Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305.
Department of Radiology, Bio-X Program and Molecular Imaging Program, Stanford University School of Medicine, Stanford, CA 94305.
Proc Natl Acad Sci U S A. 2021 Jan 5;118(1). doi: 10.1073/pnas.2008072118.
Fluorescence imaging is currently being actively developed for surgical guidance; however, it remains underutilized for diagnostic and endoscopic surveillance of incipient colorectal cancer in high-risk patients. Here we demonstrate the utility and potential for clinical translation of a fluorescently labeled cathepsin-activated chemical probe to highlight gastrointestinal lesions. This probe stays optically dark until it is activated by proteases produced by tumor-associated macrophages and accumulates within the lesions, enabling their detection using an endoscope outfitted with a fluorescence detector. We evaluated the probe in multiple murine models and a human-scale porcine model of gastrointestinal carcinogenesis. The probe provides fluorescence-guided surveillance of gastrointestinal lesions and augments histopathological analysis by highlighting areas of dysplasia as small as 400 µm, which were visibly discernible with significant tumor-to-background ratios, even in tissues with a background of severe inflammation and ulceration. Given these results, we anticipate that this probe will enable sensitive fluorescence-guided biopsies, even in the presence of highly inflamed colorectal tissue, which will improve early diagnosis to prevent gastrointestinal cancers.
荧光成像是目前用于手术指导的一种活跃的研究方法，但它在高风险患者的结直肠肿瘤的早期诊断和内镜监测中仍未得到充分利用。在这里，我们展示了一种荧光标记的组织蛋白酶激活化学探针的实用性和临床转化的潜力，该探针可用于突出胃肠道病变。这种探针在未被蛋白酶激活之前一直处于暗态，只有在被肿瘤相关巨噬细胞产生的蛋白酶激活后，才会在病变部位积累，并通过配备荧光探测器的内窥镜进行检测。我们在多个小鼠模型和人类规模的胃肠道癌变猪模型中评估了该探针。该探针可提供胃肠道病变的荧光引导监测，并通过突出小于 400µm 的异型增生区域来增强组织病理学分析，即使在伴有严重炎症和溃疡的组织中，也能以高肿瘤与背景的比值来清晰地分辨出这些区域。鉴于这些结果，我们预计该探针将能够进行敏感的荧光引导活检，即使在存在高度炎症性结直肠组织的情况下，也能提高早期诊断，以预防胃肠道癌症。
