Two-Photon Photodynamic Therapy Targeting Cancers with Low Carboxylesterase 2 Activity Guided by Ratiometric Fluorescence
Karishma Kailass, Oleg Sadovski, Warren R. Zipfel, Andrew A. Beharry
Abstract
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.