Evaluation of Novel Tumor-Targeted Near-Infrared Probe for Fluorescence-Guided Surgery of Cancer

Because the most reliable therapy for cancer involves quantitative resection of all diseased tissue, considerable effort has been devoted to improving a surgeon’s ability to locate and remove all malignant lesions. With the aid of improved optical imaging equipment, we and others have focused on developing tumor-targeted fluorescent dyes to selectively illuminate cancer nodules during surgery. We describe here the design, synthesis, optical properties, in vitro and in vivo tumor specificity/affinity, pharmacokinetics, preclinical toxicology, and some clinical application of a folate receptor (FR)-targeted NIR dye (OTL38) that concentrates specifically in cancer tissues and clears rapidly from healthy tissues. We demonstrate that OTL38 binds FR-expressing cells with ∼1 nM affinity and eliminates from receptor negative tissues with a half-time of <30 min. We further show that OTL38 enables visualization of malignant lesions at concentrations less than 100-fold those required to elicit signs of toxicity. Since OTL38 also provides excellent tumor contrast in both murine tumor models and human cancer patients, we conclude that OTL38 constitutes an excellent NIR dye for fluorescence-guided resection of malignant lesions in cancer patients.鉴于癌症最可靠的治疗方案需对所有病变组织进行精准切除，学界已投入大量精力以提升外科医生定位并切除全部恶性病灶的能力。借助改良后的光学成像设备，我们与其他研究团队均致力于开发肿瘤靶向荧光染料，从而在手术过程中选择性点亮癌结节。本文详述了一款靶向叶酸受体（folate receptor, FR）的近红外（near-infrared, NIR）染料OTL38的设计、合成、光学特性、体外与体内肿瘤特异性/亲和力、药代动力学、临床前毒理学及部分临床应用场景；该染料可特异性富集于癌组织，并能快速从健康组织中清除。研究证实，OTL38以约1纳摩尔的亲和力结合表达FR的细胞，且能在受体阴性组织中以小于30分钟的半衰期完成清除。进一步研究表明，OTL38可在远低于引发毒性反应所需浓度（仅为其1/100以下）的条件下，实现恶性病灶的可视化成像。鉴于OTL38在小鼠肿瘤模型与人类癌症患者中均能提供优异的肿瘤对比度，我们认为其是一款适用于癌症患者恶性病灶荧光引导切除的优质近红外染料。