Gd-LC6-SH is a
thiol-bearing
DOTA complex of
gadolinium designed to bind
plasma albumin at the conserved Cys(34) site. The binding of Gd-LC6-SH shows sensitivity to the presence of competing
thiols. We hypothesized that Gd-LC6-SH could provide magnetic resonance imaging (MRI) enhancement that is sensitive to
tumor redox state and that the prolonged retention of
albumin-bound Gd-LC6-SH in vivo can be exploited to identify a saturating dose above which the shortening of MRI longitudinal relaxation time (T(1)) of tissue is insensitive to the injected
gadolinium dose. In the Mia-PaCa-2 pancreatic
tumor xenograft model in SCID mice, both the small-molecule
Gd-DTPA-BMA and the macromolecule Galbumin MRI
contrast agents produced dose-dependent decreases in
tumor T(1). By contrast, the decreases in
tumor T(1) provided by Gd-LC6-SH at 0.05 and 0.1 mmol/kg were not significantly different at longer times after injection. SCID mice bearing Mia-PaCa-2 or NCI-N87
tumor xenografts were treated with either the
glutathione synthesis inhibitor
buthionine sulfoximine or the
thiol-oxidizing anticancer
drug Imexon, respectively. In both models, there was a significantly greater increase in
tumor R(1) (=1/T(1)) 60 minutes after injection of Gd-LC6-SH in
drug-treated animals relative to saline-treated controls. In addition,
Mercury Orange staining for nonprotein sulfhydryls was significantly decreased by
drug treatment relative to controls in both
tumor models. In summary, these studies show that
thiol-bearing complexes of
gadolinium such as Gd-LC6-SH can serve as redox-sensitive MRI
contrast agents for detecting differences in
tumor redox status and can be used to evaluate the effects of redox-active drugs.