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Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

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Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

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Gd-DTPA l-Cystine bisamide copolymers

GCAC

, PhD, , PhD, and , BS.

Author Information

Created: ; Last Update: January 22, 2008.

Chemical name:Gd-DTPA l-Cystine bisamide copolymers
Image GCAC.jpg
Abbreviated name:GCAC
Synonym:
Agent Category:Compound, polymers
Target:Non-targeted, vasculature, liver, kidneys.
Target Category:Nonspecific confinement to the vascular space
Method of detection:Magnetic resonance imaging (MRI)
Source of contrast /signal:Gadolinium (Gd)
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents

Gd-DTPA l-cystine bisamide copolymers structure.
Click on PubChem (SID 46501388) for more information.

Background

[PubMed]

The Gd-DTPA l-cystine bisamide copolymer (GCAC) is a biodegradable, macromolecular contrast agent designed for contrast enhancement of the blood pool, liver, and kidneys for magnetic resonance imaging (MRI) (1). The gadolinium(III) ion (Gd3+) is a paramagnetic lanthanide metal ion with seven unpaired electrons.

MRI signals depend on a wide range of parameters. The key factor of conventional MRI contrast is the interaction of the total water signal (proton density) and the magnetic properties of the tissues (2, 3). Various paramagnetic and superparamagnetic contrast agents can increase the sensitivity and specificity of MRI. Current clinical agents are predominately Gd-based contrast agents (GBCA) and are largely nonspecific, low molecular weight compounds. These agents have transient tissue retention, a wide distribution into the extracellular space, and rapid excretion from the body (3-5). There is a need to develop intravascular MRI contrast agents that have a sufficiently long intravascular half-life (t½) to allow imaging of the vasculature and aid in the detection of cancer and cardiovascular diseases (6, 7).

Current strategies to prolong the intravascular t½ include the chelation of paramagnetic ions to macromolecules and the use of superparamagnetic nanoparticles (1, 6, 7). Macromolecular contrast agents are generally large enough (>20 kDa) so that they do not readily diffuse across the healthy vascular endothelium and are not rapidly excreted. These agents are retained in the vasculature for a sufficiently prolonged period of time to allow for imaging, and they also preferentially accumulate in disease tissues with leaky vasculature, such as cancers and vascular disease. Most macromolecular GBCAs are prepared by the conjugation of Gd3+ chelates to biomedical polymers including poly(amino) acids (8, 9), polysaccharides (10, 11), dendrimers (12, 13), and proteins (14), or by the copolymerization of diethylenetriamine pentaacetic acid (DTPA) dianhydride with diamines and the complexation with Gd3+ (15, 16). However, the development of these macromolecular GBCAs has been hampered by potential Gd toxicity associated with the slow degradation of chemically modified biomedical polymers (6, 17). Smaller macromolecules (<20 kDa) are cleared more rapidly by the kidneys but their effectiveness may also be compromised. One approach to improve the safety of macromolecular GBCAs is the development of small molecules (<1.2 kDa) with a hydrophilic Gd3+ complex and a hydrophobic region for reversible noncovalent binding to serum albumin (6, 18). Lu et al. (17, 19) proposed another approach by designing biodegradable macromolecular polydisulfide GBCAs. These agents have disulfide bonds incorporated into a polymeric backbone, and these bonds can be readily reduced by the thiol-disulfide exchange reaction with endogenous or exogenous thiols, such as glutathione and cysteine. As a result, these macromolecules are broken down into smaller complexes that are readily excreted by the kidneys. The Gd-DTPA-cystamine copolymer was the first such agent synthesized by the copolymerization of cystamine and DTPA dianhydride (17). A series of polydisulfide-based macromolecular GBCAs with different structural modifications around the disulfide bonds have been synthesized and evaluated by the same research team of Lu et al. (17, 20-23). Kaneshiro et al. (1) reported the synthesis and evaluation of GCAC and two other derivatives with different amide substituents at the cystine carboxylic groups. All three agents were cleaved in vivo into low molecular weight Gd3+ chelates and were cleared rapidly in rats.

Both renal and extrarenal toxicities have been reported after the clinical use of GBCAs in patients with underlying kidney disease (24-26). In 2007, the US FDA requested manufacturers of all GBCAs to add new warnings that exposure to GBCAs increases the risk for nephrogenic systemic fibrosis in patients with advanced kidney disease.

