From monomers to micelles: investigation of the parameters influencing proton relaxivity

Abstract

17O NMR and (1)H NMRD studies have been performed on a series of Gd(III) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) derivatives as potential liver-specific magnetic resonance imaging (MRI) contrast agents. They bear aliphatic side chains which make them capable of micellar self-organization. The compounds differ in the length (C10-C18) and in the chemical nature (alkyl or monoamide-alkyl) of their lipophilic chain. We have established a convenient method to determine the critical micellar concentration (cmc) of paramagnetic surfactants by (1)H relaxivity measurements. This technique can be easily used over a large temperature range; thus, it can find wide application outside the field of MRI contrast agents. The knowledge of the cmc allowed us to determine the parameters governing the water proton relaxivity of the Gd(III) chelates in both nonaggregated and aggregated micellar forms. The relaxation data of the micellar complexes have been interpreted with the Lipari-Szabo approach. This model allows a local motion to be separated from the global tumbling of the whole micelle (modulated by a local, tau(l), and a global, tau(g), rotational correlation time, respectively). The aggregation substantially affects the rotational dynamics and thus increases the proton relaxivity of the Gd(III) chelates. The global rotational correlation times increase with increasing length of the side chain (500-2800 ps for C10-C18). Local motions are also influenced by the length and by the hydrophobicity of the side chain. The analysis of the relaxation data reveals considerable flexibility for these micellar aggregates. The rate of water exchange obtained for these chelates is identical to that for [Gd(DOTA)(H(2)O)](-) (k(ex)(298)= 4.8 x 10(6)s(-1))and is not sensitive either to micellization or to differences in the aliphatic chain. A relaxivity gain in such systems could be attained by simultaneously optimizing the water exchange by modifications of the chelate and increasing the micelle rigidity by using water-soluble surfactants with more hydrophobic side chains.

High‐Relaxivity MRI Contrast Agents: Where Coordination Chemistry Meets Medical Imaging

“…[5,80,81] Construction of macromolecular entities with multiple contrast agents has the advantage of increased ionic (per mM Gd) and molecular (per particle) relaxivity. The ionic relaxivity increase is due to slower molecular tumbling, and the use of multiple attachment sites leads to high molecular relaxivities.…”

“…[92] Virus capsids have recently been explored as potential scaffolds for attachment of Gd-chelates. [73,77,81,93] Covalent attachment of TREN-bis-HOPO-TAM-based chelates onto bacteriophage MS2 capsids (90 chelates per capsid) has led to one of the highest relaxivities yet reported for these systems (Figure 12). [94] The capsid shell consists of 180 copies of the coat protein (relative molecular mass (M r ) 13,700) assembled into an icosahedral arrangement ( Figure 12).…”

High Relaxivity Gadolinium Hydroxypyridonate−Viral Capsid Conjugates: Nanosized MRI Contrast Agents1

“…7 For HOPO based and other complexes, relaxivity enhancement has been demonstrated through the attachment of contrast agents to proteins, [8][9][10] polypeptides, 11 dendrimers, 12,13 nanospheres, 14 and micellar nanoparticles. [15][16][17] Nanometer scale contrast agents also offer the potential to differentiate non-nervous-system tissue. They should be large enough to be retained in blood capillaries by normal endothelial barriers, and yet they should diffuse across the distorted endothelium associated with pathological lesions.…”

Multiple‐Frequency and Variable‐Temperature EPR Study of Gadolinium(III) Complexes with Polyaminocarboxylates: Analysis and Comparison of the Magnetically Dilute Powder and the Frozen‐Solution Spectra

“…While the molecular factors influencing (1) and (2) are rather well understood [2][3][4][5] , the electronic spin relaxation of Gd(III) complexes relevant for MRI remains the subject of much discussion [6][7][8][9][10][11][12][13][14][15] .…”