Perfluorocarbon Nanodroplets for the Detection and Treatment of Nodal Metastases

摘要

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.