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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的乳腺癌的精准手术切除直接影响患者的预后。然而，往往是外科医生在切除过程中很难或不可能在不进行手术的情况下将乳腺肿瘤与正常组织区分开来。任何术中图像引导。准确识别肿瘤边缘并彻底切除初次手术时的肿瘤将对乳腺肿瘤手术有很大帮助。最近，光学成像在图像引导手术领域越来越受到关注，特别是当耦合时具有近红外（NIR）荧光剂。近红外荧光图像引导手术也为外科医生提供了帮助具有高分辨率图像实时检测、仪器灵活等众多优点无电离辐射。此外，近红外成像加上增强对比度可以使疾病可视化在横切之前，并且不会改变手术视野的外观。吲哚青绿 (ICG)是一种近红外荧光剂，目前已在FDA注册用于临床应用，但尚未注册用于临床应用。肿瘤学。为了使用无毒的ICG作为术中肿瘤标志物，开发了一种肿瘤- 靶向载体至关重要。在载体分子的开发方面已经进行了许多尝试，特别是细胞穿透性载体分子肽（CPP）已被证明是改善递送和细胞内摄取的有前途的策略的诊断剂和治疗剂。我们已经确定无毒的 CPP p28 优先进入并且在乳腺癌细胞中保留的时间明显更长。我们假设将 p28 开发为 ICG的无毒肿瘤靶向载体将提供理想的术中显像剂区分肿瘤和周围正常组织。这种新成像分子的初步数据 (p28 与 ICG 化学缀合，ICG-p28）支持这一假设。我们将采取战略方法来测试我们在多种乳腺癌动物模型的临床相关环境中的假设。它可能提供基于防止复发的独特方法产生重大影响，从而降低风险转移性疾病和死亡率。