Iron ion-coordinated carrier-free supramolecular co-nanoassemblies of dual DNA topoisomerase-targeting inhibitors for tumor suppression
Abstract
Overexpressed DNA topoisomerase II alpha (TOP-2A) is closely related to the invasion and metastasis of malignant breast tumors. Mitoxantrone (MTX) has been identified as a TOP-2A inhibitor with significant inhibitory activity against breast tumors. The tumor-homing ability of MTX has been further enhanced by using nanodrug delivery systems (nano-DDSs), reducing off-target side effects. However, conventional MTX nano-DDSs are still limited by low drug-loading capacity and material carrier-related toxicity. In this study, we developed metal iron-coordinated carrier-free supramolecular co-nanoassemblies of dual DNA topoisomerase-targeting inhibitors with high drug loading for superimposed DNA damage-augmented tumor regression. By introducing iron ions (Ⅲ) and another TOP-2A inhibitor quercetin (QU) onto the building blocks, Fe3+-mediated QU-MTX co-nanoassemblies are fabricated (QU-MTX-Fe) via intermolecular coordination interactions. The PEGylated co-nanoassemblies (P-QU-MTX-Fe) exhibit distinct advantages over QU/MTX solution (Sol) alone or MTX-QU mixture Sol in terms of therapeutic efficacy and systemic toxicity. Meanwhile, P-QU-MTX-Fe could efficiently suppress primary and distal breast tumor relapse by activating the CD 8+-mediated antitumor immune response. Overall, such iron-coordinated nanomedicines provide insights into the rational design of drug-likeness compounds with undesirable therapeutic performance for cancer therapy. STATEMENT OF SIGNIFICANCE: Aimed at the key…
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