PGE 1—Heparin conjugate releasing polymers

Abstract

Previous work in our laboratories has shown prostaglandin E 1 (PGE 1) releasing polymers reduce platelet adhesion and aggregation. Heparin released from polyurethane maintained bioactivity as measured by APTT, TT and Factor Xa assays. In in vivo animal studies using a dog model, heparin releasing polyurethane catheters showed small fibrin formation compared to the untreated polyurethane catheter. However, platelet adhesion and aggregation on both the heparin releasing system and untreated catheter were similar, which indicates significant thrombus was still present on the surfaces. A covalently bonded conjugate of commercial grade heparin and (PGE 1) was synthesized for use as a controlled releasing system for blood contacting sur faces in order to improve the blood compatibility of polymer surfaces. The compound was synthesized using a modified mixed carbonic anhydride method of amide bond formation between the carboxylic acid moiety of PGE 2 and a primary amine group on heparin. Quantitation of coupling was measured by spectroscopically monitoring the PGB 1 conjugate. Bioactivity tests on the conjugates (APTT and platelet aggregation) confirmed that the antithrombic activity of heparin was maintained. However, PGE 1 bioactivity, as measured by ADP induced platelet aggregation, had decreased, but was still active. Rabbit arteriovenous (A-V) shunt experiments revealed that heparin—PGE 1 releasing polyurethane demonstrated the prevention of both fibrin formation and platelet interactions. This approach can be utilized for the design of nonthrombogenic medical devices in contact with blood.