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

摘要 乳腺癌手术切除的准确与否直接影响患者的预后。然而，它经常是 外科医生在无手术切除的情况下很难或不可能区分乳腺肿瘤和正常组织 任何术中影像指导。准确识别肿瘤边缘并完全切除肿瘤边缘 肿瘤在最初的外科手术中将会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了吸引力，特别是在耦合时 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 具有高分辨率图像实时检测、仪器灵活等诸多优点 没有电离辐射。此外，添加增强对比度的近红外成像可以显示疾病 并且不改变手术视野的外观。吲哚青绿 (ICG)是一种近红外荧光剂，目前已由FDA注册用于临床，但未用于 肿瘤学。为了使用无毒的ICG作为术中肿瘤标志物，肿瘤的发展- 瞄准航母是必不可少的。 已经在开发载体分子方面进行了许多尝试，特别是穿透细胞的载体分子 多肽(Cpp)已被证明是一种很有前途的策略，可以改善药物的释放和细胞内摄取。 诊断和治疗药物。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要长得多。我们假设发展p28作为一种 无毒的肿瘤靶向ICG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。这一新的成像分子的初步数据(p28 与ICG化学结合，ICG-p28)支持这一假说。我们将采取战略方法进行测试 我们的假设在多个乳腺癌动物模型中具有临床相关性。它潜在地提供了 基于防止复发从而降低风险的独特方法产生重大影响 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.