The impact of rigidity and water exchange on the relaxivity of a dendritic MRI contrast agent.
ABSTRACT Variable-temperature, multiple magnetic field (17)O NMR, EPR and variable-temperature (1)H nuclear magnetic relaxation dispersion (NMRD) measurement techniques have been applied to Gadomer 17, a new dendritic contrast agent for magnetic resonance imaging. The macromolecule bears 24 Gd(dota)-monoamide chelates (dota=N,N',N",N"'-tetracarboxymethyl-1,4,7,10-tetraazacyclododecane) attached to a lysine-based dendrimer. (17)O NMR and (1)H NMRD data were analysed simultaneously by incorporating the Lipari-Szabó approach for the description of rotational dynamics. The water exchange rate k(298)(ex)was found to be (1.0 +/- 0.1) x 10(6) s(-1), a value similar to those measured for other Gd(dota)-monoamide complexes, and the activation parameters DeltaH++ =24.7 +/- 1.3 kJ mol(-1) and DeltaS++ = -47.4 +/- 0.2 JK(-1) mol(-1). The internal flexibility of the macromolecule is characterised by the Lipari-Szabó order parameter S(2)=0.5 and a local rotational correlation time tau(298)(l)= 760 ps, whereas the global rotational correlation time of the dendrimer is much longer, tau(298)(g)=3050 ps. The analysis of proton relaxivities reveals that, beside slow water exchange, internal flexibility is an important limiting factor for imaging magnetic fields. Electronic relaxation, though faster than in similar, but monomeric, Gd(III) chelates, does not limit proton relaxivity of this contrast agent (r(1)=16.5mM(-1)s(-1) at 298 K and 20 MHz). This analysis provides direct clues for the design of high-efficiency contrast agents.
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ABSTRACT: We present a series of hydrogel nanoparticles (nanogels) incorporating either acyclic or cyclic metal chelates as crosslinkers. These crosslinkers are used to formulate polyacrylamide-based nanogels (diameter 50 to 85 nm) yielding contrast agents with enhanced relaxivities (up to 6-fold greater than Dotarem®), because this nanogel structure slows the chelator's tumbling frequency and allows fast water exchange. Importantly, these nanogels also stabilize Gd(3+) within the chelator thermodynamically and kinetically against metal displacement through transmetallation, which should reduce toxicity associated with release of free Gd(3+). This chelation stability suggests that the chelate crosslinker strategy may prove useful for other applications of metal-chelating nanoparticles in medicine, including other imaging modalities and radiotherapy.Journal of materials chemistry. B, Materials for biology and medicine. 12/2013; 1(46):6359-6364.
- Angewandte Chemie. 01/2008; 120(45):8696-8709.
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ABSTRACT: Dendrimers are versatile macromolecules with tremendous potential as magnetic resonance imaging (MRI) contrast agents. Dendrimer-based agents provide distinct advantages over low-molecular-weight gadolinium chelates, including enhanced r1 relaxivity due to slow rotational dynamics, tunable pharmacokinetics that can be adapted for blood pool, liver, kidney, and lymphatic imaging, the ability to be a drug carrier, and flexibility for labeling due to their inherent multivalency. Clinical applications are increasingly being developed, particularly in lymphatic imaging. Herein we present a broad overview of dendrimer-based MRI contrast agents with attention to the unique chemistry and physical properties as well as emerging clinical applications. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology 10/2013; · 5.68 Impact Factor