Real‐Time Multi‐Photon Tracking and Bioimaging of Glycosylated Theranostic Prodrugs upon Specific Enzyme Triggered Release

Abstract

Real-time tracking of prodrug uptake, delivery and activation in vivo represents a major challenge for prodrug development. Herein, we demonstrate the use of novel glycosylated theranostics of the cancer pharmacophore Amonafide in highly-selective, enzymatic triggered release. We show that the use of endogenous enzymes for activated release of the therapeutic component can be observed, in real time, and monitored using one and two-photon bioimaging, offering unique insight into the prodrug pharmacokinetic profile. Furthermore, we demonstrate that the potent cytotoxicity of Amonafide is preserved using this targeted approach.

Photoinduced electron transfer (PeT) based fluorescent probes for cellular imaging and disease therapy

“…Gratifyingly, while no effective toxicity was observed for the prodrug probes 45a or b , the release of the active Amonafide form upon enzymatic triggering gave rise to IC 50 values that were comparable with that of Amonafide itself. 216 Hence, these results demonstrate the potential and emerging application of PeT-based prodrugs for use as cancer therapeutics.…”

“…Recently, Gunnlaugsson, Scanlan and co-workers have developed several examples of enzyme-triggered probes or drug-release systems. 215,216 The first family of these systems is based on the concept of a “pro-probe”, where a 1,8-naphthalimide-derived glycan system ( probes 44a–d ) is released into cancer cells that overexpress a glycosidase (Fig. 41A).…”

Glycosidase activated prodrugs for targeted cancer therapy

“…This process facilitates selective delivery of the Amonafide to the desired site of action and allows for real-time bioimaging in cancer cell lines; this has also been verified by recording the emission spectra within the cells after delivery, which was red shifted due to enhanced internal charge transfer mechanism in the delivered compounds vs. the prodrug. 63 This development was based on some prior work from our laboratory, where in a related study we employed the same principle for the delivery of naphthalimide imaging probes into cells. This system, which we described as a pro-probe ( e.g.…”

Cysteine-responsive prodrug of the anti-cancer drug amonafide: fluorogenic adjuvant drug delivery with hydrogen sulfide (H2S)

“…Very recently, H 2 S-triggered and β-galactosidase-responsive prodrugs of amonafide were reported towards anti-cancer drug delivery applications. 16 Interestingly, the protective effects of H 2 S were better utilized during its adjuvant delivery with the potent anti-cancer drug doxorubicin (Dox) with minimized cardiovascular side-effects and chemoresistance. 17 In the present study, we have developed the Cys-activatable isothiocyanate-based prodrug of amonafide ( AM-ITC ) for the turn-on fluorogenic delivery of the potent anti-cancer drug amonafide along with the gasotransmitter H 2 S (Fig.…”