STRATEGIES FOR COVALENT ATTACHMENT OF DOXORUBICIN TO POLY(PEG-LYS), ANEW WATER-SOLUBLE POLY(ETHER URETHANE)

Poly(PEG-Lys) is a new, water soluble poly(ether methane) that has sho wn promise as an injectable drug carrier. To evaluate the possible use of this drug carrier in chemotherapy, three different approaches for the covalent attachment of doxorubicin to the pendent carboxylic acid groups of poly(PEG-Lys) were developed. In one approach, the pendent c arboxylic acid groups of poly(PEG-Lys) were converted to N-hydroxysucc inimide active esters, which spontaneously formed hydrolytically stabl e amide bonds upon reaction with the amino group located on the daunos amine ring of doxorubicin. The amount of amide-bound doxorubicin was a bout 7.3 mg/100 mg of conjugate. In a second approach, the degradable hydrazone linkage was formed by reaction of the polymeric hydrazide de rivative of poly(PEG-Lys), designated as poly(PEG-Lys hydrazide), with the 13-keto group of doxorubicin. After purification, the amount of c arrier-bound doxorubicin was 13.5 mg/100 mg of conjugate. In the third approach, the conjugation of doxorubicin via secondary amine linkages was explored. In this approach, the aldehyde derivative of poly(PEG L ys), designated as poly(PEG-Lys-aldehyde), was reacted with doxorubici n, followed by reduction of the intermediate Schiff base with sodium c yanoborohydride. After extensive purification of the carrier, the amou nt of bound doxorubicin was 10 mg/100 mg of conjugate. All conjugates were characterized by UV/Vis and FTIR spectroscopy and by thin layer c hromatography. The conjugates were free of detectable contamination by unbound drug.