Rotational Dynamics Account for pH‐Dependent Relaxivities of PAMAM Dendrimeric, Gd‐Based Potential MRI Contrast Agents

Abstract

The EPTPA5) chelate, which ensures fast water exchange in GdIII complexes, has been coupled to three different generations (5, 7, and 9) of polyamidoamine (PAMAM) dendrimers through benzylthiourea linkages (H5EPTPA = ethylenepropylenetriamine-N,N,N',N'',N''-pentaacetic acid). The proton relaxivities measured at pH 7.4 for the dendrimer complexes G5-(GdEPTPA)111, G7-(GdEPTPA)253 and G9-(GdEPTPA)1157 decrease with increasing temperature, indicating that, for the first time for dendrimers, slow water exchange does not limit relaxivity. At a given field and temperature, the relaxivity increases from G5 to G7, and then slightly decreases for G9 (r1 = 20.5, 28.3 and 27.9 mM(-1) s(-1), respectively, at 37 degrees C, 30 MHz). The relaxivities show a strong and reversible pH dependency for all three dendrimer complexes. This originates from the pH-dependent rotational dynamics of the dendrimer skeleton, which was evidenced by a combined variable-temperature and multiple-field 17O NMR and 1H relaxivity study performed at pH 6.0 and 9.9 on G5-(GdEPTPA)111. The longitudinal 17O and 1H relaxation rates of the dendrimeric complex are strongly pH-dependent, whereas they are not for the [Gd(EPTPA)(H2O)]2- monomer chelate. The longitudinal 17O and 1H relaxation rates have been analysed by the Lipari-Szabo spectral density functions and correlation times have been calculated for the global motion of the entire macromolecule (tau(gO)) and the local motion of the GdIII chelates on the surface (tau(lO)), correlated by means of an order parameter S2. The dendrimer complex G5-(GdEPTPA)111 has a considerably higher tau(gO) under acidic than under basic conditions (tau(298)gO = 4040 ps and 2950 ps, respectively), while local motions are less influenced by pH (tau(298)lO = 150 and 125 ps). The order parameter, characterizing the rigidity of the macromolecule, is also higher at pH 6.0 than at pH 9.9 (S2 = 0.43 vs 0.36, respectively). The pH dependence of the global correlation time can be related to the protonation of the tertiary amine groups in the PAMAM skeleton, which leads to an expanded and more rigid dendrimeric structure at lower pH. The increase of tau(gO) with decreasing pH is responsible for the pH dependent proton relaxivities. The water exchange rate on G5-(GdEPTPA)111(k(298)ex = 150 x 10(6) s(-1)) shows no significant pH dependency and is similar to the one measured for the monomer [Gd(EPTPA)(H2O)]2-. The proton relaxivity of G5-(GdEPTPA)111 is mainly limited by the important flexibility of the dendrimer structure, and to a small extent, by a faster than optimal water exchange rate.

Study of Thermodynamic and Kinetic Stability of Transition Metal and Lanthanide Complexes of DTPA Analogues with a Phosphorus Acid Pendant Arm

“…The steric strain was usually reached by introduction of one extra methylene group into the backbone (propylene group instead of ethylene bridge) or in one of the pendant arms (i.e. with propionate pendant instead of acetate), [8][9][10][11] or by substitution of ligand backbone by alkyl/aryl group. [12,13] The complexes formed with these new ligands are thermodynamically usually slightly less stable than those of H 4 dota and H 5 dtpa.…”

A Starburst‐Shaped Heterometallic Compound Incorporating Six Densely Packed Gd3+ Ions

“…As for rotational dynamics, from studies of diverse macromolecular contrast agents it became evident that rigid systems are indispensable for achieving maximum proton relaxivities. By detailed analysis of the rotational dynamics of dendrimers, [10,11] micelles, [12,13] and linear polymers [14,15] by means of the Lipari-Szabo approach, [16] it has been unambiguously proved that these macromolecular systems possess a significant degree of internal flexibility, which is either inherent to the macromolecule itself (linear polymers) or originates from the linker that connects the Gd III chelate to the large molecule. In this respect, heterometallic self-assembled structures with a welldefined, rigid topology may represent a promising approach.…”

Targeted gadolinium-loaded dendrimer nanoparticles for tumor-specific magnetic resonance contrast enhancement

“…The relaxivity of Gd chelates bonded to these dendrimers is more than 4 times greater than Omniscan ™ . The increased relaxivity is due to a decrease of the rotational correlation time of the Gddendrimer complex (Bryant et al 1999;Nicolle et al 2002;Laus et al 2005;Rudovsky et al 2006). For contrast agents such as these molecules, increased relaxivity is one of the most important measures of the effectiveness of the contrast agent.…”