Novel Bioorthogonal Theranostic Scaffold Enables on-Target Drug Release and Real Time Monitoring In Vivo

Bioorthogonal chemistry-based prodrug strategy features
spatiotemporally
controlled release of therapeutic agent and/or imaging probe. However,
the integration of diagnosis and therapy into a single molecule paired
with a single bioorthogonal trigger remains a challenge. In this study,
we devised a novel bioorthogonal theranostic scaffold amenable to
the conjugation of various targeting agent and click-to-release reaction
with the bioorthogonal prodrug to enable targeted drug liberation
with concomitant fluorescence emission. Such one-stone-three-birds
scaffold consists of a new fluorophore phenanthrodioxine (PDO) linked
with a fluorescence masking group, tetrazine (Tz) which serves as
a dual switch for the activation of fluorophore and drug. Further
installation of a warhead of phenylboronic acid (PBA) ensures the
targeted accumulation of the resultant PBA-PDO-Tz conjugate in tumor
cells, thereby achieving on-demand activation of trans-cyclooctene-caged anticancer drug Doxorubicin with real-time monitoring
and on-target cytotoxicity in live cells and an A549 xenograft mouse
model. The targeted single trigger-dual response scaffold holds promise
for precise theranostics applications in vivo.