B7-H3 Targeted Ultrasound Molecular Imaging System for Early Breast Cancer and Metastatic Detection

摘要 乳腺癌是美国女性癌症相关死亡的第二大原因， 预计到2030年发病率将增长50%以上。如果早期发现，妇女的生存率可以 与后期检测相比大幅增加。超声分子成像，利用分子- 靶向造影剂微泡，是一种有前途的技术，用于乳腺癌的早期检测，特别是在 X光检查显示乳腺致密的女性。在超声分子成像中，分子靶向配体 附着在微泡上的蛋白质可以与肿瘤新生血管系统上表达的蛋白质结合 可以早期发现癌症。这种方法有很大的潜力，提高诊断的准确性， 超声和非侵入性表征局灶性乳腺病变。成功的关键超声分子 在这方面的成像是：（1）具有对乳腺癌高度特异性的分子靶标，以及（2）具有对乳腺癌高度特异性的分子靶标。 灵敏的成像系统，可以正确地显示与乳腺癌结合的微泡， 从背景组织中提取气泡此外，该系统必须与现有的超声波 成像技术，以便实际上可分配到现有的乳房成像诊所。 在这个应用中，我们提出建立一个实时超声分子成像平台， 一种新的超声造影成像技术，针对新发现的乳腺癌生物标志物。 我们建议利用靶向微泡来增强对比信号，并提高灵敏度， 成像系统，并建议将这些微泡与靶向B7-H3的高亲和力抗体偶联 生物标志物，其是对乳腺癌高度特异性的血管生物标志物，并且在良性疾病中不表达 流程.此外，我们的初步结果表明，这种生物标志物可能潜在地允许 在成像时检测转移性疾病，可能使成像的能力， 转移性疾病的治疗决定之前。本提案中的实时成像技术基于 需要低计算资源并避免破坏的用于对比成像的神经网络设计 并且能够对靶向造影剂进行实时成像。在这个项目中，我们将优化 这些B7-H3靶向微泡的超声参数对于乳房超声成像频率， 利用微泡的缀合化学，以允许B7- H3靶向微泡。我们将设计并构建此超声分子成像平台（非 破坏性成像系统加上单分散B7-H3靶向微泡），并在 Phanomenon、体外流动室和几种原发性和转移性乳腺癌的临床前动物模型。

ABSTRACT Breast cancer is the second leading cause of cancer-related deaths in women in the United States, and its incidence is expected to grow by more than 50% by 2030. If detected early, the survival of women can be substantially increased compared to late-stage detection. Ultrasound molecular imaging, using molecularly- targeted contrast microbubbles, is a promising technique for the early detection of breast cancer, particularly in women with radiographically dense breast. In ultrasound molecular imaging, a molecularly-targeted ligand attached to a microbubble can bind to proteins expressed on the tumor neovasculature and produce contrast that can identify cancer early. This approach has large potential for improving the diagnostic accuracy of ultrasound and noninvasive characterization of focal breast lesions. The keys to successful ultrasound molecular imaging in this regard are: (1) having a molecular target that is highly specific to breast cancer, and (2) having a sensitive imaging system that can correctly visualize the microbubbles bound to breast cancer and differentiate those bubbles from background tissue. In addition, the system must integrate well with existing ultrasound imaging technology so as to be practically distributable to existing breast imaging clinics. In this application, we propose to build a real-time ultrasound molecular imaging platform that consisting of a novel ultrasound contrast imaging technology that is targeted to a newly identified biomarker of breast cancer. We propose to utilize targeted microbubbles to enhance the contrast signal and improve the sensitivity of the imaging system and propose to conjugate these microbubbles with a high-affinity affibody targeted to the B7-H3 biomarker, which is a vascular biomarker highly specific to breast cancer, and is not expressed in benign disease processes. In addition, our preliminary results demonstrate that this biomarker may potentially allow for the detection of metastatic disease at the time of imaging, potentially enabling the ability to image the extent of metastatic disease prior to treatment decisions. The real-time imaging technology in this proposal is based on a neural network design for contrast imaging that requires low computational resources and avoids destruction of bubbles, and enable real-time imaging of the targeted contrast agent. During this project, we will optimize the ultrasound parameters of these B7-H3 targeted microbubbles for breast ultrasound imaging frequencies and will utilize conjugation chemistry for the microbubbles to permit the potential for future clinical translation of the B7- H3-targeted microbubbles. We will design and construct this ultrasound molecular imaging platform (non- destructive imaging system plus monodisperse B7-H3-targeted microbubbles) and thoroughly test it in phantoms, in vitro flow chambers, and several preclinical animal models of primary and metastatic breast cancer.