Per Strande

Polysaccharides as carriers for magnetic resonance imaging contrast agents: Synthesis and stability of a new amino acid linker derivative

Abstract The relative hydrolytic stability of contrast agents for magnetic resonance imaging (MRI), consisting of paramagnetic metal chelates bound to polysaccharides through an ester bond, has been investigated. Four preparations of biodegradable, cross-linked starch particles were studied as model compounds: diethylenetriaminepentaacetic acid (DTPA)-starch particles ( 1 ), two batches of gadolinium-DTPA (GdDTPA)-starch particles ( 2a,2b ) with different Gd content, and N -(2-phenylethyl)succinamoyl starch ester particles ( 4 ). In a study of hydrolytic rates in water suspension, the derivatives with GdDTPA bound directly to the particle via the carboxylic acid groups in DTPA ( 2a,2b ) showed 74 and 86% remaining matrix-bound GdDTPA, respectively, after 21 days. The unchelated derivative ( 1 ) showed 96% remaining matrix-bound DTPA, while for the succinamoyl-linked derivative ( 4 ), no significant hydrolysis took place during the same time span. To investigate the corresponding stability of ester bonds in water-soluble, blood-pool agents for MRI, the degradation rate of the macromolecular derivatives dextran-DTPAGd ( 5 ) and dextran-β-alanine-DTPAGd ( 6c ) were compared in artificial blood plasma. The remaining fraction of undegraded ester bond in 6c was approximately 95% after 100 min, while 5 was approximately fully degraded over the same time span. These results indicate that the conjugate with the β-alanine spacer may have a more suitable degradation rate for blood-pool MRI contrast purposes than the derivatives with GdDTPA directly ester bound. It was also shown by relaxation measurements that gadolinium-ethylenediaminetetraacetic acid (GdEDTA) was demetalated in a test solution of phosphate (3 mM) at 37 °C. No demetalation was observed for GdDTPA derivatives of water-soluble polysaccharides, represented by the dextran-GdDTPA conjugate 5 and aminoethyldextran-GdDTPA 7 , lacking an ester bond between GdDTPA and the dextran matrix.

Starch microspheres as carriers for X-ray imaging contrast agents: Synthesis and stability of new amino-acid linker derivatives

Abstract The relative stability of particulate contrast agents for X-ray imaging, consisting of a succinic-acid derivative of a water-soluble X-ray contrast agent bound to starch particles through an amino-acid ester bond, has been studied. To investigate the effect of chain length of the amino-acid linker on degradation rate, two glycine-linked derivatives and a corresponding β-alanine-linked derivative were prepared as model compounds. The cleavage rate of the amino-acid ester bond in the starch particle β-alanine derivative had a significantly lower cleavage rate than in the corresponding glycine derivatives; after 22 h in human blood serum at 37 °C the remaining fraction of the undegraded β-alanine-linked derivative was 78%, while 31.1 and 29.3% were the remaining fractions of the two glycine-linked derivatives. The cleavage data correlated well with biphasic cleavage processes with two distinct half lives for the respective pseudo first order processes. The second preparation with the glycine linker had a cleavage profile and rate equivalent to that of the first one in human blood serum, but the corresponding hydrolysis in phosphate buffer was significantly slower with 79.9%-remaining fraction after 22 h, and was apparently a monophasic pseudo first order reaction. Variation of the degradability of the starch matrix had apparently no significant effect on the cleavage rates of the linker. This suggests that components in the human blood serum catalyze the cleavage of the ester bond in these derivatives and that a fraction of the covalently bound contrast agent had a significantly slower cleavage rate from the matrix. The derivative with a glycine linker between the carrier matrix and the contrast agent is a promising candidate for liver and spleen directed X-ray contrast with respect to density of contrast generating iodine and biodegradability.