CASEIN AS A CARRIER MATRIX FOR 5-FLUOROURACIL - DRUG-RELEASE FROM MICROSPHERES, DRUG-PROTEIN CONJUGATES AND IN-VIVO DEGRADATION OF MICROSPHERES IN RAT MUSCLE

Glutaraldehyde cross-linked casein microspheres were loaded with 5-flu orouracil (5-FU) from concentrated aqueous solutions of the drug after the microspheres were synthesized and cleaned. In-vitro release of th e drug was examined in phosphate buffer in the absence and in the pres ence of protease at 37 degrees C. Drug release data showed that only a bout 20% of the drug is released in the absence of protease even after 5 days, while digestion of the matrix with protease released the entr apped drug completely in about 24 h. A protein-drug conjugate was synt hesized via carbamoyl linkage using 6-(5-FU-1-yl)hexyl isocyanate and the drug release was examined in phosphate buffer at 37 degrees C. Rel ease from the protein-5-FU conjugate was slower compared with the rele ase from microspheres in the presence of protease. Implantation of pla cebo microspheres of different cross-linking densities in the gluteal muscle of rats showed no adverse tissue reactions over a one-year peri od. Histopathological examination of the tissues containing injected m icrospheres suggested that the biological life of casein microspheres in muscle is about 6 months, which is three times that of cross-linked albumin microspheres.