MACROMOLECULAR PRODRUGS .20. FACTORS INFLUENCING MODEL DEXTRANASE-MEDIATED DEPOLYMERIZATION OF DEXTRAN DERIVATIVES INVITRO

Endo-dextranase-mediated depolymerization of dextran and dextran deriv atives under various experimental conditions in vitro was determined. By a simultaneous determination of M(n) and M(W) of dextrans treated w ith the enzyme in aqueous buffer, an initial increase of the polydispe rsity of the polysaccharide sample was observed, indicating that dextr anase cleaved the dextran molecules into chains which differed signifi cantly in length. A pH optimum of 5 for the enzyme action was found. H owever, in the pH range 5-8, which prevails in the colon, the initial depolymerization rates differed by a factor of less than 2. Dextranase treatment of a dextran sample resulted in a constant increase of the concentration of terminal reducing glucose residues per time unit sugg esting, that the initial depolymerization reaction followed zero-order kinetics. For degrees of substitution below 12 the efficacy of dextra nase fragmentation of dextran conjugates decreased almost linearly wit h increasing DS. The chemical nature of the attached drug did not sign ificantly affect the depolymerization rates. Maximally depolymerized d extran derivatives were obtained by the combined action of dextranase and various alpha-glucosidases. Treatment of such solutions with: a) m odel esterases b) 80% plasma and c) 20% liver homogenate did not give rise to an acceleration of the initial drug regeneration, as compared to identical experiments carried out in pure buffer solution (pH 7.4 a nd 37-degrees-C).