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Gd-DTPA l-Cystine bisisopropyl amide copolymers.

Source

Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.
2008 Feb 07 [updated 2008 Mar 03].

Author information

1
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD, Email: micad@ncbi.nlm.nih.gov
2
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, Corresponding Author, Email: Zhengrong.lu@utah.edu
3
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, Email: T.Kaneshiro@utah..edu

Excerpt

The Gd-DTPA l-cystine bisisopropyl amide copolymer (GCIC) 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 GCIC and two other derivatives (Gd-DTPA l-cystine bisamide copolymers (GCAC) and Gd-l-cystine bispropyl amide copolymer (GCPC)) with different amide substituents at the cystine carboxylic groups. All three neutral 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.

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