Synthesis

[PubMed]

Kaneshiro et al. (1) described the synthesis of GCAC from commercially available cystine bisamide. The DTPA l-cystine bisamide copolymer was first synthesized by condensation copolymerization of equimolar amounts of DTPA dianhydride and l-cystine bisamide. Briefly, cystine bisamide was dissolved in triethylamine (TEA) and anhydrous dimethyl sulfoxide (DMSO) while stirred in an ice-water bath at 5ºC. TEA acted as a base to neutralize the salts of monomers and as a solvent to increase the solubility of the copolymers. DTPA dianhydride was then added over a 25-min period. After 40 min, the solidified mixture was removed and allowed to come to room temperature. Additional DMSO was added and the mixture was stirred overnight at room temperature. DTPA l-cystine bisamide copolymers were precipitated in acetone and dissolved in double ionized water (DI H2O) at pH 7. The copolymer was dialyzed and concentrated to dryness. The resulting product was mixed with a large excess of Gd triacetate in DI H2O (pH 5.5) and stirred at room temperature for 1 h. Free Gd3+ ions were removed by size-exclusion chromatography. The yield was 81%. The DTPA l-cystine bisamide copolymers were anionic and had a large hydrodynamic volume. The complexation of the copolymers with Gd3+ ions produced a neutral GCAC with a significant reduction in hydrodynamic volume. Using size-exclusion chromatography, the number average molecular weight (Mn) and the weight average molecular weight (Mw) were determined to be 14.1 kDa and 22.3 kDa, respectively. The Gd content was determined to be 16.9% on the inductively coupled argon plasma optical emission spectrometer. This was lower than the calculated value of 20.4%; Kaneshiro et al. (1) suggested that this difference might be attributed to the association of water molecules to the hydrophilic polymers.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

The in vitro longitudinal relaxivity (R1) of GCAC based on T1 relaxation time measurement at room temperature by a 3T scanner (inversion recovery prepared turbo spin-echo pulse sequence) was 4.37 mM−1s−1 (1). The in vitro transverse relaxivity (R2) was 6.21 mM−1s−1. In comparison, the R1 of Gd-DTPA-BMEA was 4.62 mM−1s−1.

GCAC was stable in the solid state for at least 6 months of cold storage as its molecular weight distribution did not change.

In vitro degradation of DTPA l-cystine bisamide copolymers (DCAC - copolymers without Gd) and GCAC with and without the presence of l-cysteine (15 μM) at 37ºC was studied (1). In the presence of cysteine, DCAC completely degraded into low molecular weight species within 24 h. GCAC completely degraded into low molecular weight oligomers after 75 min. Measurement by matrix-assisted laser desorption ionization time of flight (MALDI-TOF) mass spectrometry indicated that the mass of degradation products with one or two repeat units was ~753.0 and ~1501.2 (m/z).

Animal Studies

Rodents

[PubMed]

In vivo metabolic studies of GCAC were conducted in rats with a dose of 0.1 mmol Gd/kg by i.v. injection (1). Only one major metabolite with a mass (m/z) of 988.02 was identified in urine samples measured by positively-charged labeled MALDI-TOF mass spectrometry (α-cyano-4-hydroxycinnamic acid matrix) at 8 h. There were no major metabolites identified in urine samples at 24 h. With negatively-charged labeled MALDI-TOF mass spectrometry, the masses (m/z) identified in urine samples at 8 h were 589.06, 707.09, and 734.10. The structures of these metabolites were not known (20). No metabolites were observed at 24 h.

In vivo MRI imaging was performed with a 3T MRI scanner in three rats (1). Each rat received an i.v. dose of 0.1 mmol Gd/kg. Images were obtained with a wrist coil using a 3D FLASH pulse sequence. Strong contrast enhancement was observed within the heart, blood vessels, liver, and kidneys at 2 min. The contrast enhancement gradually decreased but was still visible at 30 min. Contrast enhancement was also observed and gradually increased over time in the urinary bladder.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

No publication is currently available.

NIH Support

R01 EB00489, R33 CA095873,

References

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    21.
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    22.
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    23.
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    26.
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    This MICAD chapter is not included in the Open Access Subset, because it was authored / co-authored by one or more investigators who was not a member of the MICAD staff.

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