Tumor xenograft response to redox-active therapies assessed by magnetic resonance imaging using a thiol-bearing DOTA complex of gadolinium

Gerald P. Guntle, Bhumasamudram Jagadish, Eugene A Mash, Garth Powis, Robert T Dorr, Natarajan Raghunand

Research output: Contribution to journalArticle

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Abstract

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 R1 (=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.

Original languageEnglish (US)
Pages (from-to)190-199
Number of pages10
JournalTranslational Oncology
Volume5
Issue number3
DOIs
StatePublished - Jun 2012

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Gadolinium
Heterografts
Oxidation-Reduction
Magnetic Resonance Imaging
Neoplasms
Sulfhydryl Compounds
SCID Mice
gadodiamide
Therapeutics
Pharmaceutical Preparations
Contrast Media
Buthionine Sulfoximine
Injections
2,2',2''-(10-(2-(2-mercaptoethylamino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid
Serum Albumin
Glutathione
Albumins
Staining and Labeling

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Tumor xenograft response to redox-active therapies assessed by magnetic resonance imaging using a thiol-bearing DOTA complex of gadolinium. / Guntle, Gerald P.; Jagadish, Bhumasamudram; Mash, Eugene A; Powis, Garth; Dorr, Robert T; Raghunand, Natarajan.

In: Translational Oncology, Vol. 5, No. 3, 06.2012, p. 190-199.

Research output: Contribution to journalArticle

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