Development of a New Fluorescent Agent for Intraoperative Image-Guided Breast Cancer Surgery

开发用于术中图像引导乳腺癌手术的新型荧光剂

• 批准号: 9903292
• 负责人: Tohru Yamada
• 金额: $ 35.98万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9903292
• 关键词: 3-Dimensional; Address; Angiography; Animal Cancer Model; Animals; Appearance; Breast Cancer Cell; Breast Cancer Treatment; Breast-Conserving Surgery; Cell Cycle Arrest; Cells; Clinic; Clinical; Clinical Trials; Coupled; Data; Detection; Development; Diagnostic; Disease; Early Diagnosis; Excision; FDA approved; Fluorescence; Fluorescent Dyes; Goals; Hepatic; Human; Image; Image-Guided Surgery; Ionizing radiation; Knowledge; Label; Left; Link; Localized Lesion; Location; Magnetic Resonance Imaging; Malignant Neoplasms; Mammary Neoplasms; Mammography; Mediating; Methods; Near-infrared optical imaging; Neoplasm Metastasis; Noise; Noninfiltrating Intraductal Carcinoma; Normal Cell; Normal tissue morphology; Oncology; Operating Rooms; Operative Surgical Procedures; Palpation; Pathologic Processes; Patients; Peptides; Positioning Attribute; Pre-Clinical Model; Primary Neoplasm; Protocols documentation; Recurrence; Repeat Surgery; Research; Risk; Safety; Signal Transduction; Study Section; Surgeon; TP53 gene; Technology; Testing; Therapeutic Agents; Time; Tissues; Traction; Transgenic Mice; Transplantation; Tumor Markers; Ultrasonography; Visual; Visual Perception; Xenograft Model; Xenograft procedure; base; cancer cell; cancer surgery; chemical conjugate; clinical application; clinical translation; clinically relevant; contrast enhanced; cost effective; design; expectation; flexibility; fluorescence imaging; high resolution imaging; image guided; imaging agent; imaging modality; imaging system; improved; instrument; malignant breast neoplasm; molecular imaging; mortality; mouse model; novel; operation; optical imaging; outcome forecast; pre-clinical; prevent; standard of care; targeted delivery; targeted imaging; tool; tumor; uptake

ABSTRACT The precise surgical resection of breast cancer directly influences patient prognosis. However, it is often difficult or impossible for surgeons to distinguish breast tumor from normal tissue during resection without any intraoperative image guidance. Accurate identification of tumor margins and complete removal of the tumor at the initial surgical operation will be of considerable help in a breast tumor operation. Recently, optical imaging is gaining traction in the image-guided surgery field especially when coupled with near infrared (NIR) fluorescence agent. NIR fluorescent image-guided surgery also affords surgeons numerous advantages such as real-time detection with high-resolution image, and flexible instrument without ionizing radiation. Furthermore, NIR imaging with addition of enhanced-contrast visualizes disease prior to transection, and does not change the appearance of the surgical field of view. Indocyanin green (ICG) is a NIR fluorescence agent and currently registered by the FDA for clinical applications, but not for oncology. In order to use non-toxic ICG as an intraoperative tumor marker, development of a tumor- targeting carrier is essential. Many attempts have been made in the development of carrier molecules, in particular, cell-penetrating peptides (CPPs) have shown to be a promising strategy for improving the delivery and intracellular uptake of diagnostic and therapeutic agents. We have identified that a non-toxic CPP, p28, preferentially enters and is retained significantly longer in breast cancer cells. We hypothesize that developing p28 as a nontoxic tumor-targeting carrier for ICG will provide an ideal intraoperative imaging agent to clearly distinguish tumor and surrounding normal tissue. Preliminary data with this new imaging molecule (p28 chemically conjugated to ICG, ICG-p28) support the hypothesis. We will take a strategic approach to test our hypothesis in clinically relevant setting in multiple breast cancer animal models. It potentially provides significant impact based on unique approach to prevent recurrence and consequently reduce risk of metastatic disease and mortality.

抽象的 乳腺癌的精确手术切除直接影响患者的预后。但是，通常是 外科医生在切除过程中很难区分乳腺肿瘤和正常组织 任何术中图像指导。准确鉴定肿瘤边缘并完全去除 最初的手术手术中的肿瘤将在乳腺肿瘤手术中有很大帮助。 最近，光学成像正在在图像引导的手术场中获得吸引力，尤其是当耦合时 带有近红外（NIR）荧光剂。 NIR荧光图像引导手术也提供外科医生 许多优点，例如具有高分辨率图像的实时检测和灵活的仪器 没有电离辐射。此外，NIR成像并增加了增强对比的对比度可视化疾病 在横断之前，不会改变手术视野的外观。吲哚美蛋白绿 （ICG）是NIR荧光剂，目前由FDA注册用于临床应用，但不是 肿瘤学。为了将无毒的ICG用作术中肿瘤标记，肿瘤的发展 定位载体至关重要。 在载体分子的开发中已经进行了许多尝试，尤其是细胞渗透 肽（CPP）已证明是改善递送和细胞内摄取的有前途的策略 诊断和治疗剂。我们已经确定无毒的CPP P28优先进入 并在乳腺癌细胞中保持更长的时间。我们假设将p28作为一个 ICG的无毒肿瘤携带者将提供理想的术中成像剂，以清楚 区分肿瘤和周围正常组织。使用这种新成像分子的初步数据（p28 化学结合到ICG，ICG-P28）支持该假设。我们将采用战略方法进行测试 我们在多种乳腺癌动物模型中与临床相关环境中的假设。它有可能提供 基于独特的方法来防止复发，从而降低的风险 转移性疾病和死亡率。