Tandem post-synthetic modification of a zeolitic imidazolate framework for CXCR4-overexpressed esophageal squamous cell cancer imaging and therapy

Zeolitic imidazolate frameworks (ZIFs) as emerging porous materials have attracted remarkable attention for their unprecedented porosity and acidic sensitive degradation that enables high drug loading and microenvironment responsive fast payload release. However, the limited functions and disadvantages of ZIFs such as early drug release, potential cytotoxicity inducing damage to major organs, and even death of animals, impede their further biomedical application. In this work, we report the first tandem post-synthetic modification of ZIF-7 with both metal ions and organic ligands. Inspired by the benzimidazole-like inhibitors that are similar to the organic ligand of ZIF-7, a chemokine (C-X-C motif) receptor 4 (CXCR4) inhibitor AMD-070 (AMD) and magnesium ions (Mn²⁺) were successfully tandem exchanged to the ZIF-7 framework, forming an active-targeting framework AMD-ZIF-7(Mn) for CXCR4-overexpressed esophageal squamous cell cancer. The obtained AMD-ZIF-7(Mn) showed good biocompatibility in vitro and in vivo. Meanwhile, it exhibited an excellent T₁-weighted magnetic resonance imaging performance and CXCR4 targeting ability. With 5-Fu loading, AMD-ZIF-7(Mn)/5-Fu showed a synergistic therapeutic effect in DNA damage and CXCR4 inhibition of esophageal squamous cell cancer. Therefore, we propose a structural reconstruction method to effectively explore and improve the biomedical application of ZIFs in esophageal squamous cell cancer theranostics.