Dual‐Stimuli‐Activatable Hybrid Prodrug for the Self‐Immolative Delivery of an Anticancer Agent and Hydrogen Sulfide with Turn‐On Fluorescence

Abstract

AbstractStimuli‐responsive fluorogenic prodrugs are advantageous for the targeted drug delivery enabling real‐time non‐invasive monitoring with turn‐on fluorescence. We report herein the dual‐stimuli (ROS and CA)‐responsive thiocarbamate‐based prodrug (AM‐TCB) for the turn‐on fluorogenic delivery of the naphthalimide‐based anticancer agent amonafide along with the gasotransmitter hydrogen sulfide (H2S). A carbamate‐based prodrug AM‐CB was also designed, capable of releasing the anticancer agent amonafide without any H2S. The prodrugs were synthesized using multi‐step organic synthesis. UV‐Vis and fluorescence spectroscopic studies revealed selective reactivity of the boronate ester group of prodrugs towards ROS (primarily H2O2) with the release of amonafide and COS/CO2 via self‐immolative processes. Hydrolysis of the generated COS by carbonic anhydrase (CA) produces H2S. While the prodrug AM‐TCB retained the anticancer activity of free amonafide in cancer cells (MDA‐MB‐231 and HeLa), unlike amonafide, it enhanced the cellular viability of the non‐malignant cells (HEK‐293). Fluorescence imaging in HeLa cells revealed the simultaneous delivery of the anticancer agent and H2S from AM‐TCB with turn‐on fluorescence. Western blot studies further revealed the cytoprotective effects of the released H2S from AM‐TCB. The present adjuvant strategy therefore would be helpful in future for ameliorating the anticancer drug‐induced side‐effects.