Polymeric Conjugates of Gd³⁺−Diethylenetriaminepentaacetic Acid and Dextran. 2. Influence of Spacer Arm Length and Conjugate Molecular Mass on the Paramagnetic Properties and Some Biological Parameters

Abstract

Macromolecular conjugates of dextran 40 (Mn = 38 kg/mol, Mw = 43 kg/mol) and diethylenetriaminepentaacetic acid (DTPA), capable of complexing Gd3+, were synthesized in order to obtain contrast agents for nuclear magnetic resonance imaging, with long intravascular persistence. As already reported, relaxivity of these macromolecular complexes was greater than that of molecular complexes (2-2.5 times). On the other hand, as relaxivity of paramagnetic agents partially depends on their rotation speed, the influence of the length of the spacer arm inserted between DTPA and dextran was investigated. Various conjugates with spacer arms comprised of methylenic chains (-(CH2)n-) with varying lengths (2 < or = n < or = 6) were prepared. The result was that, whatever the distance between DTPA and dextran, all of the Gd(3+)-complexed polymeric conjugates with similar DTPA content (0.6-0.8 mmol/g) exhibited, at 20 MHz, about the same relaxivity values. On the other hand, in the same way, no significant effect of the molecular masses (Mn between 166 and 224 kg/mol and Mw between 332 and 865 kg/mol) of the polymeric conjugates on relaxivity were observed. Toxicity studies carried out on mice, showed very similar LD50 values whatever the spacer arm and molecular mass of the macromolecular conjugates. Finally the urinary excretion studied on rats (after 4 h) and on rabbits (after 24 h) was relatively low (15-20% of the administered dose), and, as expected, the lower values were obtained with the higher molecular mass conjugates.

Promoted Adipogenesis of Rat Mesenchymal Stem Cells by Transfection of Small Interfering RNA Complexed with a Cationized Dextran

“…[43][44][45] In addition, paramagnetic or radiolabeled polysacchrides have been applied for diagnostic imaging. [46][47][48][49][50][51][52][53][54] Another notable feature of polysaccharide is to compose different sugars that can be recognized by the respective cell receptors of sugar specificity. This biological recognition not only permits the receptor-specific targeting of agents to the cell but also accelerates their cell uptake via the receptor-mediated endocytosis.…”

Polymeric 1H MRI Probes for Visualizing Tumor In Vivo

“…[19] The conjugate of the polysaccharides dextran [20] with Gd-DTPA (Figure 3(iv)) was synthesized, which showed the relaxivity 2.5-fold higher than that of Gd-DTPA. [21] Tumor imaging in rabbit by MRI was successfully achieved with 165 kDa of a dextran-Gd-DTPA CA, and a dextran-CA was also shown to be suitable for MR angiography. [22] The relaxivity increases by suppression of molecular rotation and tumbling of the flexibility of macromolecular CAs in addition to increase of the local concentration P m .…”

Basic Design and Synthesis of Sulfonated Contrast Agents for Magnetic Resonance Imaging Based on Gadolinium Complexes

“…As a physical parameter to assess the balance between the lipophilicity and the hydrophilicity of the sulfonated starting materials and the serially synthesized 1161 ANALYTICAL SCIENCES OCTOBER 2007, VOL. 23 contrast agents, we used the octanol-PBS partition coefficient (P) value in this study.…”

“…However, these macromolecular contrast agents have some limitations for clinical applications: (i) the possibility of eliciting an immune response due to the use of proteins and large molecules and/or (ii) significantly slow elimination from the body and subsequent metabolism, which could lead to the release of toxic by-products including free Gd 3+ . 14,[21][22][23][24][25] To address such limitations and potentials of these macromolecular MRI contrast agents, low molecular-weight gadolinium complexes have been chemically designed to bind noncovalently to substances like plasma proteins. 8,[26][27][28][29][30] As an example, due to its specific structure, MS-325 (Vasovist ® ) can bind strongly but noncovalently to human serum albumin (HSA), resulting in an extension of the plasma half-life (23.1 ± 2.9 min in rats 31 and approximately 2 -3 h in primates) 31 and an appropriate elimination from the organism.…”