Effect of varying the molecular weight of the MR contrast agent Gd‐DTPA‐polylysine on blood pharmacokinetics and enhancement patterns

Abstract

The effects of varying the molecular weight of gadolinium-DTPA (diethylenetriaminepentaacetic acid)-polylysine, a macromolecular magnetic resonance (MR) imaging contrast agent, on blood pharmacokinetics and dynamic tissue MR imaging signal enhancement characteristics were studied in normal rats. Blood elimination half-life, total blood clearance, volume of the central compartment (Vcc) and the steady-state distribution volume (Vssd) were calculated for four Gd-DTPA-polylysine polymers with average molecular weights of 36, 43.9, 139, and 480 kd and compared with corresponding values for Gd-DTPA (0.57 kd) and Gd-DTPA-albumin (92 kd). Blood elimination half-life increased seven-fold with an increase in molecular weight from 36 to 480 kd. The Vcc values for all polylysine polymers did not differ significantly from the Vcc value for Gd-DTPA-albumin but were significantly smaller than the Vcc value for Gd-DTPA. The Vssd value for Gd-DTPA did not differ significantly from the Vssd value for the 36- and 43.9-kd polymers but was significantly larger than the Vssd values for the 139- and 480-kd polymers and for Gd-DTPA-albumin. On T1-weighted coronal spin-echo MR images, dynamic signal enhancement profiles in liver and kidney for the 36-, 43.9-, and 480-kd Gd-DTPA-polylysine chelates corresponded to the blood pharmacokinetic data. Increasing molecular weight of Gd-DTPA-polylysine formulations substantially slows blood clearance and produces a prolonged, almost constant tissue signal enhancement for the 60-minute observation period.

Synthesis, Characterization, and Pharmacokinetic Evaluation of a Potential MRI Contrast Agent Containing Two Paramagnetic Centers with Albumin Binding Affinity

“…[2,[11][12] This strategy, however, has proved to be rather disappointing, as the relaxivity gained by increasing the molecular size is often much less than expected, because of the internal flexibility or nonrigid attachment of the chelate to the macromolecule. [7][8][9][10][11][12][13][14] More recently, an increase in rotational correlation time was achieved by either incorporating amphiphilic gadolinium(iii) chelates into mixed micelles, [15,16] or by designing complexes that can self-assemble to form micelles. [17,18] Due to their reduced particle size (50 nm or less), these agents are less recognizable by the Kupffer cells for physiological removal, with the result that their residence time in blood increases.…”

“…[4,5] Although incorporation of paramagnetic compounds into liposomes efficiently increases rotational correlation time, the application of these particles in vivo has some disadvantages, such as their rapid physiological removal by Kupffer cells of the liver and spleen, and their relatively slow clearance rate, which may be harmful to human tissue. [6] An alternative strategy is the synthesis of macromolecular gadolinium(iii) chelates, such as dendrimers, [7] linear polymers, [8][9][10] or proteins. [2,[11][12] This strategy, however, has proved to be rather disappointing, as the relaxivity gained by increasing the molecular size is often much less than expected, because of the internal flexibility or nonrigid attachment of the chelate to the macromolecule.…”

Size-tuneable Nanometric MRI Contrast Agents for the Imaging of Molecular Weight Dependent Transport Processes

“…The potential for polymers based CAs with enhanced blood residence time has previously been explored. When poly-L-lysine-GTPA of increasing MW were explored as potential blood pool agents it has previously been shown that plasma half-life is increased and renal clearance reduced with increasing MW [18]. However, agents such as carboxy methyl dextran-GTPA have limited utility in exploring MW dependent processes because of their broad MW distribution (10-163 kD) [19].…”

MRI with Gadolinium‐Based Nanoparticles

“…It was shown that relaxivity was improved as compared to the mono Gd 3+ chelate; however, relaxivity was not influenced significantly by the size of the polymer [39]. As shown in animal studies [41,42], p-Lys-based agents are predominantly excreted through the kidneys and exhibit prolonged circulation time as the molecular weight increases, leading to constant enhancement in tissue signal over a 1 h period [43]. These characteristics make them interesting as blood pool agents.…”