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

Authors

  • Todd L. Kaneshiro
    • Department of Pharmaceutics and Pharmaceutical ChemistryUniversity of Utah
  • Tianyi Ke
    • Department of Pharmaceutics and Pharmaceutical ChemistryUniversity of Utah
  • Eun-Kee Jeong
    • Department of RadiologyUniversity of Utah
  • Dennis L. Parker
    • Department of RadiologyUniversity of Utah
    • Department of Pharmaceutics and Pharmaceutical ChemistryUniversity of Utah
Research Paper

DOI: 10.1007/s11095-006-0024-0

Cite this article as:
Kaneshiro, T.L., Ke, T., Jeong, E. et al. Pharm Res (2006) 23: 1285. doi:10.1007/s11095-006-0024-0

Purpose

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.

Methods

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.

Results

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.

Conclusion

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 agentblood pool imagingGd-DTPA l-cystine bisamide copolymersmagnetic resonance imagingpolydisulfide

Abbreviations

DCAC

DTPA l-cystine bisamide copolymers

DCC

dicyclohexylcarbodiimide

DCIC

DTPA l bisisopropyl amide copolymers

DCPC

DTPA l-cystine bispropyl amide copolymers

DCU

dicyclohexylurea

DI

deionized

DMSO

dimethylsulfoxide

DTPA dianhydride

diethylenetriamine penta acetic acid dianhydride

ESI-MS

electrospray ionization mass spectrometry

GCAC

Gd-DTPA l-cystine bisamide copolymers

GCIC

Gd-DTPA l-cystine bisisopropyl amide copolymers

GCPC

Gd-DTPA l-cystine bispropyl amide copolymers

GDCC

Gd-DTPA cystamine copolymers

GDCEP

Gd-DTPA cystine diethyl ester copolymers

GDCP

Gd-DTPA cystine copolymers

Gd-(DTPA-BMA)

Gd-(DTPA-bismethyl amide)

Gd(OAc)3

gadolinium triacetate

HPMA

poly[N-(2-hydroxypropyl)methacrylamide]

ICP-OES

inductively coupled argon plasma optical emission spectrometer

MALDI-TOF

matrix-assisted laser desorption ionization time of flight

MRI

magnetic resonance imaging

MWCO

molecular weight cutoff

PBS

phosphate-buffered saline

r1

longitudinal relaxivity

r2

transverse relaxivity

SEC

size exclusion chromatography

T1

longitudinal

T2

transverse

TEA

triethylamine

TFA

trifluoroacetic acid

THF

tetrahydrofuran

1/T1

proton longitudinal relaxation rate

1/T2

proton transverse relaxation rate

Copyright information

© Springer Science + Business Media, Inc. 2006