pH-responsive aminotriazole doped metal organic frameworks nanoplatform enables self-boosting reactive oxygen species generation through regulating the activity of catalase for targeted chemo/chemodynamic combination therapy

The rational integration of chemotherapy and hydroxyl radical (.OH)-mediated chemodynamic therapy (CDT) via functional metal-organic frameworks (MOF) carriers has great potential in cancer therapy. In this work, aminotriazole (3-AT) doped polyhedral metal organic frameworks (denoted as MAF) were prepared by template ligand replacement, where CDT was initiated by Cu2+/Cu+ modulated Fenton reaction and enhanced by effectively regulating the catalase activity with 3-AT. However, a rod-like Cu-MOF with 3-AT served as a ligand was obtained by the hydrothermal method without using template. In contrast to Cu-MOF, pH-responsive MAF was chosen as the carrier for targeted drug delivery due to its higher drug load of 17.6% and relatively uniform size, where doxorubicin (DOX) as a model drug was loaded in its cavity and hyaluronic acid (HA) was coated on its surface via electrostatic interactions (denoted as HAMAF@DOX). In vitro experiments demonstrated that HA-MAF@DOX had high transport efficiency of DOX, effective regulation of catalase (CAT) activity and enhanced cytotoxicity to HepG2 cells. This work is the first use of enzyme inhibitors as ligands to construct functional MOFs via template ligand replacement for effective regulating enzyme activity, mediating intracellular redox homeostasis and enhancing CDT efficacy, which provides a feasible strategy for the construction the functional MOFs in cancer therapy. (c) 2021 Elsevier Inc. All rights reserved.

Automated summary

This study demonstrates the rational integration of chemotherapy and CDT via functional metal-organic frameworks. The pH-responsive MAF carrier showed high drug load and uniform size, making it a promising candidate for targeted drug delivery in cancer therapy. Additionally, the use of enzyme inhibitors as ligands in constructing functional MOFs provides a feasible strategy for regulating enzyme activity and enhancing CDT efficacy.