Hypoxia-Activated Albumin-Binding Exatecan Prodrug for Cancer Therapy

Abstract

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 .

68Ga-Labeled Maleimide for Blood Pool and Lymph PET Imaging through Covalent Bonding to Serum Albumin In Vivo

“…The albumin-binding prodrug of doxorubicin (DOXO–EMCH) had been approved by the FDA, which was based on the maleimide strategy. This strategy was also reported for the prodrugs of Exatecan and SN38, released from Mal-azo-Exatecan and Mal-Glu-SN38, respectively.…”

Camptothecin-based prodrug nanomedicines for cancer therapy

“…18). 225 All in all, the valuable and significant difference within the physiological environments of normal tissues and tumors is hypoxia. It is possible to treat tumors using this distinct characteristic of solid tumors to flexibly change the treatment approaches.…”