STARCH MICROSPHERES AS CARRIERS FOR X-RAY-IMAGING CONTRAST AGENTS - SYNTHESIS AND STABILITY OF NEW AMINO-ACID LINKER DERIVATIVES

The relative stability of particulate contrast agents for X-ray imagin g, consisting of a succinic-acid derivative of a water-soluble X-ray c ontrast agent bound to starch particles through an amino-acid ester bo nd, 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 beta-alanine-linked derivative were prepared as m odel compounds. The cleavage rate of the amino-acid ester bond in the starch particle beta-alanine derivative had a significantly lower clea vage rate than in the corresponding glycine derivatives; after 22 h in human blood serum at 37 degrees C the remaining fraction of the undeg raded beta-alanine-linked derivative was 78%, while 31.1 and 29.3% wer e the remaining fractions of the two glycine-linked derivatives. The c leavage 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 sl ower with 79.9%-remaining fraction after 22 h, and was apparently a mo nophasic pseudo first order reaction. Variation of the degradability o f the starch matrix had apparently no significant effect on the cleava ge rates of the linker. This suggests that components in the human blo od serum catalyze the cleavage of the ester bond in these derivatives and that a fraction of the covalently bound contrast agent had a signi ficantly slower cleavage rate from the matrix. The derivative with a g lycine linker between the carrier matrix and the contrast agent is a p romising candidate for liver and spleen directed X-ray contrast with r espect to density of contrast generating iodine and biodegradability. (C) 1997 Elsevier Science Ltd.