Lipari-Szabo approach as a tool for the analysis of macromolecular gadolinium(III)-based MRI contrast agents illustrated by the [Gd(EGTA-BA-(CH2)12)] n n + polymer

Abstract

The parameters governing the water proton relaxivity of the [Gd(EGTA-BA-(CH2)12)]nn+ polymeric complex were determined through global analysis of 17O NMR, EPR and nuclear magnetic relaxation dispersion (NMRD) data [EGTA-BA2- = 3,12-bis(carbamoylmethyl)- 6,9-dioxa-3,12-diazatetradecanedioate(2-)]. The Lipari-Szabo approach that distinguishes the global motion of the polymer (tau g) from the local motion of the Gd(III)-water vector (tau l) was necessary to describe the 1H and 17O longitudinal relaxation rates; therefore for the first time it was included in the global simultaneous analysis of the EPR, 17O NMR and NMRD data. The polymer consists on average of only five monomeric units, which limits the intramolecular hydrophobic interactions operating between the (CH2)12 groups. Hence the global rotational correlation time is not very high (tau g298 = 3880 +/- 750 ps) compared to the corresponding DTPA-BA-based polymer (about 15 monomeric units), where tau g298 = 6500 ps. As a consequence, the relaxivity is limited by the rotation, which precludes the advantage obtained from the fast exchanging chelating unit (kex298 = 2.2 +/- 0.1 x 10(6) s-1).

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

“…Recently, the model-free Lipari-Szabo approach, commonly used for the description of motional dynamics of proteins, oligosaccharides, and so forth, [50,51] was adapted to paramagnetic 17 O longitudinal relaxation. [21] This approach was successfully used to characterise rotation of different macromolecular Gd III complexes, like linear polymers, [21,23] micellar systems [32] or dendrimers. [30] In several cases, proton relaxivities were also included in the analysis and fitted simultaneously with the 17 O data.…”

“…[21,23] In these polymers, the chain consists of alternating Gd III poly(amino carboxylate) and (CH 2 ) x segments. Here each of the Gd III chelates has two points of attachment to the macromolecule that can contribute to a slower local motion of the Gd-coordinated water oxygen vector.…”

“…[15] For example, macromolecular agents tend to be retained in the vascular space by virtue of their size, hence they are useful for blood-pool imaging by magnetic resonance angiography [16][17][18] or for evaluation of the microvasculature in tumour tissues. [19,20] The conjugation of low-molecularweight chelates to macromolecules can be achieved through different ways, involving linear polymers, [21][22][23][24][25] dendrimers, [26][27][28][29][30] micelles [31][32][33][34][35] or protein-bound complexes. [36][37][38][39] In the past, the non-optimal water exchange rate has been a critical issue for macromolecular, Gd III -based MRI contrast agents, since low exchange rates often limit proton relaxivity.…”

Paramagnetic liposomes containing amphiphilic bisamide derivatives of Gd-DTPA with aromatic side chain groups as possible contrast agents for magnetic resonance imaging

“…A Lipari-Szabo model of the inner sphere relaxivity was also used to take into account the rotational motion of the liposomal structure and that of the Gd-complex (Dunand et al 2001;Nicolle et al 2002). The rotational correlation time value of the liposome (s g ) calculated from the PCS diameter is of the order of 10 À4 s. This value was fixed during the fittings as well as s M that was fixed at 500 ns in order to reduce the number of fitted parameters.…”

Molecular Dynamics Simulations of the Internal Mobility of Gd3+-Based MRI Contrast Agents: Consequences for Water Proton Relaxivity

“…This reduces the number of water molecules in close contact with the metal (down to one single inner sphere water molecule) and slows down the exchange with the bulk. The latter is especially problematic when combined with the favoured route towards high-relaxivity contrast agents, namely macromolecules with slow rotational diffusion [6][7][8][9][10][11][12]. For these compounds, the slow water exchange limits the relaxivity gain obtained through the longer rotational time.…”