γ-Glutamyltranspeptidase-Triggered Intracellular Gadolinium Nanoparticle Formation Enhances the T₂-Weighted MR Contrast of Tumor

Magnetic resonance imaging (MRI) is advantageous in the diagnosis of deep internal cancers, but contrast agents (CAs) are always needed to improve MRI sensitivity. Gadolinium (Gd)-based agents are routinely used as T₁-dominated CAs in clinic but using intracellularly formed Gd nanoparticles to enhance the T₂-weighted MRI of tumor in vivo at high magnetic field has not been reported. Herein, we rationally designed a "smart" Gd-based probe Glu-Cys(StBu)-Lys(DOTA-Gd)-CBT (1), which was subjected to γ-glutamyltranspeptidase (GGT) cleavage and an intracellular CBT-Cys condensation reaction to form Gd nanoparticles (i.e., 1-NPs) to enhance the T₂-weighted MR contrast of tumor in vivo at 9.4 T. Living cell experiments indicated that the 1-treated HeLa cells had an r₂ value of 27.8 mM⁻¹ s⁻¹ and an r₂/r₁ ratio of 10.6. MR imaging of HeLa tumor-bearing mice indicated that the T₂ MR contrast of the tumor enhanced 28.6% at 2.5 h post intravenous injection of 1. We anticipate that our probe 1 could be employed for T₂-weighted MRI diagnosis of GGT-related cancers in the future when high magnetic field is available in clinic.