Biodegradable polymeric hydroxamic acids for the elimination of iron from the body

Abstract

For cases of hemosiderosis and hemochromatosis having different origins, the product Desferal (DF) [10], which is a natural trihydroxamic acid, has been used for more than 20 years for the elimination of pathological iron from the body. The pressure of three hydroxamic acid groups (-CO-NOH-) makes it possible for DF under physiological conditions to form a stable characteristic complex with Fe(3+) that can be readily eliminated from the body (the half-elimination period is 1-1.5 h [14]). However, DF has a number of significant shortcomings. Because of its low molecular weight, DF is rapidly eliminated from the body (half-elimination period 5-10 min [14]), which significantly reduces its efficiency and makes it necessary to use it repeatedly and for long periods, which in turn not infrequently leads to sepsis [15], malfunctioning of the organs of vision [13], and the development of allergic and anaphylactic reactions [7]. Therefore studies are being conducted into the preparation of polymeric hydroxamic acids (PHAs) that can stay in the body for a longer period than DF. Thus, Winston et al., [16] synthesized PHAs that could eliminate iron from the body of animals in a similar manner to DF [17] and circulate in the bloodstream for a longer time than DF. However, the use of these compounds as a basis for a drug encounters a fundamental problem which relates to the absence in the body of mechanisms for cleavage of the long carbon chains contained in these PHAs. This can result in their accumulation in the fibres and hence to the effects of intoxication being exhibited. We have �9 therefore concentrated our efforts on the preparation and study of those PHAs which would be able to undergo biodegradation in the body [4]. We have used for this purpose dextran, which has found application in the production of the blood substitute rheopolyglucin and which can be administered in large doses and is cleaved by a particular enzyme - a-l,6-dextranglucosidase [5]. In their article published in 1989, Hallaway et al. [9] described the properties of DF attached to dextran and confirmed its potential for use as a polymer matrix, since after addition of DF to this polymer its toxicity decreased while at the same time its period of circulation in the bloodstream increased. The aim of the present study was to determine the optimum number of hydroxamic acids in PHAs. The research tasks comprised the preparation of PHAs with a variable number of hydroxamic acids in the PHAs and a study of the capacity of the PHAs prepared to undergo biodegradation and eliminate iron from the body of animals. The preparation of the PHAs involved the oxidation of dextran with a molecular weight of 30-35,000 Da by 104- ions to form dialdehydedextran (DAD) and subsequent reactions with e-aminocaprohydroxamic acid (ACHA) and reduction of the resulting Schiff bases with sodium borohydride. A number of N-dextrano-e-aminocaprohydroxamic acids containing from 5