Macromolecular prodrugs I. Kinetics and mechanism of hydrolysis of O-benzoyl dextran conjugates in aqueous buffer and in human plasma

Abstract

Benzoate esters of dextran (M w = 65,600) with varying degrees of substitution have been synthesized. The kinetics and mechanism of hydrolytic cleavage of the ester bond in aqueous solution over the pH range 3.0–9.5 (60°C) has been investigated. The degradation reactions followed strict first-order kinetics and a rate expression encompassng hydrogen ion-, hydroxide ion- and water-catalyzed hydrolysis of the conjugates is derived. General acid-base catalysis of release of benzoic acid from the conjugates was negligible. No influence of the degree of substitution on the reaction rates was observed. Nearly identical rates of release of benzoic acid from the conjugates at 37°C in 80% human plasma and in 0.05 M phosphate buffer pH 7.40 have been found (t 1 2 ∼ 190 h), revealing that hydrolysis in plasma proceeds without enzymatic catalysis. The lack of susceptibility to undergo enzyme-mediated hydrolysis is most likely due to steric hindrance by the dextran backbone. Various chemical methods to attach drug compounds covalently to dextrans and the potential, therapeutic utility of the conjugates are discussed.