Pharmaceutical Research

, Volume 23, Issue 6, pp 1285–1294

Gd-DTPA l-Cystine Bisamide Copolymers as Novel Biodegradable Macromolecular Contrast Agents for MR Blood Pool Imaging

  • Todd L. Kaneshiro
  • Tianyi Ke
  • Eun-Kee Jeong
  • Dennis L. Parker
  • Zheng-Rong Lu
Research Paper


The purpose of this study was to synthesize biodegradable Gd-DTPA l-cystine bisamide copolymers (GCAC) as safe and effective, macromolecular contrast agents for magnetic resonance imaging (MRI) and to evaluate their biodegradability and efficacy in MR blood pool imaging in an animal model.


Three new biodegradable GCAC with different substituents at the cystine bisamide [R = H (GCAC), CH2CH2CH3 (Gd-DTPA l-cystine bispropyl amide copolymers, GCPC), and CH(CH3)2 (Gd-DTPA cystine bisisopropyl copolymers, GCIC)] were prepared by the condensation copolymerization of diethylenetriamine pentaacetic acid (DTPA) dianhydride with cystine bisamide or bisalkyl amides, followed by complexation with gadolinium triacetate. The degradability of the agents was studied in vitro by incubation in 15 μM cysteine and in vivo with Sprague-Dawley rats. The kinetics of in vivo contrast enhancement was investigated in Sprague-Dawley rats on a Siemens Trio 3 T scanner.


The apparent molecular weight of the polydisulfide Gd(III) chelates ranged from 22 to 25 kDa. The longitudinal (T1) relaxivities of GCAC, GCPC, and GCIC were 4.37, 5.28, and 5.56 mM−1 s−1 at 3 T, respectively. The polymeric ligands and polymeric Gd(III) chelates readily degraded into smaller molecules in incubation with 15 μM cysteine via disulfide–thiol exchange reactions. The in vitro degradation rates of both the polymeric ligands and macromolecular Gd(III) chelates decreased as the steric effect around the disulfide bonds increased. The agents readily degraded in vivo, and the catabolic degradation products were detected in rat urine samples collected after intravenous injection. The agents showed strong contrast enhancement in the blood pool, major organs, and tissues at a dose of 0.1 mmol Gd/kg. The difference of their in vitro degradability did not significantly alter the kinetics of in vivo contrast enhancement of the agents.


These novel GCAC are promising contrast agents for cardiovascular and tumor MRI, which are later cleaved into low molecular weight Gd(III) chelates and rapidly cleared from the body.

Key Words

biodegradable macromolecular contrast agent blood pool imaging Gd-DTPA l-cystine bisamide copolymers magnetic resonance imaging polydisulfide 



DTPA l-cystine bisamide copolymers




DTPA l bisisopropyl amide copolymers


DTPA l-cystine bispropyl amide copolymers







DTPA dianhydride

diethylenetriamine penta acetic acid dianhydride


electrospray ionization mass spectrometry


Gd-DTPA l-cystine bisamide copolymers


Gd-DTPA l-cystine bisisopropyl amide copolymers


Gd-DTPA l-cystine bispropyl amide copolymers


Gd-DTPA cystamine copolymers


Gd-DTPA cystine diethyl ester copolymers


Gd-DTPA cystine copolymers


Gd-(DTPA-bismethyl amide)


gadolinium triacetate




inductively coupled argon plasma optical emission spectrometer


matrix-assisted laser desorption ionization time of flight


magnetic resonance imaging


molecular weight cutoff


phosphate-buffered saline


longitudinal relaxivity


transverse relaxivity


size exclusion chromatography








trifluoroacetic acid




proton longitudinal relaxation rate


proton transverse relaxation rate


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Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  • Todd L. Kaneshiro
    • 1
  • Tianyi Ke
    • 1
  • Eun-Kee Jeong
    • 2
  • Dennis L. Parker
    • 2
  • Zheng-Rong Lu
    • 1
  1. 1.Department of Pharmaceutics and Pharmaceutical ChemistryUniversity of UtahSalt Lake CityUSA
  2. 2.Department of RadiologyUniversity of UtahSalt Lake CityUSA

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