Tumor-specific nanomedicine via sequential catalytic reactions for accurate tumor therapy

Abstract

Catalytic medicine based on various catalysts has attracted increasing interest for the treatment of tumors. However, the direct application of conventional catalysts may cause serious side effects to healthy tissue and low therapeutic efficiency against tumor tissue, due to their weak specificity for the tumor microenvironment (TME). Herein, a tumor-targeting and TME-responsive nanoreactor containing ferroferric oxide nanoparticles (Fe₃O₄ NPs) and glucose oxidase (GOD) was developed to perform hyaluronidase (HAase) and glutathione (GSH)-triggered chain catalytic reactions in tumor tissue. This nanoreactor was designed to take advantage of the unique biological molecules in tumors and several therapeutic agents to adjust the local microenvironments, and achieved satisfactory and accurate tumor therapy. The reactions started with the consumption of intratumoral glucose to inhibit tumor growth, and simultaneously produced hydrogen peroxide (H₂O₂) to make up for the deficiency of H₂O₂ in the original tumor microenvironment, resulting in the generation of a high quantity of hydroxyl radicals as a result of the catalysis of Fe₃O₄ NPs to further eliminate tumor tissue. The tumor-specific catalytic medicine formed by our nanocomposite guaranteed both therapeutic efficiency and accuracy, avoiding potential risks to healthy tissue and leading to a four-fold improvement in the cytotoxicity against tumor cells compared with normal cells after incubations of 48 h. In vivo data from mouse models provided further evidence for its therapeutic efficacy: the tumor growth was completely inhibited after two weeks of the synergistic therapy, which indicated the promise of our nanocomposite for tumor treatment.