Specific Targeting of Somatostatin Receptor Subtype-2 for Fluorescence-Guided Surgery.
Specific Targeting of Somatostatin Receptor Subtype-2 for Fluorescence-Guided Surgery.
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用于荧光引导手术的生长抑素受体亚型 2 的特异性靶向。
DOI：
10.1158/1078-0432.ccr-18-3312
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Azhdarinia,Ali
中科院分区：
文献类型：
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作者：
HernandezVargas,Servando;Kossatz,Susanne;Voss,Julie;Ghosh,SukhenC;TranCao,HopS;Simien,Jo;Reiner,Thomas;Dhingra,Sadhna;Fisher,WilliamE;Azhdarinia,Ali
临床上可用于辅助外科医生识别隐匿性病变的术中影像工具是有限的，也是神经内分泌肿瘤(Net)患者疾病复发率高的部分原因。以放射性标记的生长抑素类似物的临床疗效为模型，我们证明了荧光生长抑素类似物选择性靶向过度表达生长抑素受体亚型2(SSTR2)的肿瘤的能力，并展示了其在荧光引导手术(FGS)中的实用性。实验设计使用多模络合剂(MMC)作为“放射性连接物”来合成荧光标记的生长抑素类似物67/68Ga-MMC(IR800)-TOC。在体内研究中，确定了表达SSTR2的组织的药代动力学、最佳成像时间点和特异性。切除的组织和冰冻切片也进行了中观和显微成像，以进一步评估特异性结合，并使用来自胰腺NET患者的外科生物显微镜检测与人Net的结合。结果67Ga/68Ga直接标记提供了与荧光数据相一致的定量生物分布分析。受体介导的摄取在活体中观察到在宏观、中观和微观尺度上。来自胰腺网络患者的外科生物显微镜也显示了受体特异性的试剂结合，可以清楚地描绘出与病理结果相匹配的肿瘤边界。结论MMC的放射性效用使我们能够验证一种新型FGS试剂的结合特性，该试剂可以通过为外科医生配备实时术中成像能力来对癌症预后产生广泛影响。
PurposeClinically available intraoperative imaging tools to assist surgeons in identifying occult lesions are limited and partially responsible for the high rate of disease recurrence in patients with neuroendocrine tumors (NET). Using the established clinical efficacy of radiolabeled somatostatin analogs as a model, we demonstrate the ability of a fluorescent somatostatin analog to selectively target tumors that overexpress somatostatin receptor subtype-2 (SSTR2) and demonstrate utility for fluorescence-guided surgery (FGS).Experimental DesignA multimodality chelator (MMC) was used as a “radioactive linker” to synthesize the fluorescently labeled somatostatin analog,67/68Ga-MMC(IR800)-TOC.In vivostudies were performed to determine the pharmacokinetic profile, optimal imaging time point, and specificity for SSTR2-expressing tissues. Meso- and microscopic imaging of resected tissues and frozen sections were also performed to further assess specific binding, and binding to human NETs was examined using surgical biospecimens from patients with pancreatic NETs.ResultsDirect labeling with67Ga/68Ga provided quantitative biodistribution analysis that was in agreement with fluorescence data. Receptor-mediated uptake was observedin vivoandex vivoat the macro-, meso-, and microscopic scales. Surgical biospecimens from patients with pancreatic NETs also displayed receptor-specific agent binding, allowing clear delineation of tumor boundaries that matched pathology findings.ConclusionsThe radioactive utility of the MMC allowed us to validate the binding properties of a novel FGS agent that could have a broad impact on cancer outcomes by equipping surgeons with real-time intraoperative imaging capabilities.