Preparation, Physico-Chemical and Pharmacokinetic Characterization of Monomethoxypoly(Ethylene Glycol)-Derivatized Superoxide Dismutase

Abstract

The surface modification of enzymes by polymers has recently been proposed in order to improve their use in therapy. It is found that the derivatization with monomethoxypoly(ethylene glycol) (MPEG) of Superoxide dismutase (SOD), an enzyme now used in inflammatory diseases, gives a heterogenous product. It is demonstrated that this heterogeneity depends on the presence of bifunctional PEG coming from non-methoxylated molecules. Covalent binding of PEG is accompanied by some loss in enzymatic activity, which has been demonstrated to be due to the decrease in the affinity of the Superoxide ion at the SOD surface, while the active site structure at the metals is not modified. The MPEG bound to the SOD surface modifies certain physico-chemical properties of the enzyme, such as solvent solubility, metal binding and structural stability. The pharmacokinetic parameters of the enzyme, which were evaluated in rats following i.V., i.m., i.p. and s.c. administration, has been found to be greatly modified by the polymer binding.