Use of Paramagnetic Chelated Metal Derivatives of Polysaccharides and Spin‐Labeled Polysaccharides as Contrast Agents in Magnetic Resonance Imaging

Abstract

Soluble and insoluble polysaccharides were derivatized with diethylenetriaminepentaacetic acid (DTPA) and/or spin-labeled with 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO). Polysaccharides derivatized with DTPA were prepared via cyanogen bromide activation, coupling to a diamine linker, and to DTPA anhydride. Spin-labeled polysaccharides were also prepared via cyanogen bromide activation. The extent of derivatization for dextran (18 kDa) was about 120 glucose units per DTPA, and for cellulose and starch about 15-30 units per DTPA. For spin-labeled polysaccharides, the average loading ranged from 1 nitroxide per 16 glucose units for starch to 181 for dextran (82 kDa). These derivatized paramagnetic polysaccharides were shown to be more effective relaxants than the small paramagnetic molecules alone. Both soluble and insoluble polysaccharide-linker-DTPA-Gd(III) complexes were effectively cleared from the body (rats) after oral administration. After intravenous administration, the biodistribution of dextran-linker-DTPA-Gd(III) complexes differed significantly from that of GdDTPA. Reduction of the nitroxide by ascorbic acid was retarded in the polysaccharide derivatives, particularly in starch derivatized with both nitroxide and linker-DTPA-Cu(II). These agents showed contrast enhancement in the gastrointestinal tract of rabbits.

Carboxymethyldextran-A2-Gd-DOTA enhancement patterns in the abdomen and pelvis in an animal model

“…A variety of dextran-based tracers have been investigated [16,17,18,24,25,26]. Previous formulations had a molecular weight which was either too high (up to 75 kDa) to provide renal elimination or too small (17 kDa) to permit efficient blood-pool enhancement [17,25].…”

“…The search for clinically applicable macromolecular MR contrast agents is broadly pursued [3,12,13,14,18,22]. The optimal size of a macromolecular contrast agent, however, has yet to be determined.…”

“…Therefore, contrast agents have to be developed that provide the enhancement properties of a macromolecule but are still completely eliminated within a reasonable time frame [12,13,14,15]. Dextranbased contrast agents are advantageous because of their hydrophilicity and their low toxicity; besides, dextrans have been used clinically as plasma expanders for decades [16,17,18,19]. The purpose of this study was to investigate the abdominal and pelvic enhancement patterns of a new formulation of a dextran-based contrast agent, carboxymethyldextran-A2-Gd-DOTA (CMD-A2-Gd-DOTA), which undergoes glomerular filtration and has a preserved polydispersity [19].…”

Metals in Medicine

“…The derivatization of soluble and insoluble polysaccharides allows the delivery of multiple paramagnetic ions. [8] Complex 1 does not enter cells and is excreted almost exclusively by the kidney. Introduction of a benzyloxymethyl substituent on the a-C atom of a terminal acetate of DTPA as in BOPTA produces a Gd III complex (5, Gadobenate, Figure 3) which enters hepatocytes and is excreted in bile.…”

Tuftsin derivatives of FITC, Tb–DOTA or Gd–DOTA as potential macrophage‐specific imaging biomarkers

“…This is the reason why its relaxivity is comparable with that observed for other DOTA-monoamide complexes of gadolinium. The relaxivity of Gd-DOTA-tuftsin in PBS containing 8% BSA solution was 2.64 mM À1 s À1 , which suggests that a quite low percentage of Gd-tuftsin integrates noncovalently with BSA, possibly in the form of (Gd-tuftsin)ÁBSA (46,47). Serum albumin is the richest protein of human blood plasma, and would play a crucial role on the uptake, transportation, biodistribution and excretion of contrast agent in the human body (34,48).…”