Improved synthesis of polystyrene-poly(ethylene oxide)-heparin block copolymers

A novel procedure for the synthesis of block copolymers composed of a hydrophobic block of polystyrene, a hydrophilic block of poly(ethylene oxide) and a bioactive block of nitrous acid-degraded heparin was developed. Amino-semitelechelic polystyrene was prepared by anionic polymerization of styrene in cyclohexane, using sec-butyllithium as initiator and N-(benzylidene)trimethylsilylamide as terminator. After purification using preparative column chromatography, polystyrene with one amino group per chain and a narrow molecular weight distribution was obtained. The terminal amino group was used in the coupling reaction with amino-telechelic poly(ethylene oxide) using toluene 2,4-diisocyanate to produce amino-semitelechelic polystyrene-poly(ethylene oxide) diblock copolymer (PS-PEO-NH2). The block copolymer was purified by preparative column chromatographic separations and had a narrow molecular weight distribution. Approximately one amino group per chain was found. When methylene 4,4-diphenyl diisocyanate or hexamethylene diisocyanate were used as coupling agents low yields of PS-PEO-NH2 were obtained. Polystyrene-poly(ethylene oxide)-heparin triblock copolymer was synthesized in a DMF-H20 (40:1, v/v) mixture by a coupling reaction of PS-PEO-NH2 with nitrous acid-degraded heparin, in which aldehyde groups react with the primary amino groups of PS-PEO-NH2 at pH 7 in the presence of NaBH3CN via reductive amination. Using this procedure, 18-32% w/w heparin was incorporated, corresponding to ±1 PS-PEO chain per heparin molecule. These procedures enable the synthesis of well defined heparin containing block copolymers, which will be further evaluated for thier blood compatibility.