Acoustic Imaging of Sentinel Node Matastasis using Plasmonic Nanosensors

描述(申请人提供)：在癌症患者中，确定恶性肿瘤是否扩散是制定治疗计划和预测预后的唯一最重要的因素。在大多数情况下，癌细胞最初是通过区域淋巴结扩散的。因此，临床评估区域淋巴结转移的存在是至关重要的。不幸的是，目前还没有一种实时、非侵入性的临床方法可以可靠地检测和诊断淋巴结微转移。因此，临床迫切需要一种广泛可用的、非侵入性的、操作简单的、安全的、能够可靠地实时检测和充分诊断淋巴结微转移的成像技术。我们研究计划的总体目标是开发一种先进的在体、非侵入性、分子特异性成像技术，即集成的超声和光声成像与靶向血浆纳米传感器相结合，能够即时、准确地实时评估前哨淋巴结微转移。该项目的基本假设是，光声成像与广泛使用的临床超声成像相结合是可能的，超声和光声成像都可以实时进行，从而产生即时诊断并允许早期实施治疗。必须解决广泛的科学和工程、生物医学和临床问题，以充分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方面的能力。目前的应用主要集中在MS-USPAL成像临床翻译的重要方面。我们将为MS-USPAL开发和验证临床可翻译的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)，它在鳞癌和许多其他上皮性肿瘤中过度表达。为了高灵敏地检测癌细胞，我们将探索EGF受体介导的内吞作用以及紧密间隔的分子特定纳米颗粒之间的等离子体共振耦合的影响。纳米颗粒的超小尺寸将非常有利于快速从体内清除，这将允许安全地过渡到临床实践。此外，5纳米配基封顶的金纳米颗粒将极大地减少非特异性相互作用，并减少由于淋巴结炎而出现的免疫细胞(如巨噬细胞)对纳米颗粒的摄取，从而减少假阳性结果。此外，我们将设计和构建一个临床MS-USPAL成像系统的原型，能够在体内对5 nm纳米粒子进行成像。 公共卫生相关性：在癌症患者中，确定恶性肿瘤的扩散是制定治疗计划和预测预后的唯一最重要的因素。在大多数情况下，癌细胞最初是通过区域淋巴结扩散的。因此，分子特异性超声和光声淋巴成像等技术，能够在体内、无创、准确地实时评估区域转移，可以简化和改善对上皮性恶性肿瘤患者的管理，显著改善公共卫生，降低医疗成本。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: In cancer patients, the determination of the spread of malignancy is the single most important factor to develop a therapeutic plan and predict prognosis. In most cases, cancer cells initially spread through regional lymph nodes. Thus, a technology such as molecular specific ultrasound and photoacoustic lymphatic imaging, capable of in-vivo, noninvasive and accurate assessment of regional metastases in real time, can simplify and improve management of patients with epithelial malignancies, significantly improve public health, and reduce medical costs.