Smart Interactive System for the Enhanced Bioimaging and Multi-Drug Synergistic Therapy in Tumor-Microenvironment

Tumor microenvironment (TME) interactive platforms are promising for accurate diagnostics and therapeutics. Herein, a smart interactive system (G⊂H) consisting of a hypoxia-acid dual triggered multifunctional guest (G) and an amphipathic metal-organic capsule (H) was successfully established for bioimaging and treatment. Hydrophobic G is encapsulated in cavity of H to form the homogeneous soluble G⊂H, which enhances its accumulation in tumor cells, controls the interactive regulation between G⊂H and TME, and facilitates the sensitivity of tumor cell therapy. When triggered in TME, G⊂H selectively releases an alkylating agent and a doxifluridine (DFUR) via the activation of azo and ketal linkers for multidrug chemotherapy, and the fluorescence emission from the activated G⊂H is used for real-time release visualization of the hypoxia-activating drug in cell substructure and hypoxia imaging. Owing to its homogeneous delivery, TME regulation and TME response properties toward the hypoxia tumor cells, G⊂H exhibits significantly higher toxicity in a hypoxic environment (0.1% O₂) than that in normoxia. As expected, G⊂H performs good imaging capability and treatment effect in hypoxia tumor cells, flow cytometry assay and tumor-bearing mice, implying its great potential in bioimaging and multidrug synergistic therapy.