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The multiplexity of cancer has rendered it the second leading cause of mortality worldwide and theragnostic prodrugs have gained popularity in recent years as a means of treatment. Theragnostic prodrugs enable the simultaneous diagnosis and therapy of tumors via high-precision real-time drug release monitoring. Herein, we report the development of the small theragnostic prodrug GF, based on the nucleoside anticancer agent gemcitabine and the fluorescent dye 5(6)-carboxyfluorescein. We have successfully demonstrated its efficient internalization in tumor cells, showing localization throughout both the early and late endocytic pathways. Its mechanism of cell internalization was evaluated, confirming its independence from nucleoside transporters. Its cellular localization via confocal microscopy revealed a clathrin-mediated endocytosis mechanism, distinguishing it from analogous compounds studied previously. Furthermore, GF exhibited stability across various pH values and in human blood plasma. Subsequently, its in vitro cytotoxicity was assessed in three human cancer cell lines (A549, U87 and T98). Additionally, its pharmacokinetic profile in mice was investigated and the consequent drug release was monitored. Finally, its in vivo visualization was accomplished in zebrafish xenotransplantation models and its in vivo efficacy was evaluated in A549 xenografts. The results unveiled an intriguing efficacy profile, positioning GF as a compelling candidate warranting further investigation., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Simple Summary: This review highlights the recent advances in the development and application of dual function kinase inhibitors that also bear fluorescent properties (fluorescent kinase inhibitors), thus can be used as theranostics in the field of cancer. This is a rapidly growing field with significant potential for cancer therapy and diagnosis. This work mainly focuses on the key design principles that guide the development of these multifunctional compounds, emphasizing the integration of essential components such as the kinase cytotoxic warhead, the fluorophore, the linkers, and additional modular elements to enhance the efficacy of the final assembled compound. We anticipate this review to propel the advancement of this field by improving the understanding of the design principles and ultimately leading to the development of more effective tools for the concurrent diagnosis and treatment of cancer. Kinase inhibitors are potent therapeutic agents in cancer treatment, but their effectiveness is frequently restricted by the inability to image the tumor microenvironment. To address this constraint, kinase inhibitor–fluorophore conjugates have emerged as promising theranostic agents, allowing for simultaneous cancer diagnosis and treatment. These conjugates are gaining attention for their ability to visualize malignant tissues and concurrently enhance therapeutic interventions. This review explores the design principles governing the development of multimodal inhibitors, highlighting their potential as platforms for kinase tracking and inhibition via bioimaging. The structural aspects of constructing such theranostic agents are critically analyzed. This work could shed light on this intriguing field and provide adequate impetus for developing novel theranostic compounds based on small molecule inhibitors and fluorophores. [ABSTRACT FROM AUTHOR]

The multiplexity of cancer has rendered it the second leading cause of mortality worldwide and theragnostic prodrugs have gained popularity in recent years as a means of treatment. Theragnostic prodrugs enable the simultaneous diagnosis and therapy of tumors via high‐precision real‐time drug release monitoring. Herein, we report the development of the small theragnostic prodrug GF, based on the nucleoside anticancer agent gemcitabine and the fluorescent dye 5(6)‐carboxyfluorescein. We have successfully demonstrated its efficient internalization in tumor cells, showing localization throughout both the early and late endocytic pathways. Its mechanism of cell internalization was evaluated, confirming its independence from nucleoside transporters. Its cellular localization via confocal microscopy revealed a clathrin‐mediated endocytosis mechanism, distinguishing it from analogous compounds studied previously. Furthermore, GF exhibited stability across various pH values and in human blood plasma. Subsequently, its in vitro cytotoxicity was assessed in three human cancer cell lines (A549, U87 and T98). Additionally, its pharmacokinetic profile in mice was investigated and the consequent drug release was monitored. Finally, its in vivo visualization was accomplished in zebrafish xenotransplantation models and its in vivo efficacy was evaluated in A549 xenografts. The results unveiled an intriguing efficacy profile, positioning GF as a compelling candidate warranting further investigation. [ABSTRACT FROM AUTHOR]