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Cerenkov-Activated Sticky Tag for In Vivo Fluorescence Imaging
The Journal of Nuclear Medicine ( IF 9.1 ) Pub Date : 2018-01-01 , DOI: 10.2967/jnumed.117.198549
Sudeep Das , Katja Haedicke , Jan Grimm

A big challenge in the clinical use of Cerenkov luminescence (CL) imaging is its low signal intensity, which is several orders of magnitude below ambient light. Consequently, highly sensitive cameras, sufficient shielding from background light, and long acquisition times are required. To alleviate this problem, we hypothesized a strategy to convert the weak CL signal into a stronger fluorescence signal by using CL-activated formation of nitrenes from azides to locally fix a fluorescent probe in tissue by the formation of a covalent bond. CL-activated drug delivery was also evaluated using the same azide chemistry. The specific delivery of the CL-activated drug to cancer cells could reduce systemic toxicity, which is a limitation in chemotherapy. Methods: A cyanine-class near-infrared fluorescent dye, Cy7, and doxorubicin were synthetically attached to polyfluorinated aryl azide to form Cy7 azide and DOX azide, respectively. Fibrosarcoma cells were incubated with 18F-FDG and exposed to Cy7 azide with subsequent fluorescence imaging. For CL-activated tagging in vivo, tumor-bearing mice were injected first with 90Y-DOTA-RGD, targeting αvβ3 integrins, and then with the Cy7 azide. Fluorescence signal was imaged over time. Breast cancer cells were incubated with DOX azide and 68Ga, after which cell viability was quantified using an assay. Results: CL photoactivation of Cy7 azide in vitro showed significantly higher fluorescence signal from 18F-FDG–treated than untreated cells. In vivo, CL photoactivation could be shown by using the tumor-specific, integrin-targeting 90Y-DOTA-RGD and the localized activation of Cy7 azide. Here, localized CL-induced fluorescence was detected in the tumors and remained significantly higher over several days than in tumors without CL. We also established as a next step CL-activated drug delivery of DOX azide by showing significantly decreasing cell viability of breast cancer cells in a CL dose–dependent manner in vitro using CL photoactivation of DOX azide. Conclusion: We were able to develop a CL-activated “sticky tag” that converts the low CL signal into a stable and long-lasting, highly intense fluorescence signal. This fluorescent footprint of the radioactive signal might be clinically used for intraoperative surgery. The CL-targeted drug delivery strategy may potentially be used for dual-step targeted therapy.



中文翻译:

切伦科夫激活的体内荧光成像粘性标签

切伦科夫发光(CL)成像的临床应用中的一大挑战是其低信号强度,该信号强度比环境光低几个数量级。因此,需要高灵敏度的相机,对背景光的充分屏蔽以及较长的采集时间。为了缓解此问题,我们假设了一种策略,该方法是通过使用CL活化的叠氮化物形成的腈,通过共价键的形成将荧光探针局部固定在组织中,从而将弱CL信号转换为更强的荧光信号。还使用相同的叠氮化物化学评估了CL激活的药物递送。CL活化药物向癌细胞的特异性递送可以降低全身毒性,这是化学疗法的局限性。方法:将花青类近红外荧光染料Cy7和阿霉素合成连接到多氟芳基叠氮化物上,分别形成Cy7叠氮化物和DOX叠氮化物。将纤维肉瘤细胞与18 F-FDG孵育,并暴露于Cy7叠氮化物,随后进行荧光成像。对于体内CL-激活标记,荷瘤小鼠用第一注射90 Y型DOTA-RGD靶向α v β 3点整联,然后与叠氮化Cy7的。荧光信号随时间成像。将乳腺癌细胞与DOX叠氮化物和68 Ga孵育,然后使用测定法对细胞活力进行定量。结果:Cy7叠氮化物的体外CL光活化显示,经18 F-FDG处理的细胞的荧光信号明显高于未处理的细胞。在体内,CL光活化可以通过使用肿瘤特异性,整联蛋白靶向的90 Y-DOTA-RGD和Cy7叠氮化物的局部活化来显示。在这里,在肿瘤中检测到局部CL诱导的荧光,并且在几天内仍显着高于没有CL的肿瘤。我们还通过下一步使用CL光激活DOX叠氮化物以CL剂量依赖性方式显示乳腺癌细胞的细胞活力,从而显着降低了DOX叠氮化物的CL激活药物的递送。结论:我们能够开发出CL激活的“粘性标签”,将低CL信号转换为稳定且持久的高强度荧光信号。放射性信号的这种荧光足迹可能在临床上用于术中手术。CL靶向的药物递送策略可以潜在地用于双步靶向治疗。

更新日期:2018-01-02
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