A multimodal imaging system and targeted nanoprobes for image-guided treatment of breast cancer

用于乳腺癌图像引导治疗的多模态成像系统和靶向纳米探针

• 批准号: 9513881
• 负责人: HUABEI JIANG
• 金额: $ 60.57万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9513881
• 关键词: Animals; Area; Beds; Breast Cancer Detection; Breast Cancer Treatment; Cancer Biology; Cancer Patient; Cells; Clinical; Colon Carcinoma; Conventional Surgery; Crystallization; Detection; Development; Devices; Dimensions; Distant; Drug resistance; Dyes; Endoscopes; Endoscopy; Engineering; Estrogen Receptors; Excision; Fiber Optics; Fluorescence; Goals; Healthcare; Human; IGF1R gene; Image; Image-Guided Surgery; Imaging technology; Insulin-Like-Growth Factor I Receptor; Interdisciplinary Study; Kinetics; Label; Lasers; Lesion; Lilium; Location; Luciferases; Magnetism; Malignant neoplasm of esophagus; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Mammary Neoplasms; Modality; Modeling; Multimodal Imaging; Mus; Neoplasm Metastasis; Nude Mice; Operative Surgical Procedures; Optics; Pathologic; Patients; Primary Neoplasm; Principal Investigator; Progesterone Receptors; Recurrence; Recurrent tumor; Research Personnel; Residual Tumors; Resistance; Resolution; Scanning; Sensitivity and Specificity; Side; Signal Transduction; Specificity; Surgical Oncology; System; Tail; Technology; Time; Tissues; Transducers; Translating; Tumor Markers; Tumor stage; Tumor-Derived; Ultrasonography; Urokinase Plasminogen Activator Receptor; Veins; Xenograft Model; Yang; base; bioluminescence imaging; breast surgery; cancer cell; cancer imaging; cancer surgery; chemotherapy; clinical application; cyanine dye; effective therapy; experimental study; fluorescence imaging; fluorescence molecular tomography; image guided; imaging approach; imaging probe; imaging system; in vivo; innovation; instrumentation; intraoperative imaging; iron oxide; lymph nodes; malignant breast neoplasm; molecular imaging; multimodality; nanoparticle; nanoprobe; neoplastic cell; novel; novel strategies; optical imaging; optoacoustic tomography; outcome forecast; photoacoustic imaging; preclinical study; programs; receptor; targeted imaging; temporal measurement; tomography; triple-negative invasive breast carcinoma; tumor; tumor xenograft

Principal Investigator/Program Director (Last, First, Middle): Jiang, Huabei /Yang, Lily About 20% of breast cancers have a distinct signature of estrogen receptor (ER), progesterone receptor (PR) and Her-2/Neu negative. Over 60% of triple negative breast cancer (TNBC) are highly resistant to chemotherapy and have a poor prognosis. More than 50% of the TNBC patients with drug resistant residual tumors after pre-operative chemotherapy developed local and distant recurrent tumor within three years after surgery and most of them died due to tumor recurrence. This unmet clinical challenge underscores an urgent need for novel approaches for effective treatment of drug resistant TNBCs. One of the approaches that may have the most impact is to develop specific and sensitive image-guided surgery to completely remove small drug resistant tumor lesions and tumor cell involved lymph nodes. We hypothesize that a novel multimodal approach that integrates photoacoustic tomography (PAT) and fluorescence molecular tomography (FMT) in combination with multiplexed tumor biomarker targeted imaging probes can most accurately detect small drug resistant breast tumors and tumor involved lymph nodes in 3D at the microns resolution scale, thus serving as an ideal guidance for surgery of breast cancer. This first ever integrated PAT and FMT device will allow us to three-dimensionally detect small tumors (~30µm) at a depth of ~3cm, which are previously unachievable. The goal of this proposal is to advance this cutting-edge imaging technology to engineer a multimodal approach that integrates PAT and FMT into a single endoscope for optimized 3D detection of breast cancer through the use of microelectromechanical systems (MEMS). In particular, we will use multiplexed “smart” nanoprobes that are targeted to cellular receptors that are highly expressed in TNBC cancer cells, especially aggressive drug resistant cells, such as urokinase plasminogen activator receptor (uPAR) and insulin-like growth factor 1 receptor (IGF-1R) to realize multiplexed specific and sensitive molecular imaging of heterogeneous TNBC cells. A marked pathological feature of TNBC is the presence of extensive tumor stroma expressing high levels of uPAR and IGF1R. Targeting those two receptors further enhances the sensitivity of detection of small tumors (< 1 mm) with poor tumor vessels. Beyond image-guided surgery of breast cancer, we anticipate the technology to be much more broadly applicable to other pressing healthcare problems such as endoscopic detection of esophageal, colon, pancreatic and prostate cancers. This application has put together a truly multi- disciplinary research team involving investigators in imaging, MEMS, probe synthesis, cancer biology, and surgical oncology. With a long-term goal of translating the proposed technology into a clinical application, we propose to complete the following specific aims: (1) To develop a MEMS-based photoacoustic tomography system for intraoperative tumor imaging in real time; (2) To develop a MEMS based multi-modal PAT/FMT system for intraoperative tumor imaging in real time; (3) To validate and optimize the MEMS-PAT and MEMS- PAT/FMT systems using phantom and in vivo experiments; and (4) To determine sensitivity and specificity of PAT and PAT/FMT imaging using the multiplexed targeted imaging probes and evaluate the efficacy of in vivo PAT- and PAT/FMT-guided surgery in two orthotopic human TNBC patient tissue derived tumor xenograft (PDX) models in nude mice.

