Human carboxylesterase 2 (hCES2) converts anticancer prodrugs, such as irinotecan, into their active metabolites via phase I drug metabolism. Owing to interindividual variability, hCES2 serves as a predictive marker of patient response to hCES2-activated prodrug-based therapy, whereby a low intratumoral hCES2 activity leads to therapeutic resistance. Despite the ability to identify nonresponders, effective treatments for resistant patients are needed. Clinically approved photodynamic therapy is an attractive alternative for irinotecan-resistant patients. Here, we describe the application of our hCES2-selective small-molecule ratiometric fluorescent chemosensor, Benz-AP, as a single theranostic agent given its discovered functionality as a photosensitizer. Benz-AP produces singlet oxygen and induces photocytotoxicity in cancer cells in a strong negative correlation with hCES2 activity. Two-photon excitation of Benz-AP produces fluorescence, singlet oxygen, and photocytotoxicity in tumor spheroids. Overall, Benz-AP serves as a novel theranostic agent with selective photocytotoxicity in hCES2-prodrug resistant cancer cells, making Benz-AP a promising agent for in vivo applications.

中文翻译：

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由比率荧光引导的低羧基酯酶 2 活性靶向癌症的双光子光动力疗法

人羧酸酯酶 2 (hCES2)通过I 期药物代谢将抗癌前药（如伊立替康）转化为其活性代谢物。由于个体间的变异性，hCES2 可作为患者对基于 hCES2 激活的前药治疗反应的预测标志物，从而低肿瘤内 hCES2 活性导致治疗抗性。尽管能够识别无反应者，但仍需要对耐药患者进行有效治疗。临床批准的光动力疗法是伊立替康耐药患者的一种有吸引力的替代方案。在这里，我们描述了我们的 hCES2 选择性小分子比率荧光化学传感器Benz-AP作为单一治疗诊断剂的应用，因为它具有作为光敏剂的发现功能。奔驰-AP产生单线态氧并在癌细胞中诱导光细胞毒性，与 hCES2 活性呈强负相关。Benz-AP的双光子激发在肿瘤球体中产生荧光、单线态氧和光细胞毒性。总体而言，Benz-AP作为一种新型治疗诊断剂，在 hCES2 前药耐药癌细胞中具有选择性光细胞毒性，使Benz-AP成为一种有前途的体内应用药物。