A Metal-Organic Framework Nanocarrier System for Precise Targeted Delivery and Reduced Systemic Toxicity of Mitoxantrone in Breast Cancer Therapy.

Abstract

Mitoxantrone (MTX) is a first-line chemotherapeutic agent. However, it has some limitations, such as poor tumor targeting, systemic toxicity, etc. A precise delivery system for MTX was developed using β-Cyclodextrin-modified redox/pH dual-responsive metal-organic framework nanoparticles (β-CD-nMOF). Metal-organic framework nanomaterials based on metal zinc (Zn-MOF) and organic ligand dithiodiglycolic acid were synthesized, and then β-cyclodextrin was modified on its surface for loading MTX, and a targeted drug delivery system of β-CD-nMOF@MTX was prepared. Zn-MOF was uniformly spherical (80-100 nm) and modified by cyclodextrin to form floral spherical β-CD-nMOF (400 nm). The effects of β-CD-nMOF@MTX on the growth of 4T1 human breast cancer cells were investigated in vitro. A 4T1 tumor-bearing Balb/c mouse model was established for in vivo β-CD-nMOF@MTX pharmacodynamic evaluation and its targeting studies. In vitro experiments showed that β-CD-nMOF@MTX was more toxic to 4T1 cancer cells than MTX injection at the same dose. Animal experiment results demonstrated that β-CD-nMOF@MTX effectively inhibited the growth of solid tumors while reducing MTX systemic in vivo toxicity and enhancing targeting properties. This occurs because, upon entering the tumor microenvironment, β-CD-nMOF@MTX undergoes collapse of its Zn-MOF framework structure under acidic conditions and glutathione mediation, releasing the loaded MTX to achieve precise targeted antitumor activity. The design principle of β-CD-nMOF@MTX may provide a promising strategy for smart antitumor agents with great potential in targeted cancer therapy.