首席研究员/项目主任（后、一、中）：蒋华北/杨莉莉 大约 20% 的乳腺癌具有雌激素受体 (ER)、孕激素受体 (PR) 的独特特征 超过 60% 的三阴性乳腺癌 (TNBC) 对 Her-2/Neu 阴性具有高度耐药性。 超过50%的TNBC患者存在耐药残留。 术前化疗后的肿瘤在术后三年内出现局部和远处复发肿瘤 手术中大多数人因肿瘤复发而死亡，这一未解决的临床挑战凸显了紧迫性。 需要有效治疗耐药 TNBC 的新方法，这可能是其中之一。 影响最大的是开发特异性和灵敏的图像引导手术以彻底去除微小的 我们努力寻找一种新的多模式方法来治疗耐药性肿瘤病灶和涉及淋巴结的肿瘤细胞。 结合光声断层扫描（PAT）和荧光分子断层扫描（FMT）的方法 与多重肿瘤生物标志物靶向成像探针结合可以最准确地检测小药物 抗性乳腺肿瘤和涉及淋巴结的肿瘤以微米分辨率的 3D 形式显示，因此可以作为 这是乳腺癌手术的理想指导，这是首个集成 PAT 和 FMT 设备，使我们能够 三维检测~3cm深度的小肿瘤（~30μm），这是以前无法实现的。 该提案的目标是推进这种尖端成像技术，以设计多模态方法 将 PAT 和 FMT 集成到单个内窥镜中，通过 特别是，我们将使用多路复用“智能”纳米探针。 针对 TNBC 癌细胞中高表达的细胞受体，尤其是侵袭性药物 耐药细胞，例如尿激酶纤溶酶原激活剂受体 (uPAR) 和胰岛素样生长因子 1 受体（IGF-1R）来实现异质 TNBC 细胞的多重特异性和敏感分子成像。 TNBC 的一个显着病理特征是存在广泛的肿瘤基质，表达高水平的 uPAR 和 IGF1R 靶向这两种受体进一步增强了小肿瘤检测的灵敏度。 (< 1 mm) 的肿瘤血管较差，除了乳腺癌的图像引导手术外，我们预计 技术更广泛地适用于其他紧迫的医疗保健问题，例如内窥镜检查 该应用程序汇集了真正的多癌症检测。 学科研究团队包括成像、MEMS、探针合成、癌症生物学和 我们的长期目标是将所提出的技术转化为临床应用。 提出完成以下具体目标：（1）开发基于MEMS的光声层析成像技术 术中肿瘤实时成像系统；（2）开发基于MEMS的多模态PAT/FMT 术中肿瘤实时成像系统；（3）验证和优化MEMS-PAT和MEMS- 使用模型和体内实验的 PAT/FMT 系统；以及 (4) 确定 PAT/FMT 系统的敏感性和特异性。 使用多重靶向成像探针进行 PAT 和 PAT/FMT 成像并评估体内效果 PAT 和 PAT/FMT 引导的两名原位人类 TNBC 患者组织来源的肿瘤异种移植手术 (PDX) 裸鼠模型。