ALBUMIN MICROSPHERES FOR THE CONTROLLED RELEASE OF THERAPEUTIC AGENTS

There is a growing interest in the use of human serum albumin microspheres (HSA/MS) as insoluble drug carriers for controlled delivery of therapeutic agents. HSA/MS synthesized by methods reported to date are somewhat hydrophobic and require surfactants for preparing injectable aqueous dispersions. Drugs must be incorporated during preparation and only moderate concentrations have been achieved (less than 15 wt %).; A new method for preparing hydrophilic, chemically cross-linked HSA/MS was developed in this study. Important aspects of this method include addition of the cross-linking reagent in the organic phase and use of concentrated polymer solutions as dispersion media. Uniform, round, solid, hydrophilic microspheres were readily prepared by this process.; Surface properties were altered by chemical modification using amino acids, proteins, lectins or amino alcohols to quench residual aldehyde groups. Optical and scanning electron microscopy and electronic particle size characterization indicated that the process is versatile in producing solid MS in a wide size range (0.2-150 (mu)). HSA/MS prepared in this study are dispersed in aqueous media for injection, without the need for surfactants. Incorporation of synthetic polypeptides or modified dextrans into the HSA/MS was also achieved, thereby enabling modification of ionicity.; The hydrophilic HSA/MS reported here allow for the incorporation of therapeutic agents into the HSA/MS after synthesis. Although HSA/MS were readily prepared with up to 18 wt % adriamycin (AD), addition of polyglutamic acid (PGA) made possible the preparation of AD-PGA-HSA/MS containing up to 45 wt % of the AD through formation of the AD-PGA salt complex. HSA/MS containing other drugs were also prepared.; Drug release properties were measured in vitro. Different drug binding mechanisms (covalent, salt complexed and physical association) allowed for a wide range of release rates in both dynamic flow and static systems.; Drug-containing HSA/MS demonstrated reduced toxicity in vivo. HSA/MS injected into rabbit muscle remained immobilized for 2 to 6 weeks before biodegradation.; The results of this study indicate that HSA/MS have significant potential as carriers for intratumoral chemotherapy and other types of localized drug delivery.