Background-free molecular imaging using modulated photoacoustics and targeted contrast agent

摘要 这项研究计划的目标是开发一种先进的、非侵入性的、分子特异性的成像技术-- 生物学.超声引导的调制光声成像增强的光学可激活的，靶向的 Trast试剂，能够立即、准确、无背景地评估体内的病理。潜在的 该项目的假设是超声引导的光声成像光学调制造影剂 可以实时执行，产生即时诊断信息。这种方法是基于独特的 一种可光学激活的分子靶向成像造影剂与相应的激光/UL-1的组合 跨声学成像设备。具体地说，开发一种由以下组成的高灵敏度成像造影剂 二氧化硅纳米颗粒，掺杂了可光学激活的光吸收材料，并被一种抗体功能化 将承接脂质外壳。镶嵌在硅芯中的光吸收材料表现出约50的S寿命和瞬变特性 先前红光照射下的近红外光吸收。造影剂将使用临床成像 超声(US)成像系统，与两个(泵浦/探头)脉冲激光源接口，在 超声波或光声成像模式。泵浦激光脉冲将反复激活造影剂，因此 允许探测激光脉冲产生可被处理以产生背景的光声信号- 自由调制光声(MPA)图像与灰度超声(US)图像空间共配准。毛皮- 此外，通过探测不同的光学激活造影剂的暗状态寿命，多个甲基帕斯卡“颜色”。 将同时在组织内成像。这些US-MPA图像将显示分子和功能信号- 在组织的结构内容物内的疾病的结构。这个项目的具体目标是开发 一种超声引导的调制光声成像方法并在 利用小鼠转移性模型无背景检测前哨淋巴结微转移 乳腺癌。事实上，临床癌症管理的关键组成部分之一就是分析再诊断。 区域淋巴结目前的诊断方法，包括成像，灵敏度和特异度较低。 因此，这种US-MPA系统将专门设计用于前哨淋巴微转移的成像 节点。超声-甲孕酮成像的灵敏度和特异度将通过合成MO-MAP而得到证明。 有针对性的造影剂和协调的器械开发，以最大限度地发挥这些新产品的影响 材料和成像方法。这项研究的成功结果将使设计和开发 临床成像系统和造影剂，用于各种病理的无背景分子成像。

ABSTRACT The goal of this research program is to develop an advanced, noninvasive, molecularly specific imaging tech- nology – ultrasound-guided modulated photoacoustic imaging augmented by optically-activatable, targeted con- trast agents, capable of immediate, accurate, background-free assessment of pathologies in vivo. The underlying hypothesis of this project is that ultrasound-guided photoacoustic imaging of optically modulated contrast agents can be performed in real time, yielding immediate diagnostic information. The approach is based on the unique combination of an optically-activatable molecularly-targeted imaging contrast agent and corresponding laser/ul- trasound imaging device. Specifically, development of a highly-sensitive imaging contrast agent consisting of silica nanoparticles doped with optically-activatable photoabsorbers and coated by an antibody-functionalized lipid shell will be undertaken. The photoabsorbers embedded in the silica core exhibit ~50s-lived, transient near-infrared optical absorption upon prior red laser irradiation. The contrast agent will be imaged using a clinical ultrasound (US) imaging system, interfaced with two (pump/probe) pulsed laser sources, operating in either ultrasound or photoacoustic imaging modes. Pump laser pulses will repeatedly activate the contrast agent, thus allowing for probe laser pulses to generate photoacoustic signal that can be processed to generate background- free modulated photoacoustic (mPA) images spatially co-registered with grayscale ultrasound (US) images. Fur- thermore, by probing different dark state lifetimes of optically activated contrast agents, multiple mPA “colors” will be simultaneously imaged within tissue. These US-mPA images will display molecular and functional signa- tures of the disease within the structural content of the tissue. The specific objective of this project is to develop an ultrasound-guided modulated photoacoustic imaging approach and demonstrate the developed approach in the background-free detection of micrometastases in sentinel lymph nodes using a murine model of metastatic breast cancer. Indeed, one of the critical components of the clinical cancer management is the analysis of re- gional lymph nodes where current diagnostic methods including imaging suffer from low sensitivity and specificity. Therefore, this US-mPA system will be specifically designed for imaging micrometastases in sentinel lymph nodes. Improved sensitivity and specificity of US-mPA imaging will be demonstrated through synthesis of mo- lecularly targeted contrast agent and coordinated instrumentation development to maximize impact of these new materials and the imaging approach. The successful outcome of this study will enable design and development of a clinical imaging system and contrast agents for background-free molecular imaging of various pathologies.