title: A Thioacetal Photocage Designed for Dual Release: Application in the Quantitation of Therapeutic Release by Synchronous Reporter Decaging.
abstract: Despite the immense potential of existing photocaging technology, its application 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 enabled control of the simultaneous release of two payloads linked to a single TNB unit. By 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 performed in vitro, dual release could also be controlled by UV exposure, resulting in increased cellular fluorescence and cytotoxicity with potency equal to that of unmodified drug towards the KB carcinoma cell line. The extent of such dual release was quantifiable by reporter fluorescence measured in situ and was found to correlate with the extent of cytotoxicity. Thus, this novel dual arm cage strategy provides a valuable tool that enables both active control and real-time monitoring of drug activation at the delivery site.
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan Medical School, 1150 W. Medical Ctr. Drive, Ann Arbor, MI, 48109, USA.|Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
authors.forename: Pamela T
authors.identifier: http://orcid.org/0000-0002-4387-4723
authors.initials: PT
authors.lastname: Wong
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan Medical School, 1150 W. Medical Ctr. Drive, Ann Arbor, MI, 48109, USA.|Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
authors.forename: Shengzhuang
authors.initials: S
authors.lastname: Tang
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan Medical School, 1150 W. Medical Ctr. Drive, Ann Arbor, MI, 48109, USA.|Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
authors.forename: Jayme
authors.initials: J
authors.lastname: Cannon
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan Medical School, 1150 W. Medical Ctr. Drive, Ann Arbor, MI, 48109, USA.|Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
authors.forename: Jhindan
authors.initials: J
authors.lastname: Mukherjee
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan Medical School, 1150 W. Medical Ctr. Drive, Ann Arbor, MI, 48109, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Isham
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan Medical School, 1150 W. Medical Ctr. Drive, Ann Arbor, MI, 48109, USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Gam
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan Medical School, 1150 W. Medical Ctr. Drive, Ann Arbor, MI, 48109, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Payne
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan Medical School, 1150 W. Medical Ctr. Drive, Ann Arbor, MI, 48109, USA.
authors.forename: Sean A
authors.initials: SA
authors.lastname: Yanik
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan Medical School, 1150 W. Medical Ctr. Drive, Ann Arbor, MI, 48109, USA.|Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Baker
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan Medical School, 1150 W. Medical Ctr. Drive, Ann Arbor, MI, 48109, USA.|Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
authors.forename: Seok Ki
authors.identifier: http://orcid.org/0000-0001-5633-4817
authors.initials: SK
authors.lastname: Choi
mesh_terms: D001547:Benzaldehydes / Q000737:chemistry*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003374:Coumarins / Q000737:chemistry; D004317:Doxorubicin / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D004337:Drug Carriers / Q000737:chemistry*; D065546:Drug Liberation / Q000528:radiation effects; D005456:Fluorescent Dyes / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D017239:Paclitaxel / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D010782:Photolysis / Q000528:radiation effects; D014466:Ultraviolet Rays
chemical_list: D001547:Benzaldehydes; D003374:Coumarins; D004337:Drug Carriers; D005456:Fluorescent Dyes; C043850:2-nitrobenzaldehyde; D004317:Doxorubicin; C030123:coumarin; D017239:Paclitaxel
keywords: antitumor agents; caged compounds; controlled release; dual arm cage; fluorescence reporter; photolysis