Significance: The use of cancer-targeted contrast agents in fluorescence-guided surgery (FGS) has the potential to improve intraoperative visualization of tumors and surgical margins. However, evaluation of their translational potential is challenging. Aim: We examined the utility of a somatostatin receptor subtype-2 (SSTR2)-targeted fluorescent agent in combination with a benchtop near-infrared fluorescence (NIRF) imaging system to visualize mouse xenografts under conditions that simulate the clinical FGS workflow for open surgical procedures. Approach: The dual-labeled somatostatin analog, Ga67-MMC(IR800)-TOC, was injected into mice (n = 24) implanted with SSTR2-expressing tumors and imaged with the customized OnLume NIRF imaging system (Madison, Wisconsin). In vivo and ex vivo imaging were performed under ambient light. The optimal dose (0.2, 0.5, and 2 nmol) and imaging time point (3, 24, 48, and 72 h) were determined using contrast-to-noise ratio (CNR) as the image quality parameter. Video captures of tumor resections were obtained to provide an FGS readout that is representative of clinical utility. Finally, a log-transformed linear regression model was fitted to assess congruence between fluorescence readouts and the underlying drug distribution. Results: The drug–device combination provided high in vivo and ex vivo contrast (CNRs > 3, except lung at 3 h) at all time points with the optimal dose of 2 nmol. The optimal imaging time point was 24-h post-injection, where CNRs > 6.5 were achieved in tissues of interest (i.e., pancreas, small intestine, stomach, and lung). Intraoperative FGS showed excellent utility for examination of the tumor cavity pre- and post-resection. The relationship between fluorescence readouts and gamma counts was linear and strongly correlated (n = 334, R2 = 0.71; r = 0.84; P < 0.0001). Conclusion: The innovative OnLume NIRF imaging system enhanced the evaluation of Ga67-MMC(IR800)-TOC in tumor models. These components comprise a promising drug–device combination for FGS in patients with SSTR2-expressing tumors.

中文翻译：

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开发用于神经内分泌肿瘤荧光引导手术的药物-设备组合


意义：在荧光引导手术（FGS）中使用癌症靶向造影剂有可能改善肿瘤和手术边缘的术中可视化。然而，评估它们的转化潜力具有挑战性。目的：我们检查了生长抑素受体亚型 2 (SSTR2) 靶向荧光剂与台式近红外荧光 (NIRF) 成像系统相结合的实用性，以在模拟开放式外科手术临床 FGS 工作流程的条件下可视化小鼠异种移植物。方法：将双标记的生长抑素类似物 Ga67-MMC(IR800)-TOC 注射到植入表达 SSTR2 的肿瘤的小鼠 (n = 24) 中，并使用定制的 OnLume NIRF 成像系统（威斯康星州麦迪逊）进行成像。体内和离体成像在环境光下进行。使用对比度噪声比（CNR）作为图像质量参数确定最佳剂量（0.2、0.5和2 nmol）和成像时间点（3、24、48和72小时）。获得肿瘤切除的视频捕获以提供代表临床实用性的 FGS 读数。最后，拟合对数转换线性回归模型来评估荧光读数和潜在药物分布之间的一致性。结果：药物-器械组合在所有时间点都提供了高体内和离体对比度（CNR > 3，除了 3 小时的肺），最佳剂量为 2 nmol。最佳成像时间点是注射后 24 小时，此时感兴趣组织（即胰腺、小肠、胃和肺）的 CNR > 6.5。术中 FGS 对于切除术前和切除后的肿瘤腔检查显示出极好的实用性。 荧光读数和伽玛计数之间的关系呈线性且强相关（n = 334，R2 = 0.71；r = 0.84；P < 0.0001）。结论：创新的 OnLume NIRF 成像系统增强了 Ga67-MMC(IR800)-TOC 在肿瘤模型中的评估。这些组件构成了一种有前途的药物-设备组合，可用于表达 SSTR2 的肿瘤患者的 FGS。