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，其 预计到2030年，发病率将增长50%以上。如果及早发现，女性的存活率可以 与后期检测相比大幅增加。超声分子成像，使用分子- 靶向造影剂微泡是一种很有前途的乳腺癌早期检测技术，尤其是在 胸片致密的女性。在超声分子成像中，一种分子靶向配体 附着在微泡上可以与肿瘤新生血管上表达的蛋白质结合并产生对比度 可以及早发现癌症。这种方法在提高诊断准确率方面有很大的潜力。 乳腺局灶性病变的超声和非侵入性定性。超声分子成功的关键 在这方面的成像是：(1)具有高度特异性的乳腺癌分子靶点，以及(2)具有 灵敏的成像系统，可以正确地显示与乳腺癌结合的微泡并区分 那些来自背景组织的气泡。此外，该系统必须与现有的超声波很好地集成 成像技术，以便几乎可以分发到现有的乳房成像诊所。 在这一应用中，我们提出了建立一个实时超声分子成像平台，该平台由一个 针对一种新发现的乳腺癌生物标志物的新型超声对比成像技术。 我们建议利用靶向微泡来增强对比度信号，并提高 成像系统，并建议将这些微泡与靶向B7-H3的高亲和力粘附体偶联 生物标记物是一种高度特异的乳腺癌血管生物标记物，在良性疾病中不表达 流程。此外，我们的初步结果表明，该生物标记物可能潜在地允许 在成像时检测转移性疾病，潜在地能够成像 转移性疾病在治疗决定之前。该方案中的实时成像技术基于 用于对比度成像的低计算资源和避免破坏的神经网络设计 并且能够对目标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乳腺超声成像频率和Will的影响 利用微泡的结合化学来允许未来临床翻译B7- H3靶向微泡。我们将设计和建设这个超声分子成像平台(非 破坏性成像系统外加单分散B7-H3靶向微泡)，并在 体模、体外流室和几种临床前乳腺癌和转移性乳腺癌的动物模型。

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.