One essential requirement for more sensitive gadolinium-based MRI contrast agents is to slow the molecular tumbling of the gadolinium(III) ion, which increases the gadolinium's relaxivity, or the ability to speed up the NMR relaxation of nearby water molecules. One route to this is through conjugation to high-molecular weight polymers such as dendrimers. In this work, amine functionalized TREN-bis(1,2-HOPO)-TAM-ethylamine and TREN-bis(1-Me-3,2-HOPO)-TAMethylamine ligands have been synthesized and attached to biocompatible 40 kDa esteramide (EA) and poly-L-lysine based (PLL) dendrimers capable of binding up to eight gadolinium complexes. These conjugates have T 1 relaxivities of up to 38.14 ± 0.02 mM -1 s -1 per gadolinium at 37 °C, corresponding to relaxivities of up to 228 mM -1 s -1 per dendrimer molecule. This relaxivity expressed on a "per Gd" basis is several times that of the small molecule complexes, and an order of magnitude higher than that of current commercial agents. Due to their high performance and low toxicity these macromolecules may constitute an attractive complement to currently available gadolinium(III) based contrast agents.In the last three decades, magnetic resonance imaging (MRI) has become one of the most prevalent medical imaging modalities used in clinical radiology, with over 27.5 million MRI's performed in 2007. Paramagnetic gadolinium(III) contrast agents are used to enhance signal in about a third of these scans. This is done through the gadolinium's ability to slow the relaxation of water molecules after disturbance by a magnetic field, a parameter known as relaxivity (r 1 ). Concern about gadolinium dosage and release has increased because of nephrogenic systemic fibrosis (NSF), an incurable thickening of tissue and skin seen in patients with late stage renal failure. This condition appears to arise from the tendency for free gadolinium ions to bind to hydroxyapatite in bone tissue and transport across cellular Supporting Information Available: All conjugation procedures, characterization, cytotoxicity and experimental details; This material is available free of charge via the Internet at http://pubs.acs.org. All current commercial contrast agents use octadentate poly(amino) carboxylate ligands as scaffolds to coordinate gadolinium and contain only one inner coordination water molecule (q = 1). Previous research in the Raymond laboratory has developed hexadentate oxygen donor chelators for gadolinium with similar stability to commercial poly(amino)carboxylate contrast agents by utilizing the oxophilicity of gadolinium. Containing either two 1-Me-3,2-hydroxypyridinonate (HOPO) or two 1,2-HOPO rings and an amine functionalized 2,3-dihydroxyterepthalamide (TAM) ring (Figures 1 and 2),2 -7 these tris(2-aminoethyl)amine (TREN)-capped ligands have at least two coordinated water molecules, with fast exchange rates, allowing a much higher theoretical relaxivity than the small molecule amine based chelators. These complexes exhibit high T 1 relaxivities (10-13 mM -1 s -1 ) and the...
Heme proteins are exquisitely tuned to carry out diverse biological functions while employing the identical heme cofactor. Although heme protein properties are often altered through modification of the protein scaffold, protein function can be greatly expanded and diversified through replacement of the native heme with an unnatural porphyrin of interest. Thus, porphyrin substitution in proteins affords new opportunities to rationally tailor heme protein chemical properties for new biological applications. Here, a highly thermal-stable Heme Nitric oxide/OXygen binding (H-NOX) protein is evaluated as a magnetic resonance imaging (MRI) contrast agent. T1 and T2 relaxivities measured for the H-NOX protein containing its native heme are compared to the protein substituted with unnatural Mn(II)/(III) and Gd(III) porphyrins. H-NOX proteins are found to provide unique porphyrin coordination environments and have enhanced relaxivities compared to commercial small molecule agents. Porphyrin substitution is a promising strategy to encapsulate MRI-active metals in heme protein scaffolds for future imaging applications.
Magnetic resonance imaging (MRI) contrast agents represent a worldwide billion-dollar market annually. While T1 relaxivity enhancement contrast agents receive greater attention and a significantly larger market share, the commercial potential for T2 relaxivity enhancing contrast agents remains a viable diagnostic option due to their increased relaxivity at high field strengths. Improving the contrast and biocompatibility of T2 MRI probes may enable new diagnostic prospects for MRI. Paramagnetic lanthanides have the potential to decrease T1 and T2 proton relaxation times, but are not commercially used in MRI diagnostics as T2 agents. In this article, oxygen donor chelates (hydroxypyridinone, HOPO, and terephthalamide, TAM) of various lanthanides are demonstrated as biocompatible macromolecular dendrimer conjugates for the development of T2 MRI probes. These conjugates have relaxivities up to 374 mm−1s−1 per dendrimer, high bioavailability, and low in vitro toxicity.
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