Ian P. Middleton

Studies of the esterification of dextran: routes to bioactive polymers and graft copolymers

Abstract Problems associated with the esterification of dextran as a means of coupling bioactive molecules or introduction of functionality suitable for graft polymerization are considered. In particular, the importance of eliminating side-reactions which incorporate into dextran unwanted residues, e.g. groups containing nitrogen, is emphasized and practical techniques for minimizing this are described. We have developed a formamide-based solvent suitable for esterification with the aid of dicyclohexyl carbodiimide (DCC) and carbonyl di-imidazole (CDI) as coupling agents. The preferred catalyst is p -pyrrolidinopyridine. CDI has the advantage of enabling dimethylsulphoxide to be used as solvent for dextran and other hydroxylic polymers without inducing oxidation of hydroxyl groups. This coupling agent is flexible and offers a choice of two routes to esterification, each having its merits. We have optimized conditions for coupling by use of butyric acid as model. Esterification of dextran has been employed in the preparation of soluble bioactive macromolecules by coupling the anti-platelet agent (I) and also in the synthesis of graft copolymers via introduction of 2-bromopropionate groups. Crosslinking of dextran and the polymerization of dipyridamole have been effected by use of CDI.

Grafting and Attachment of Antiplatelet Agents to Poly(Ether-Urethanes)

Segmented poly(ether-urethanes) have been shown to be particularly suitable for a wide range of biomedical applications on account of their good elastomeric and other mechanical properties and their relative compatibility with blood. Consequently several commercial poly(ether-urethanes) have been exploited for the manufacture of prostheses such as artificial hearts and arteries and extracorporeal circulatory systems.1,2 Attainment of the highest possible degree of haemocompatibility of the polymers is essential in certain applications such as small-boar arterial prostheses of internal diameter 4 mm or less. The work we now describe was undertaken as part of the development of such a prosthesis and required chemical modification of commercial poly(ether-urethanes) rather than the investigation of new types with potentially improved properties.

Modification of polymers for cardiovascular applications—some routes to bioactive hydrophilic polymers

This paper is concerned with the activation of platelets by polymers, a key-process in the behaviour of prosthetic devices in contact with blood.Platelets are activated by contact with many different types of polymer surfaces, which must therefore be regarded as thrombogenic. Two procedures for reducing thrombogenicity are discussed: (i) the chemical attachment of inhibitors of platelet aggregation and (ii) gross modification of the nature of the surface, e.g. by making it more hydrophilic. For purposes of (i) the potent prostaglandin analogue BW 245C has been used, while for (ii) grafting of poly(ethylene glycol) (PEG) has been explored. Both methods give greatly reduced platelet adhesion inin vitro tests.The second part of the paper deals with the properties of adducts of inhibitors of platelet aggregation (BW 245C, dipyridamole) with water-soluble macromolecules [poly(N-vinyl pyrrolidone), PEG, dextran]. Adducts have been synthesized with terminal and side-chain coupling. On adduction the two inhibitors mentioned show opposite types of behaviour: the molar activity of BW 245C is dramatically reduced, but that of dipyridamole is significantly increased. Remarkable synergistic effects have been recorded for BW 245C adducts. These observations are interpreted in terms of differences in stereochemistry in the drug-receptor interactions.Appropriate chemical techniques for coupling are outlined, attention being drawn to the special uses of haloalkyl- and haloacyl-isocyanates and 2-isocyanatoethyl methacrylate as reagents.

Influence of molecular structure on the synergistic action of theophylline or dipyridamole derivatives in the prostaglandin-type inhibition of platelet aggregation

Approximately 30 new derivatives of theophylline and dipyridamole have been prepared and examined as potentiators of the inhibition of platelet aggregation induced by the prostaglandin analogue BW 245C. Potentiating activity has been found to be sensitive to molecular size and also to the presence of specific groups. Polymeric adducts based on dextran, poly(ethylene glycol) or poly(N-vinyl pyrrolidone), and aliphatic esters with alkyl chain-lengths greater than 7 are inactive in potentiation. Derivatives containing carboxyl groups are also inactive. Potentiation is discussed in terms of platelet membrane penetration and extra- and intra-cellular processes. The latter are invoked to account for the enhanced potentiation shown by dipyridamole and derivatives when aggregation is induced by PAF-acether rather than ADP. One derivative of particular interest is the adduct of theophylline with 1,2,5,6-diisopropylidene-D-glucose, containing a furanose ring. This is a more active potentiator than theophylline itself, possibly owing to its molecular resemblance to cAMP. On conversion to the pyranose form all activity is removed.

Professor Bamford's research in the field of biomaterials

Professor Bamford was regarded by many as the greatest British polymer chemist of the twentieth century and when Bam passed away in November 1999 tribute was quite rightly made to his considerable achievements in the field of polymer science. The aim of this paper is to highlight Bams contribution to biomaterials research that occupied his attention for over 15 years after his official retirement. In particular a review of the synthetic methods employed by Bam for the modification of polymers to improve haemocompatibility and to function as affinity separation membranes for protein purification is presented.