NYSTATIN-DEXTRAN CONJUGATES - SYNTHESIS AND CHARACTERIZATION

The coupling of nystatin (Nys), a water-insoluble antifungal agent, to dextran via an imine or amine bond was systematically investigated. D extran was first oxidized to dialdehyde dextran using potassium period ate, purified from the oxidizing agent, and reacted with Nys to form t he Schiff base. The Schiff base was reduced to the amine using borohyd ride. All reactions took place in water. The purification of the oxidi zed dextran from the oxidizing agent was essential to prevent oxidativ e degradation of Nys at the coupling step. The effects on the coupling yield of the following factors: dextran molecular weight, degree of o xidation (aldehyde content), Nys to dextran ratio, temperature, and re action pH were studied. A 95% coupling yield was obtained at the optim ized coupling conditions: pH 8.9 +/- 0.1, 50% degree of oxidation, and initial ratio of Nys to dialdehyde dextran 1 : 2.5. In all experiment s, dextran was decreased in molecular weight during the oxidation step . Both imine and amine forms of Nys-dextran conjugates were soluble in water and exhibited improved stability in aqueous solutions as compar ed to the unbound drug. The conjugates showed comparable minimum inhib itory concentration (MIC) values against Candida albicans and Cryptoco ccus neoformans. The conjugates were about 25 times less toxic than fr ee Nys after a single injection in mice. (C) 1996 John Wiley & Sons, I nc.