A Thioacetal Photocage Designed for Dual Release: Application in the Quantitation of Therapeutic Release via Synchronous Reporter Decaging

• Published in: Chembiochem : a European journal of chemical biology 2016-11, Vol.18 (1), p.126-135
• Main Authors: Wong, Pamela T., Tang, Shengzhuang, Cannon, Jayme, Mukherjee, Jhindan, Isham, Danielle, Gam, Kristina, Payne, Michael, Yanik, Sean A., Baker, James R., Choi, Seok Ki
• Format: Article
• Language: English
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.201600494

Despite the immense potential, application of existing photocaging technology is limited by the paucity of advanced caging tools. Here we report on the design of a novel thioacetal ortho -nitrobenzaldehyde (TNB) dual arm photocage that enables control of the simultaneous release of two payloads linked to a single TNB unit. Using this cage which was prepared in a single step from commercial 6-nitroverataldehyde, three drug-fluorophore conjugates were synthesized, Taxol-TNB-Fluorescein, Taxol-TNB-Coumarin and Doxorubicin-TNB-Coumarin, and long wavelength UVA light-triggered release experiments demonstrated that dual payload release occurred with rapid decay kinetics for each conjugate. In cell based assays in vitro , dual release could also be controlled by UV exposure, resulting in increased cellular fluorescence and cytotoxicity as potent as unmodified drug towards the KB carcinoma cell line. The extent of such dual release was quantifiable by reporter fluorescence measured in situ , and found to correlate with the extent of cytotoxicity. Thus, this novel dual-arm cage strategy provides a valuable tool which enables both active control and real-time monitoring of drug activation at the delivery site.