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

Abstract

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.

Engineering Intelligent Nanosystems for Enhanced Medical Imaging

“…For instance, Hai et al developed MRI‐detectable gadolinium‐based particles that were assembled in the presence of γ‐glutamyl transpeptidase (GGT) and glutathione (GSH) ( Figure A). [ 65 ] The cell surface‐associated GGT enzyme is involved in the cellular production of cysteine and found to be upregulated in several tumors, including in ovarian, liver, and cervical cancer. [ 69 ] In this case, GGT on the cell membrane first cleaves a Glu‐structure in the probe.…”

“…Adapted with permission. [ 65 ] Copyright 2019, American Chemical Society. B) A fluorescent probe is subject to molecular cleavage by active caspase‐3/7 after recognition by X‐linked inhibitor of apoptosis and subsequent self‐assembly into fibrous nanostructures, which are retained in the tumor tissue.…”

Recent Advances of Bioresponsive Nano-Sized Contrast Agents for Ultra-High-Field Magnetic Resonance Imaging

“…Alternatively, nanoparticle with magnetic responsive atom is becoming one of the most promising candidates to be used as contrast agents, such as transition metal ions (Cu 2+ , Fe 2+ /Fe 3+ ,Co 2+ , and Mn 2+ , lanthanide metal ions (Eu 3+ , Gd 3+ , Ho 3+ , and Dy 3+ ) (Tromsdorf et al, 2007;Mahmoudi et al, 2011;Busquets et al, 2015;Ni et al, 2017;Sousa et al, 2017;Guo et al, 2019;Hai et al, 2019;Wahsner et al, 2019;Botar et al, 2020). Furthermore, iron-based nano-system is highly recommended as spin-spin imaging or imaging probe because of its merits of electronic, magnetic, optical properties at nano scale and the excellent in vivo stability as well (Li et al, 2013).…”

Biomaterials based on noncovalent interactions of small molecules

“…The dual targeting strategy, that is, the use of dual targeting motif (either ligands or enzymes), also applies in molecular imaging (Chen et al, 2019[ 9 ]; Hai et al, 2019[ 30 ]; An et al, 2020[ 3 ]). As reported by Zheng et al (2016[ 118 ]), a precursor ( 14 ) is able to differentiate the extra- and intracellular environment based on the dual targeting motifs that react with both extracellular ALP and intracellular glutathione (GSH), generating different orders of assemblies ( 15 and 16 ) (Figure 5C (Fig.…”