Abstract
Multidrug resistance (MDR) often leads to the failure
of the anticancer treatment. Besides the blockage of those MDR pathways, the
development of more potent drugs are of urgent needs but largely postponed due
to imbalance between safety and efficacy. The prodrug strategy, especially with
bioorthogonal activation has shown immerse potential to balance
safety and efficacy, while recent studies focus on few drug entities such
as doxorubicin and MMAE, leaving the vast collection of toxins undetermined.
Here we have enumerated typical molecular entities
ranging from FDA approved drugs (doxorubicin, paclitaxel) to a heated ADC
warhead (MMAF-OMe) and a trichothecene toxin (Mytoxin A) to
demonstrate that the trans-cyclooctene
(TCO) caging may serve as a general prodrug design to increase the therapeutic
index for bioactive molecules. These prodrugs can be efficiently activated
on-demand by the bioorthogonal activators whose distribution is regulated by
the cell specific enzymatic non-covalent synthesis of supramolecular
self-assemblies. These cell-specific prodrugs activation could not only reduce
the toxicology of drugs but also enhance the synergistic therapeutic effect
within a broad range of dose ratio. More importantly, these prodrugs activation
share the same activator bearing assemblies, which allows the flexible shift of
drug identities to successfully combat MDR cancer in vivo. In general, this versatile bioorthogonal prodrug
activation platform is readily applicable to enlarge the therapeutic window for
various bioactive molecules. We envision that the spatiotemporal controlled
prodrug activation should facilitate the drug discovery and development.