Journal
ANALYTICAL CHEMISTRY
Volume 94, Issue 5, Pages 2536-2545Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.analchem.1c04432
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Funding
- National Institutes of Health (NIH) [R01 EB-023366, R01 MH-067528]
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This study investigates the effects of different ligand designs of lanthanide complexes on sodium-23 (Na-23) signals. The results show that gadolinium and thulium agents are mainly influenced by bulk magnetic susceptibility (BMS) and hyperfine effects. The shiftability and broadening of Na-23 signals are most sensitive to the concentration of lanthanide complexes. In brain tumor models, TmDOTP5- can separate Na+ in intracellular, blood, and interstitial pools, while GdDOTP5- can distinguish Na+ within intracellular and extracellular pools.
Nuclear magnetic resonance (NMR) agents, composed of paramagnetic lanthanide ions (Ln(3+)) complexed with negatively charged cyclic chelating agents (Che((n+3)-)) forming polyanionic lanthanide complexes (LnChe(n-)), perturb sodium-23 (Na-23) signals, a phenomenon which depends sodium ions (Na+) exchanging with LnChe(n-). We analyzed 23Na shiftability and broadening due to hyperfine and bulk magnetic susceptibility (BMS) effects that arise from LnChe(n-) designs using selective Ln(3+) ions (i.e., thulium, Tm3+; gadolinium, Gd3+; and europium, Eu3+) and macrocyclics derived from 1,4,7,10-tetraazacyclododecane (cyclen) [i.e., with phosphonate (DOTP8-) and carboxylate (DOTMA(4-)) arms] and 1,4,7-triazacyclononane (TACN) [i.e., with phosphonate (NOTP6-) arms]. All LnChe(n-) complexes showed downfield shifts, but Gd3+ and Tm3+ agents, respectively, were dominated by BMS and hyperfine effects, in good agreement with theory. While Na-23 shiftability and broadening were minimally affected by pH and competing cations (K+, Ca2+, and Mg2+) within physiological ranges, the Na-23 shiftability and broadening were most sensitive to LnChe(n-) concentration in relation to the interstitial Na+ level in vivo. Greatest Na-23 shiftability and broadening were obtained with Tm3+ and Gd3+ agents, respectively. While BMS contribution to shiftability was most impacted by the number of unpaired electrons on Ln(3+), negative charge on LnChenregulated Na+ exchange for line broadening. In brain tumor models, TmDOTP5- with Na-23-NMR has been used previously to separate Na+ in intracellular, blood, and interstitial pools, while evidence here shows that GdDOTP5- can distinguish Na+ within intracellular and extracellular (i.e., blood and interstitial) pools. Given the biological importance of Na+ in vivo, future macrocyclic designs of LnChe(n-) should be sought for Na-23-NMR biomedical applications.
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