Formulation and release characteristics of poly(lactic-co-glycolic acid) microspheres containing chemically modified protein

Chemical modification of proteins may influence their formulation into and release from polymeric microspheres. Three chemical modifications of rat se rum albumin (RSA) were effected on the amine groups of this protein:conjuga tion with a polyanion using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, intermolecular cross-linking using glutaraldehyde, and reductive alkylatio n using propyl aldehyde. The modified proteins had different physicochemica l properties as well as improved encapsulation efficiencies compared with n ative RSA microspheres. The microspheres were incubated at 37 degreesC for over one month to invest igate the influence of protein modification on the release profilers. Micro sphere degradation accelerated from the ninth day of the release studies an d this coincided with an increase in the release rates. The degradation rat es of poly(lactic-co-glycolic acid) microspheres containing either native o r crosslinked RSA were more rapid than those containing either heparin conj ugated or propylated RSA. This was in agreement with the release data, sinc e the release of the native and crosslinked RSA were more rapid than those of the other modified proteins. The release profiles of the RSA-heparin con jugates and the propylated RSA were approximately zero rather than first or der between the tenth and thirtieth day of study. Chemical modification of protein may be a useful method to increase encapsu lation efficiency and to decrease release rates of proteins that are to be used in microsphere formulations of potent therapeutic proteins.