几厘米的深度处对对比度进行光学探测。拟议的研究旨在证明肿瘤受体表达的光声分子成像。假设是，具有多重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来检测和区分表达不同受体的体内肿瘤区域。该项目的第一个目的是证明在体外光声成像的多重靶向造影剂已内吞在细胞表达相关受体。然后将含有靶细胞的内含物注射到离体动物组织中，并使用多光谱光声成像，以建立统计相关性，从而区分具有不同光学特性的造影剂和天然组织发色团。第二个目标将证明使用多重靶向造影剂的注射在鼠动物模型中的癌症肿瘤异种移植物内的复杂肿瘤受体表达的体内光声和超声成像。第三个目标是在小鼠模型中对肿瘤生长和对药物治疗的反应进行纵向研究，使用组合的光声和超声成像技术对肿瘤内摄取的靶向造影剂进行成像。为实现这些目标而提出的培训计划旨在培养具有具体技术专长的实习指导员。选定的导师分别是超声和光声成像专家;等离子体纳米粒子在生物医学应用中的合成和应用;以及癌症的细胞表达和调控。PI将参加研究伦理行为的正式培训以及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：能够提供关于患病组织的详细信息的非侵入性分子成像方法的开发将使得能够早期诊断疾病、开发定制的治疗计划以及改进对疾病进展的监测。为了实现这一目标，本研究提出了使用细胞靶向金纳米棒作为独特的可区分的成像造影剂的光声和超声成像的组合。

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.