The protein-binding and drug release properties of macromolecular conjugates containing daptomycin and dextran

Abstract

Prototype daptomycin–dextran macromolecular conjugates were prepared in an attempt to modify the biodistribution and protein-binding properties of daptomycin. Synthesis of daptomycin macromolecular conjugates involved dextran activation, daptomycin–dextran coupling, and purification. The reaction mixtures were separated on a Sephadex G-100 column using 10% acetronitrile in water as a mobile phase. UV and fluorescence characteristics of high molecular weight fractions demonstrated imine product formation while the lower molecular weight fractions contained free daptomycin, imine, and anilide products. Daptomycin macromolecular conjugates were characterized by drug loading, drug release, and binding affinity for fibrinogen using HPLC analysis and surface plasmon resonance. Drug loading was calculated to be 160 mg of daptomycin per gram of macromolecule. Approximately 9% of the conjugated daptomycin was released from the macromolecular conjugates in aqueous media in the pH range of 1–7.4. The conjugates possessed higher affinity for fibrinogen than that of daptomycin.