Gadolinium-1,4,7,10-tetraazacyclododecane- N,N',N',N'"-tetraacetic-monoamide-24-cascade-polymer
Huiming Zhang
PMID: 20641779
Abstract:
Magnetic resonance imaging (MRI) delineates soft tissues by sampling the signal of tissue water protons to detect abnormalities in anatomy, pathology, and functionality in the human body. The imaging contrast, defined as the relative brightness of various parts of the body, is primarily determined by the tissue structures and the spin relaxation times of the water protons (the longitudinal relaxation time (T1) and the transverse relaxation time (T2)). Many physiological processes, including blood flow, diffusion, perfusion, and chemical exchange, also affect the imaging contrast. To improve the imaging contrast, a variety of experimental parameters can be optimized. Imaging contrast can be improved locally by using contrast agents specifically targeted to tissues and organs (1, 2). Blood pool agents are paramagnetic contrast agents designed to remain in the blood for a prolonged time compared to the conventional contrast agents like gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA). Blood pool agents are normally macromolecules attached gadolinium chelates or iron oxide nanoparticles (1).Their large size prevents them from diffusing through the endothelium of normal tissue and entering into interstitial space in detectable amounts before being completely excreted from body. In addition to the applications in magnetic resonance angiography (3-5), blood pool agents are used to target necrotic myocardium (6, 7), to access myocardial viability (8), and to detect various tumors (9, 10).
24-Gadolinium-1,4,7,10-tetraazcyclododecane-N,N',N",N"'-tetraacetic monoamide (GdDOTA)24-cascade-polymer is a synthetic polymeric gadolinium complex designed as a blood pool contrast agent for MRI (11, 12). The main molecular frame is a dendritic structure (dendrimer) built from a tri-mesoyl[benzene-1,3,5-tricarbonyl] core surrounded by two generations of 6 and 12 L-lysine residues. 24 gadolinium-1,4,7,10-tetraazcyclododecane-N,N',N",N"'-tetraacetic monoamide (Gd-DOTA) moieties are covalently bound at the molecular surface (12, 13). Each Gd-DOTA moiety contains lanthanide Gd(III) of high electron spin (7/2) and long electron relaxation time (14). Gd(III) forms a very stable complex with DOTA and leaves one structural water in rapid exchange with the bulk water of tissues. As a result, the T1 relaxation time of tissue water protons reduces significantly. DOTA is a macrocyclic and can form a stable complex with Gd(III). Gd-DOTA has an in vitro stability five orders of magnitude greater than that of Gd-DTPA (14). This greater stability allows for reduction of the in vivo toxicity caused by the dissociation of free Gd(III) in the metabolic process (14). Attaching Gd-DOTA to a macromolecule generates a field-dependent paramagnetic enhancement effect (PRE) (15, 16). The efficacy increases substantially as a result of the increase of the effective rotation correlation time τR. The synthesis of dendrimer starts with formation of a core. Monomers are assembled radially according to certain dendritic rules and cascade to higher generations like a starburst. Dendrimers built in this way have a globular shape, which provides an open surface for attaching various species such as imaging agents and therapeutic drugs (17). As a carrier for MRI contrast agents, dendrimers possess a mono-dispersed, well-defined, and stable molecular structure with rigid branch segments, allowing the synthesis of paramagnetic particles with well-defined size and efficacy (17, 18). (GdDOTA)24-cascade-polymer is a blood pool agent of intermediate size that can effectively delineate small vessels, detect capillary permeability, improve myocardial ischemia detections, estimate blood flow and blow volume, and characterize tumors.
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