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: 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
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ABSTRACT: The improvement of commonly used Gd3+ -based MRI agents requires the design of new systems with optimized in vivo efficacy, pharmacokinetic properties, and specificity. To design these contrast agents, two parameters are usually considered: increasing the number of coordinated water molecules or increasing the rotational correlation time by increasing molecular weight and size. This has been achieved by noncovalent or covalent binding of low-molecular weight Gd3+ chelates to macromolecules or polymers. The grafting of these high-spin paramagnetic gadolinium chelates on metal oxide nanoparticles (SiO2, Al2O3) is proposed. This new synthetic strategy presents at least two main advantages: (1) a high T1-relaxivity for MRI with a 275% increase of the MRI signal and (2) the ability of nanoparticles to be internalized in cells. Results indicate that these new contrast agents lead to a huge reconcentration of Gd3+ paramagnetic species inside microglial cells. This reconcentration phenomenon gives rise to high signal-to-noise ratios on MR images of cells after particle internalization, from 1.4 to 3.75, using Al2O3 or SiO2 particles, respectively. The properties of these new particles will be further used to get new insight into gene therapy against glioma, using microglial cells as vehicles to simultaneously transport a suicide gene and contrast agents. Since microglia are chemoattracted to brain tumors, the presence of these new contrast agents inside the cells will lead to a better MRI determination of the in vivo location, shape, and borders of the tumors. These Gd3+-loaded microglia can therefore provide effective localization of tumors by MRI before applying any therapeutic treatment. The rate of carcinoma remission following a suicide gene strategy is also possible.Bioconjugate Chemistry 01/2007; 18(4):1053-63. · 4.58 Impact Factor