Tumor microenvironment responsive<i>T</i>₁–<i>T</i>₂dual-mode contrast agent Fe₃O₄@ZIF-8-Zn–Mn NPs for<i>in vivo</i>magnetic resonance imaging

Abstract

Activated <i>T</i>₁-<i>T</i>₂ 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 <i>T</i>₁-<i>T</i>₂ dual-mode contrast agent, Fe₃O₄@ZIF-8-Zn-Mn nanoparticles (NPs), with simple components was constructed <i>via</i> simply assembly of paramagnetic Mn²⁺ ions (as <i>T</i>₁ contrast agent) and Fe₃O₄ NPs (as <i>T</i>₂ 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 <i>T</i>₁-<i>T</i>₂ dual-mode MRI contrast effect (<i>r</i>₁ = 0.82 mM^-1 s^-1, <i>r</i>₂ = 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 <i>T</i>₁ and <i>T</i>₂ imaging performances with enhanced <i>r</i>₁ and <i>r</i>₂ relaxation values up to 6.9 and 9.9 times, respectively. Moreover, <i>in vivo</i> MRI experiments showed that after the intravenous injection of Fe₃O₄@ZIF-8-Zn-Mn NPs for about one hour, the <i>T</i>₁-weighted imaging of the tumor site becomes brighter with <i>T</i>₁ signal enhanced by about 31%, while the <i>T</i>₂-weighted imaging of the tumor site becomes darker with <i>T</i>₂ signal enhanced by nearly 30%, suggesting the great potential of Fe₃O₄@ZIF-8-Zn-Mn NPs to be used as a tumor microenvironment-responsive <i>T</i>₁-<i>T</i>₂ dual-mode contrast agent for sensitive tumor imaging.