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

摘要 乳腺癌的精确手术切除直接影响患者的预后。然而，它往往 外科医生在切除过程中难以或不可能区分乳腺肿瘤和正常组织， 任何术中图像引导。准确识别肿瘤边缘并完全切除肿瘤 在初次手术时对肿瘤的了解将对乳腺肿瘤手术有相当大的帮助。 最近，光学成像在图像引导手术领域获得牵引力，特别是当耦合 用近红外（NIR）荧光剂。近红外荧光图像引导手术也为外科医生提供了 具有实时检测、图像分辨率高、仪器灵活等诸多优点 没有电离辐射。此外，添加增强对比度的NIR成像使疾病可视化 并且不会改变手术视野的外观。吲哚菁绿色 (ICG)是一种NIR荧光剂，目前已由FDA注册用于临床应用，但不用于 肿瘤学为了使用无毒的ICG作为术中肿瘤标记物， 靶向载体至关重要。 在开发载体分子，特别是细胞穿透性载体分子方面，已经进行了许多尝试。 肽（CPPs）已被证明是改善递送和细胞内摄取的有前途的策略 诊断和治疗药物的。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p28的发育是一种 ICG的无毒肿瘤靶向载体将提供一种理想的术中显像剂， 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）支持该假设。我们将采取战略性的方法来测试 我们在多种乳腺癌动物模型中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，从而降低 转移性疾病和死亡率。

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.