肿瘤乏氧靶向响应的罗丹明荧光探针及其成像介导手术治疗

基于罗丹明的良好荧光性能, 经化学偶联反应制备并表征了一个偶氮乏氧特异响应的“Off-On”型荧光成像探针(FY-4). 从分子层面证实了其荧光“Off-On”性能和响应机制; 在L02正常细胞及4T1, HeLa和A549肿瘤细胞层面考察了其对受试细胞株的毒性和不同乏氧时间的荧光成像性能; 再利用4T1肿瘤模型, 分别以肿瘤原位注射和尾静脉注射的方式考察了其荧光成像性能, 并探究了其荧光成像介导切除肿瘤性能, 最后还考察了FY-4的生物安全性. 结果表明, FY-4有高的肿瘤乏氧靶向特异“关-开”响应的荧光成像差异显影及荧光成像介导切除肿瘤的潜能, 结合其良好的光物理性能、 生物安全性和明晰的给药时间等特性, 有望为生物医学荧光成像介导肿瘤切除提供新的研究工具.

Rhodamine Fluorescent Probe for Tumor Targeted Hypoxia-imaging as Intra-operative Navigators

Determination of tumor boundary during surgery has a great significance to achieving precise resection. The level of tumor hypoxia is closely related to the local concentration of reducing substances such as azobenzene reductases（azoreductases， AzoR， an important class of biocatalysts in solid tumor）， AzoR is able to reduce the nitrogen double bond（—N=N—） of azobenzene compounds to generate anilines. Therefore， the characterization might serve as optical AzoR probe during image-guided surgery， which exhibits wide range of application prospects in biomedicine field. In order to obtain a probe for tumor hypoxia fluorescence image-guided surgery with good targeting， low toxicity， good biocompatibility and high specificity， based on the molecular cleavage of azobenzene induced by azoreductase hypoxia and the good fluorescence performance of rhodamine， an “Off-On” type tumor with a specific response to near-infrared azohypoxia was prepared and characterized by chemical coupling. Then we confirmed its fluorescence “Off-On” performance and response mechanism from the molecular level； at the level of L02， 4T1， HeLa， and A549 tumor cells， the toxicity of the tested cell lines and the imaging performance on different hypoxia periods was also investigated. Next， 4T1 tumor model was further constructed， and the performance of tumor in situ injection and tail vein injection fluorescence imaging were studied respectively. Furthermore， the performance of fluorescence imaging-mediated surgery of tumors was further explored. On this basis， the biological safety performance was investigated. The results show that this rhodamine azo probe has high target-specific tumor hypoxia responsiveness and excellent fluorescence imaging-mediated tumor surgery potential， combined with its good photophysical properties， controlled administration time， and biological security， which is expected to provide new research tools for biomedical fluorescence imaging-mediated tumor resection.