Tumor microenvironment responsive T1–T2 dual-mode contrast agent Fe3O4@ZIF-8-Zn–Mn NPs for in vivo magnetic resonance imaging

Abstract

Activated T₁–T₂ contrast agents can effectively improve the sensitivity and diagnosis accuracy of magnetic resonance imaging (MRI), but the construction of such contrast agents still remains a great challenge. In this work, a pH- and glutathione (GSH)-responsive T₁–T₂ dual-mode contrast agent, Fe₃O₄@ZIF-8-Zn–Mn nanoparticles (NPs), with simple components was constructed via simply assembly of paramagnetic Mn²⁺ ions (as T₁ contrast agent) and Fe₃O₄ NPs (as T₂ contrast agent) into a pH- and GSH-sensitive Zn-zeolitic imidazole framework (ZIF-8) matrix. Under neutral conditions, Fe₃O₄@ZIF-8-Zn–Mn NPs show good stability and weak T₁–T₂ dual-mode MRI contrast effect (r₁ = 0.82 mM⁻¹ s⁻¹, r₂ = 21.28 mM⁻¹ s⁻¹) due to the magnetic interference between Fe₃O₄ NPs and paramagnetic Mn²⁺ ions. In contrast, under acidic environment (pH = 6.5–5.5) and in the present GSH (0–4 mM), Fe₃O₄@ZIF-8-Zn–Mn NPs can be disassembled and release Fe₃O₄ NPs and paramagnetic Mn²⁺ ions, which causes simultaneous recovery of T₁ and T₂ imaging performances with enhanced r₁ and r₂ relaxation values up to 6.9 and 9.9 times, respectively. Moreover, in vivo MRI experiments showed that after the intravenous injection of Fe₃O₄@ZIF-8-Zn–Mn NPs for about one hour, the T₁-weighted imaging of the tumor site becomes brighter with T₁ signal enhanced by about 31%, while the T₂-weighted imaging of the tumor site becomes darker with T₂ signal enhanced by nearly 30%, suggesting the great potential of Fe₃O₄@ZIF-8-Zn–Mn NPs to be used as a tumor microenvironment-responsive T₁–T₂ dual-mode contrast agent for sensitive tumor imaging.