Iron ion-coordinated carrier-free supramolecular co-nanoassemblies of dual DNA topoisomerase-targeting inhibitors for tumor suppression

• Published in: Acta biomaterialia 2022-05, Vol.144, p.121-131
• Main Authors: Guan, Jianhuan, Tan, Xiao, Jiao, Jian, Lai, Shuang, Zhang, Haotian, Kan, Qiming, He, Zhonggui, Sun, Mengchi, Sun, Jin
• Format: Article
• Language: English
• Subjects: Antitumor activity; Antitumor immune response; Breast cancer; Breast Neoplasms - drug therapy; Cadmium; Cell Line, Tumor; Chemical compounds; Deoxyribonucleic acid; DNA; DNA damage; DNA topoisomerase; DNA topoisomerase (ATP-hydrolysing); DNA topoisomerase II alpha (TOP-2A); DNA Topoisomerases; Drug development; Drug-likeness compounds; Female; Homing behavior; Humans; Immune response; Inhibitors; Insulators; Intermolecular coordination interactions; Ions; Iron; Iron - therapeutic use; Metastases; Mitoxantrone; Nanoparticles - chemistry; Neoplasm Recurrence, Local - drug therapy; Pharmacology; Prospective Studies; Quercetin; Side effects; Supramolecular co-nanoassemblies; Topoisomerase Inhibitors - therapeutic use; Toxicity; Tumor suppression; Tumors
• ISSN: 1742-7061; 1878-7568
• DOI: 10.1016/j.actbio.2022.03.027

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. Aimed at the key target TOP-2A in the malignant breast tumor, the metal coordination-mediated supramolecular co-assemble strategy of one-target dual inhibitors was firstly proposed for superimposed DNA damage for cancer therapy. Multiple interactions involving π-π stacking interactions, hydrogen bonds and coordination forces maintained the stability of co-nanoassemblies. Meanwhile, this co-nanoassemblies not only had potentials to increase therapeutic efficacy and decrease systemic toxicity, but also activated the CD 8+-mediated antitumor immune response against distal breast tumor relapse. Such a facile and safe nanoplatform is expected to provide an important prospective for promoting the clinical transformation of drug-likeness compounds in the suppression of difficult-to-treat breast tumor. [Display omitted]