BIOLOGICALLY ACTIVE SYNTHETIC POLYMERSt

The 1:2 divinyl ether-maleic anhydride cyclic alternating copolymer (DIVEMA) shows a wide variety of biological activities. It has antitumor activity; it induces the formation of interferon; it has antiviral, antibacterial, and antifungal activity; it is an anticoagulant and an anti-inflammatory agent. DIVEMA is an immunopotentiator; it increases the rate of phagocytosis, it activates macrophages selectivily, and it inhibits RNA-dependent DNA polymerase. The effect of molecular weight and molecular weight distribution on the biological activity and toxicity of DIVEMA has been investigated and will be discussed. It seems most fitting, in light of Prof. Aharon KatzirKatchalsky's deep interest in the field, to limit this discussion of biologically active synthetic polymers to those which are polyelectrolytes. The use of synthetic polymers in medicine is growing rapidly. But in a certain sense most polymers are not used because of their biological activity. Initially they were utilized as structural materials, first as replacements for metals, but subsequently for their own favorable properties—ease of fabrication, inertness to body fluids, low cost, and ready availability. Today many different materials are in use, from silicone rubber heart valves to polyethylene hip joints, from polyester arteries to acrylic teeth. However, these materials are used, if anything, for their biological inertness and not for their biological activity. In a similar sense, dextran and polyvinylpyrrolidone were used as plasma extenders because of their effect on osmotic pressure, and not because of any special biological activity. A considerable literature exists on the use of polymers as carries for a variety of drugs, with the pharmacon physically incorporated or covalently bound to the polymer.'3 In fact, a disk of polymer containing pilocarpine has recently become commercially available for the treatment of glaucoma, and an IUD containing a year's supply of contraceptive steroid is about to be marketed. There are a large number of naturally occurring anionic polyelectrolytes, some of which are shown in Table 1. Table 1. Naturally occurring anionic polyelectrolytes Proteins Plant gums: DNA Pectin RNA Gum Arabic Hyaluronic acid Gum Tragacanth Chondroitin sulfate Agar Heparin Carrageenan Alginic acid PAC VoL 46, No. 2-4—B The importance of proteins, DNA, and RNA needs no additional comment. Hyaluronic acid is the jelly-like matrix which is the cement substance of the tissues; It is a polysaccharide which yields D-glucuronic acid on hydrolysis. Chondroitin sulfate is widely distributed in animal tissue (cartilage, tendons, skin); it is a polysaccharide containing both carboxyl and sulfate groups. Heparin, as its name indicates, is found in the liver. It too is a polysaccharide containing carboxyl, sulfate, and sulfamic acid groups; it is used clinically as an anticoagulant. Finally there are the plant gums, which are used broadly in the food and chemical industries as thickening agents.4 They too are polysaccharides which owe their anionic character to free carboxyl groups, although agar and carrageenan contain sulfate groups as well. Materials of animal origin generally seem to contain acylated amino groups in addition, whereas the plant materials do not. In comparison, cationic polymers are relatively rare and are usually polypeptides, e.g. protamines and histones. It is not surprising that interest, which centered originally on naturally occurring polyelectrolytes, has expanded recently to include synthetic polyelectrolytes as well. Some of the earlier work involved polymers of sodium ethylenesulfonate, whose polymerization was first reported in 1954. Regelson and Holland6 found a wide spectrum of antitumor activity, in mice, for the sodium salt (Table 2). Table 2. Sodium polyethylenesulfonate tumor inhibition in mice Adenocarcinoma 775 L5178 lymphatic leukemia L1210 lymphoid leukemia Ehrlich (ascites) Krebs 2 carcinoma (ascites) Sarcoma 180 Unfortunately, the activity in humans appeared to be much lower and the polymer was too toxic for clinical use.7 Polymeric sulfates and sulfonates all appear to have heparin-like properties, and for a time Farbwerke Hoechst marketed sodium polyethylenesulfonate under the trade name Pergalen for topical application as a blood 103 tHercules Research Center Contribution No. 1674.