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Contrast‐enhanced MRI with new biodegradable macromolecular Gd(III) complexes in tumor‐bearing mice
Author(s) -
Zong Yuda,
Wang Xinghe,
Goodrich K. Craig,
Mohs Aaron M.,
Parker Dennis L.,
Lu ZhengRong
Publication year - 2005
Publication title -
magnetic resonance in medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.696
H-Index - 225
eISSN - 1522-2594
pISSN - 0740-3194
DOI - 10.1002/mrm.20402
Subject(s) - chemistry , macromolecule , cystamine , in vivo , copolymer , cysteine , in vitro , gadolinium , mri contrast agent , biochemistry , organic chemistry , polymer , enzyme , microbiology and biotechnology , biology
The structures of polydisulfide‐based biodegradable macromolecular Gd(III) complexes were modified to improve their in vivo retention time and MRI contrast enhancement. Steric hindrance was introduced around the disulfide bonds to control their access to free thiols in order to alter the degradation rate of the copolymers. Two new macromolecular agents, (Gd‐DTPA)‐cystine copolymers (GDCP) and (Gd‐DTPA)‐cystine diethyl ester copolymers (GDCEP), were prepared. Both agents were readily degraded in vitro and in vivo by the disulfide‐thiol exchange reaction, but at a slow rate. The introduction of COOH and COOEt groups slowed down the degradation of the copolymers in the incubation with 15 μM cysteine. Metabolic degradation products were identified by matrix‐assisted laser desorption/ionization time‐of‐flight (MALDI‐TOF) mass spectrometry in the urine samples from rats injected with the agents. The T 1 relaxivity (r 1 ) was 5.43 mM −1 s −1 for GDCP, and 5.86 mM −1 s −1 for GDCEP, respectively, at 3T. MRI contrast enhancement of both agents was studied in nude mice bearing MDA‐BM‐231 human breast carcinoma xenografts, on a Siemens Trio 3T scanner. The modified agents resulted in more significant contrast enhancement in the blood pool and tumor periphery than (Gd‐DTPA)‐cystamine copolymers (GDCC) and a low‐molecular‐weight control agent, Gd‐(DTPA‐BMA), at a dose of 0.1 mmol‐Gd/kg. The results demonstrate that the structural modification of the biodegradable macromolecular Gd(III) complexes resulted in a relatively slow degradation of the macromolecules and significantly improved in vivo contrast enhancement. The modified agents show promise for use in investigations of blood pool and cancer by contrast‐enhanced (CE) MRI. Magn Reson Med 53:835–842, 2005. © 2005 Wiley‐Liss, Inc.