Abstract
Two novel drug-conjugates based on a “coumarin linker” have been designed for the synergic release of a therapeutic agent and fluorescent probe for the potential application of theranostics. The drug conjugates; CC-RNS and CI-RNS were designed to be activated by reactive oxygen species or reactive nitrogen species (ROS/RNS). The fluorescence OFF-ON response was triggered by the peroxynitrite-mediated transformation of a boronic acid pinacol ester to a phenol moiety with simultaneous release of the therapeutic agents (Confirmed by HRMS). The limit of detection for peroxynitrite using CC-RNS and CI-RNS was 0.29 and 37.2 μM, respectively. Both CC-RNS and CI-RNS demonstrated the ability to visualize peroxynitrite production thus demonstrating the effectiveness of these probes for use as tools to monitor peroxynitrite-mediated drug release in cancer cell lines.
Highlights
Theranostic systems, are the combination of a diagnostic and therapeutic and represent an emerging area with regard to effective cancer treatment
CI-reactive nitrogen species (RNS) and CC-RNS were synthesized according to Scheme 2
After confirming the selectivity and sensitivity of CCRNS and CI-RNS for ONOO−, we evaluated the reaction of CC-RNS and CI-RNS with ONOO− in cells
Summary
Theranostic systems, are the combination of a diagnostic and therapeutic and represent an emerging area with regard to effective cancer treatment. The phenolic alcohol of 7hydroxycoumarin is linked to an activating group and the hydroxymethyl substituent acts as an attachment point for a drug or targeting group In this example; Cou-Melphalan incorporates melphalan as a therapeutic with attachments via carbamates. The reactive nitrogen species (RNS), peroxynitrite (ONOO−) is of interest due to its orthogonal reactivity with boronate esters and increased reactivity compared to its equivalent reactive oxygen species (ROS), hydrogen peroxide (H2O2) (Sedgwick et al, 2016, 2017; Wu et al, 2018) To this end, we set out to design ONOO− activatable systems (Figure 2) (Yang et al, 2006; Sedgwick et al, 2016, 2018). Indomethacin has been shown to reduce cell migration, invasion, and metastasis in breast and colon cancer cell lines (Ackerstaff et al, 2007; Guo et al, 2013)
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