Optimization of a Protease Activated Probe for Optical Surgical Navigation.
Optimization of a Protease Activated Probe for Optical Surgical Navigation.
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DOI：
10.1021/acs.molpharmaceut.7b00822
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发表时间：
2017-11
影响因子：
4.9
通讯作者：
Joshua J. Yim;Martina Tholen;Alwin H. Klaassen;J. Sorger;M. Bogyo
中科院分区：
文献类型：
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作者：
Joshua J. Yim;Martina Tholen;Alwin H. Klaassen;J. Sorger;M. Bogyo
分子靶向光学造影剂有可能使外科医生能够可视化特定的分子标记物，这有助于提高手术精度，从而改善结果。通过靶向在肿瘤微环境中高度丰富的蛋白酶，猝灭的底物可用于突出肿瘤病变。然而，这些和其他分子靶向光学造影剂中的大多数用报告染料标记，所述报告染料与临床照相机系统的性质不理想地匹配，所述临床照相机系统通常被优化用于检测吲哚菁绿（ICG）。虽然广泛的近红外（NIR）染料适用于高灵敏度和高度可调的研究重点小动物成像系统，但大多数尚未评估用于常用的临床成像系统。在这里，我们报告了优化的小分子荧光猝灭蛋白酶底物探针6 QC-ICG，它使用吲哚菁绿色（ICG）染料作为其光学报告。我们评估了该分子在荷瘤小鼠中的剂量和动力学参数，并在2.3 mg/kg的剂量下在短至90 min内观察到超过背景信号的最佳肿瘤。重要的是，肿瘤中探针信号的荧光强度与剂量不成线性关系，这表明详细给药研究的重要性。此外，当使用FDA批准的具有萤火虫检测的da芬奇Si手术系统成像时，与含有具有类似量子产率但具有稍微偏移的激发和发射分布的染料的相应探针相比，ICG探针的信号显著更高。ICG标记探针的最佳染料和剂量产生的增加的信号强度使得能够检测直径小于5 mm的小的平坦病变。因此，6 QC-ICG是一种高灵敏度探头，可与临床成像系统配合使用，在光学手术导航方面具有巨大的应用潜力。
Molecularly targeted optical contrast agents have the potential to enable surgeons to visualize specific molecular markers that can help improve surgical precision and thus outcomes. Fluorescently quenched substrates can be used to highlight tumor lesions by targeting proteases that are highly abundant in the tumor microenvironment. However, the majority of these and other molecularly targeted optical contrast agents are labeled with reporter dyes that are not ideally matched to the properties of clinical camera systems, which are typically optimized for detection of indocyanine-green (ICG). While a wide range of near-infrared (NIR) dyes are suitable for use with highly sensitive and highly tunable research-focused small animal imaging systems, most have not been evaluated for use with commonly used clinical imaging systems. Here we report the optimization of a small molecule fluorescently quenched protease substrate probe 6QC-ICG, which uses the indocyanine green (ICG) dye as its optical reporter. We evaluated dosing and kinetic parameters of this molecule in tumor-bearing mice and observed optimal tumor over background signals in as little as 90 min with a dose of 2.3 mg/kg. Importantly, the fluorescence intensity of the probe signal in tumors did not linearly scale with dose, suggesting the importance of detailed dosing studies. Furthermore, when imaged using the FDA approved da Vinci Si surgical system with Firefly detection, signals were significantly higher for the ICG probe compared to a corresponding probe containing a dye with similar quantum yield but with a slightly shifted excitation and emission profile. The increased signal intensity generated by the optimal dye and dose of the ICG labeled probe enabled detection of small, flat lesions that were less than 5 mm in diameter. Therefore, 6QC-ICG is a highly sensitive probe that performs optimally with clinical imaging systems and has great potential for applications in optical surgical navigation.