Acoustic Imaging of Sentinel Node Matastasis using Plasmonic Nanosensors

摘要 在癌症患者中，确定恶性肿瘤是否已经扩散是唯一最重要的因素 用于制定治疗计划和预测预后。在大多数情况下，癌细胞最初通过 局部淋巴结因此，区域淋巴结转移的临床评价是 至关重要不幸的是，没有实时的，非侵入性的临床方法，可以可靠地 检测和诊断淋巴结中的微转移。因此，临床上迫切需要一种 广泛可用的、非侵入性的、执行简单的、安全的并且可以可靠地 真实的及时检测和充分诊断淋巴结微转移。 我们研究计划的总体目标是开发一种先进的，体内，非侵入性，分子 特定的成像技术，即，集成超声和光声成像结合靶向 等离子体纳米传感器，能够立即和准确地评估前哨淋巴结 真实的实时检测微转移该项目的基本假设是， 随着广泛使用的临床超声成像是可能的，并且超声和光声成像都可以 在真实的时间进行，产生即时诊断并允许早期实施治疗。 一系列广泛的科学和工程、生物医学和临床问题必须得到充分解决， 探索分子特异性超声和光声淋巴（MS-USPAL）成像在 前哨淋巴结微转移的检测和表征。目前的应用集中在 MS-USPAL成像的临床翻译的重要方面。我们将在临床上开发和验证 MS-USPAL的可平移等离子体纳米传感器。我们将使用超小的金纳米颗粒来靶向 表皮生长因子受体（EGFR），其在鳞状细胞癌和许多其他肿瘤中过表达， 上皮肿瘤为了高灵敏度检测癌细胞，我们将探索EGF受体介导的 胞吞作用和紧密间隔的分子特异性之间的等离子体共振耦合的影响 纳米粒子纳米颗粒的超小尺寸将非常有利于从体内快速清除 这将允许安全地过渡到临床实践。此外，5 nm配体覆盖的金纳米颗粒将 大大减少非特异性相互作用，减少免疫细胞对纳米颗粒的摄取， 巨噬细胞由于淋巴结炎症而存在，从而减少假阳性结果。而且我们 将设计和构建能够成像5 nm的临床MS-USPAL成像系统的原型 纳米粒子在体内。

ABSTRACT In cancer patients, determination of whether a malignancy has spread is the single most important factor used to develop a therapeutic plan and to predict prognosis. In most cases, cancer cells initially spread through regional lymph nodes. Therefore, clinical evaluation for the presence of regional lymph node metastases is of paramount importance. Unfortunately, there are no real-time, non-invasive clinical methods that can reliably detect and diagnose micrometastases in lymph nodes. Therefore, there is an urgent clinical need for an imaging technique that is widely available, is non-invasive and simple to perform, is safe, and can reliably detect and adequately diagnose lymph node micrometastases in real time. The overall goal of our research program is to develop an advanced, in-vivo, noninvasive, molecular specific imaging technology, i.e., integrated ultrasound and photoacoustic imaging combined with targeted plasmonic nanosensors, capable of immediate and accurate assessment of sentinel lymph node micrometastases in real time. The underlying hypothesis of this project is that photoacoustic imaging integrated with widely used clinical ultrasound imaging is possible and both ultrasound and photoacoustic imaging can be performed in real time, yielding an immediate diagnosis and allowing early implementation of treatment. A wide range of scientific and engineering, biomedical and clinical problems must be addressed to fully explore the capabilities of molecular specific ultrasound and photoacoustic lymphatic (MS-USPAL) imaging in detection and characterization of sentinel lymph node micrometastases. The current application is focused on important aspects of clinical translation of MS-USPAL imaging. We will develop and validate clinically translatable plasmonic nanosensors for MS-USPAL. We will use ultra-small gold nanoparticles to target epidermal growth factor receptor (EGFR), which is overexpressed in squamous carcinoma and in many other epithelial neoplasms. For highly sensitive detection of cancer cells, we will explore EGF receptor mediated endocytosis and the effect of plasmon resonance coupling between closely spaced molecular specific nanoparticles. The ultra-small size of nanoparticles will be highly favorable for rapid clearance from the body which will allow safe transition into clinical practice. Additionally, 5 nm ligand capped gold nanoparticles will greatly reduce nonspecific interactions and reduce the uptake of nanoparticles by immune cells such as macrophages present due to lymph node inflammation, thus diminishing false positive results. Furthermore, we will design and construct a prototype of the clinical MS-USPAL imaging system capable of imaging 5 nm nanoparticles in-vivo.