As an effective
drug delivery strategy for traditional
antitumor drugs, the stimulus-responsive
albumin-based
prodrugs are getting more and more attention. These
prodrugs only release drugs in specific tumor microenvironments, which can prevent premature release of the
drug in the circulation. Tumor hypoxia is a fundamental feature of the solid tumor microenvironment. As a
hypoxia-activated linker, the 5-position branched linker of 1-methyl-2-nitro-5-hydroxymethylimidazole can be a trigger for
albumin-based
prodrugs. In this study, we report the synthesis and
biological evaluation of the
hypoxia-activated
albumin-binding
prodrug Mal-azo-
Exatecan. After
intravenous administration, the
maleimide on the side chain can rapidly bind to endogenous
albumin, enabling the
prodrugs to accumulate in
tumors, where
tumor-associated
hypoxia microenvironments trigger the selective release of
Exatecan. The 5-position branched linker of 1-methyl-2-nitro-5-hydroxymethylimidazole as a cleavable linker has high plasma stability and does not cause
Exatecan release from HSA-azo-
Exatecan during circulation in vivo, avoiding systemic side effects caused by
Exatecan.