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

B7-H3 用于早期乳腺癌和转移检测的靶向超声分子成像系统

• 批准号: 10584161
• 负责人: Jeremy Dahl
• 金额: $ 56.17万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584161
• 关键词: 4T1; Adopted; Adoption; Affinity; Animal Model; Anxiety; Benign; Binding; Biological Markers; Biopsy; Blood Vessels; Breast; Breast Cancer Detection; Breast Cancer Early Detection; Breast Cancer Model; Breast Cancer Patient; CD276 gene; Cancer Etiology; Cessation of life; Chemistry; Clinic; Clinical; Computer software; Detection; Development; Diagnosis; Disease; Early Diagnosis; Engineering; Frequencies; Future; Goals; Human; Image; Imaging Techniques; Imaging technology; In Vitro; Incidence; Lesion; Ligands; Liver; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Ultrasonography; Mammography; Metastatic breast cancer; Microbubbles; Modality; Molecular Target; Monitor; Mouse Mammary Tumor Virus; Neoplasm Metastasis; Network-based; Noise; Normal tissue morphology; Outcomes Research; Patient imaging; Patients; Process; Proteins; Research; Sensitivity and Specificity; Signal Transduction; Source; Specificity; System; Techniques; Testing; Time; Tissue imaging; Tissues; Transgenic Organisms; Translations; Ultrasonography; United States; Visualization; Woman; aggressive breast cancer; biomarker identification; breast cancer diagnosis; breast imaging; breast lesion; breast scan; clinical translation; clinically relevant; computing resources; contrast enhanced; contrast imaging; cost; design; design and construction; detection method; diagnostic accuracy; experimental study; high risk; human imaging; imaging modality; imaging platform; imaging system; improved; in vivo; lymph nodes; malignant breast neoplasm; molecular imaging; mouse model; neovasculature; neural network; novel; patient screening; performance tests; polyoma middle tumor antigen; pre-clinical; radiological imaging; real-time images; targeted imaging; tumor; ultrasound

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.

抽象的 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，女性的生存可能会受到威胁 与后期检测相比，显着增加。超声分子成像，使用分子- 靶向对比微泡是一种有前景的乳腺癌早期检测技术，特别是在 放射线检查显示乳房致密的女性。在超声分子成像中，分子靶向配体 附着在微泡上可以与肿瘤新生血管上表达的蛋白质结合并产生对比 可以及早发现癌症。该方法在提高诊断准确性方面具有巨大潜力 局灶性乳腺病变的超声和无创表征。超声分子成功的关键 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 灵敏的成像系统，可以正确地可视化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良好集成 成像技术，以便实际上可以分发到现有的乳腺成像诊所。 在此应用中，我们建议建立一个实时超声分子成像平台，该平台由 针对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信号并提高灵敏度 成像系统，并建议将这些微泡与针对 B7-H3 的高亲和力亲和体结合 生物标志物，是一种对乳​​腺癌高度特异性的血管生物标志物，在良性疾病中不表达 流程。此外，我们的初步结果表明，该生物标志物可能有助于 在成像时检测转移性疾病，可能能够对转移性疾病的范围进行成像 在做出治疗决定之前发现转移性疾病。本提案中的实时成像技术基于 用于对比成像的神经网络设计，需要低计算资源并避免破坏 气泡，并实现目标造影剂的实时成像。在这个项目中，我们将优化 这些 B7-H3 的超声参数针对乳腺超声成像频率并将 利用微泡的缀合化学来实现 B7- 未来临床转化的潜力 H3 靶向微泡。我们将设计并构建这个超声分子成像平台（非 破坏性成像系统加上单分散 B7-H3 靶向微泡）并在 体模、体外流动室以及原发性和转移性乳腺癌的几种临床前动物模型。