Perfluorocarbon Nanodroplets for the Detection and Treatment of Nodal Metastases

摘要 在美国，乳腺癌是女性最常见的诊断癌症，它导致 癌症女性的死亡率位居第二。尽管乳腺癌的治疗模式 近年来的发展，区域淋巴结转移的检测仍然是 临床方案，并对早期乳腺癌患者的复发和生存率具有强烈的意义。 前哨淋巴结活检是一种发病率相对较低的选择，可用于临床评估区域性淋巴结转移 淋巴转移，但这一过程依赖于放射性同位素，也带有相对较高的假阴性 发现转移的比率。前哨淋巴结检测和诊断的替代方法有 已探索过，但它们并不是没有弱点，尚未获得临床应用。 为了应对当前临床和研究选择中的挑战，我们建议对光学- 触发了相变全氟碳纳米液滴。这种对比度增强的成像方法具有 有可能检测前哨淋巴结，评估其转移情况，并为受控患者提供一种工具 药物输送和释放。因此，这个平台可以对糖尿病的诊断和治疗产生深远的影响 乳腺癌的淋巴结转移。因此，我们研究策略的总体目标是验证该平台 在转移性乳腺癌的小鼠模型中。在目标1中，我们将优化淋巴传输的纳米液滴 并建立他们成功检测前哨淋巴结的能力。在目标2中，我们将从分子上合成- 并评估它们区分转移性和非转移性哨兵结节的能力 用于节点检测和诊断的多路传输方法的一部分。在目标3中，我们将最终将纳米液滴改造成 在当地运送治疗货物，并评估这一战略的效果。我们寻求提供一种治疗的选择 适用于乳腺癌转移，可适应一系列转移性肿瘤疾病。因为 全氟碳纳米液滴是由生物兼容试剂合成的，其组成类似于 临床批准的微泡，临床转化的道路比其他 试验性试剂。 为实现这些目标而提出的培训计划是专门为PI提供 作为一名具有临床头脑的独立研究人员，成功所必需的环境、培训和指导。这个 PI将参加关于研究和翻译研究的道德行为的正式培训，以及联合 课程的临床经验，为他未来的职业生涯做好准备，成为内科科学家。

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.