Perfluorocarbon Nanodroplets for the Detection and Treatment of Nodal Metastases

摘要 在美国，乳腺癌是女性中最常见的癌症，它会导致 癌症妇女死亡率第二高。尽管乳腺癌的治疗模式 近年来已经发展，检测区域淋巴结转移仍然是淋巴结转移的关键方面。 临床方案，并对早期乳腺癌患者的复发和生存有很强的影响。 前哨淋巴结活检已经成为一种相对低发病率的选择，用于区域性淋巴结转移的临床评估。 淋巴转移，但这一程序依赖于放射性同位素，也进行了相对较高的假阴性 检测转移的比率。前哨淋巴结检测和诊断的替代方法已经 但是它们并非没有弱点，而且尚未获得临床牵引力。 为了解决当前临床和研究选择的挑战，我们提出了光学超声成像， 引发相变的全氟化碳纳米液滴。这种对比度增强成像方法具有 潜在的前哨淋巴结检测，以评估他们的转移，并提供一个载体， 药物输送和释放。因此，这个平台可以对诊断和治疗产生深远的影响， 乳腺癌淋巴结转移。因此，我们研究策略的总体目标是验证这个平台 在转移性乳腺癌的鼠模型中。在目标1中，我们将优化用于淋巴运输的纳米液滴 并建立他们成功检测前哨淋巴结的能力。在目标2中，我们将合成分子- 靶向纳米液滴，并评估其区分转移性与非转移性前哨淋巴结的能力， 用于节点检测和诊断的多路复用方法的一部分。在目标3中，我们最终将调整纳米液滴， 局部递送治疗性货物并评估该策略的功效。我们寻求提供一种治疗诊断选择， 用于乳腺癌转移，可以适用于一系列转移性肿瘤疾病。因为 全氟化碳纳米液滴是由生物相容性试剂合成的，并且在组成上与全氟化碳纳米液滴相似。 临床批准的微泡，临床转化的道路比其他微泡更乐观。 实验代理人 为实现这些目标而提出的培训计划专门为PI提供 环境，培训和指导必要的成功，作为一个有临床头脑的独立研究人员。的 PI将参加研究和转化研究伦理行为的正式培训，以及 课程的临床经验，为他未来的职业生涯作为一个医生，科学家。

ABSTRACT In the United States, breast cancer is the most commonly diagnosed cancer in women, and it results in the second highest mortality rate amongst women with cancer. Although the treatment paradigm for breast cancer has evolved in recent years, detection of metastases to regional lymph nodes remains a critical aspect of the clinical protocol and has strong implications for recurrence and survival in patients with early-stage breast cancer. Sentinel lymph node biopsy has emerged as a relatively low-morbidity option for the clinical evaluation of regional lymphatic metastases, but this procedure relies on radioisotopes and also carries a relatively high false-negative rate in detecting metastases. Alternative methods for sentinel lymph node detection and diagnosis have been explored, but they are not without weaknesses and have yet to gain clinical traction. To address the challenges in current clinical and research options, we propose ultrasound imaging of optically- triggered phase-change perfluorocarbon nanodroplets. This contrast-enhanced imaging approach has the potential to detect sentinel lymph nodes, to assess them for metastases, and to provide a vehicle for controlled drug delivery and release. As such, this platform can have a profound impact on the diagnosis and treatment of breast cancer nodal metastases. Therefore, the overall goal of our research strategy is to validate this platform in a murine model of metastatic breast cancer. In Aim 1, we will optimize nanodroplets for lymphatic trafficking and establish their ability to successfully detect the sentinel lymph node. In Aim 2, we will synthesize molecularly- targeted nanodroplets and assess their ability to differentiate metastatic from non-metastatic sentinel nodes as part of a multiplexed approach for nodal detection and diagnosis. In Aim 3, we will finally adapt nanodroplets to deliver a therapeutic cargo locally and assess the efficacy of this strategy. We seek to deliver a theranostic option for breast cancer metastases that can be adapted to an array of metastatic neoplastic diseases. Because perfluorocarbon nanodroplets are synthesized from biocompatible reagents and are similar in composition to clinically-approved microbubbles, the path towards clinical translation is more optimistic than with other experimental agents. The training plan proposed to accomplish these goals has been specifically designed to provide the PI with the environment, training, and mentorship necessary to succeed as a clinically-minded independent researcher. The PI will participate in formal training in the ethical conduct of research and translational research as well as in co- curricular clinical experiences to prepare him for a future career as a physician-scientist.