Extracellular biodegradable macromolecular gadolinium(III) complexes for MRI
The clinical application of macromolecular gadolinium (Gd) complexes as MRI contrast agents is limited by the slow excretion of Gd(III) complexes and consequent long‐term tissue accumulation of toxic Gd ions. To alleviate the problem of slow excretion, biodegradable polydisulfide‐based macromolecula...
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Published in | Magnetic resonance in medicine Vol. 51; no. 1; pp. 27 - 34 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
Hoboken
Wiley Subscription Services, Inc., A Wiley Company
01.01.2004
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Subjects | |
Online Access | Get full text |
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Summary: | The clinical application of macromolecular gadolinium (Gd) complexes as MRI contrast agents is limited by the slow excretion of Gd(III) complexes and consequent long‐term tissue accumulation of toxic Gd ions. To alleviate the problem of slow excretion, biodegradable polydisulfide‐based macromolecular Gd(III) complexes were designed and prepared based on the disulfide‐thiol exchange to allow degradation of the macromolecules by endogenous thiols and to facilitate excretion of Gd(III) complexes after the MRI examination. The in vitro degradation study showed that the polydisulfide agent was readily degraded by cysteine at plasma thiol concentrations. No cross‐reaction was observed between the cysteine‐34 on human serum albumin (HSA) with the agent. Concentration‐dependent blood pool contrast enhancement was observed for the polydisulfide agents. The agents of both high molecular weight (35,000 Da) and low molecular weight (17,700 Da) produced significant contrast enhancement in the heart and aorta in rats at relatively high doses. Except for the bladder, the signal intensities gradually decreased over time. Significant blood pool contrast enhancement was also observed for the high molecular weight agent at a low dose (0.03 mmol‐Gd/kg), but not for the agent with a lower molecular weight. The contrast enhancement in the urinary bladder increased over time for the polydisulfide agents and Gd(III)‐(DTPA‐BMA). Degradation products were identified by mass spectrometry in the urine samples from the rats administered with both polydisulfide agents, which confirmed that the polydisulfide agents were degraded in vivo and excreted through renal filtration. The preliminary results demonstrated the in vitro and in vivo degradability, superior blood pool contrast enhancement, and rapid clearance through renal filtration of the novel biodegradable macromolecular agent. This agent has a great potential for further preclinical and clinical development with application in contrast‐enhanced blood pool and cancer MR imaging. Magn Reson Med 51:27–34, 2004. © 2003 Wiley‐Liss, Inc. |
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Bibliography: | istex:CBE800E275496C237758E1297678F37A6F65A508 ark:/67375/WNG-BPFXDPBK-K ArticleID:MRM10656 NIH - No. R21 CAO95873; No. R01 EB00489 ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 |
ISSN: | 0740-3194 1522-2594 |
DOI: | 10.1002/mrm.10656 |