Maleic Copolymer Conjugates

Polymer-protein and polymer-drug conjugates are both based on the covalent attachment of therapeutic agents onto polymer. Initially, the rationale for the design of the two systems was different proteins were modified with polymers to reduce the 

Maleic copolymers are proper candidates for the conjugation with therapeutic agents due to their anhydride cycle that can easily react with -NH, -OH or -SH groups. The carboxylic groups obtained after these reactions or by subsequent hydrolysis, can offer water solubility and pH sensitivity to the obtained conjugates. 

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Keywords Maleic copolymers, controlled water solubility, antitumor activity, DIVEMA, male contraception, RISUG, protein conjugates, SMANCS, drug delivery systems... 

Pharmaceutical applications of maleic copolymers are favored by several properties such as biocompatibility, generally well-defined structure, the possibility to vary the hydrophilic/hydrophobic balance by the proper choice of comonomer or by further chemical reactions on the copolymer, and solubility in organic media when the copolymers are in anhydride form and in water when they are in acid/salt form. The reactivity of the maleic anhydride cycle offers the possibility to bind drugs, protein, or enzymes to the copolymer chain. The obtained conjugation products also have a carboxylic add group that can confer water solubility and pH sensibility. 

The NCS was also modified with DIVEMA copolymer. The in-vivo toxicity of the resulting conjugate was reduced, but the EPR effect was not observed. This was explained by the hydrophilicity of DIVEMA that did not favor the binding with albumin which would increase the apparent size, as in the case of SMANCS [103]. Some efforts were also made in order to obtain a conjugate of tumor necrosis factor with DIVEMA copolymer [104]. In this case, several free amino groups of the protein need to be protected before the reaction with the maleic copolymer. In the in-vivo test, the conjugate had a much higher antitumor effect than the native tumor necrosis factor. 

Table 10.1. Conjugates of therapeutic agent and maleic copolymers...

Examples of clinically validated water-insoluble, biodegradable polymers include material such as poly(D,L,lactide-c< -glycolide (PLGA) poly(ortho esters) (POE) and polyisohexylcyanoacrylate (PIHCA) These materials have been used for the preparation of nanoparticles, biodegradable implants and viscous injectable materials. In addition, one amphiphilic material, poly(styrene-co-maleic acid) copolymer conjugated with neocarzinostatin (SMANCS) dissolved in lipid contrast medium Lipiodol, has proven efficacious in several clinical tri s for the treatment of cancer... 

A very original application is the use of insoluble, polymeric Gd(III)-chelates as coating materials e.g., on the polypropylene catheters used for medical purposes (97). To poly(styrene-maleic acid) copolymer (SMA), HEDTA was conjugated and the Gd(III) ions were complexed by the resulting polymer, forming SMA-HEDTA-Gd(III). As a variation, the citric acid-HEDTA-SMA polymer was synthesized and used for chelating the Gd(III)ions, forming SMA-HEDTA-citric acid-Gd(III). The Gd(III) contents were 3.75 and... 

DIVEMA (Hydrolyzed form of divinyl ether and maleic anhydride copolymer) Cyclophos- phamide Ester bond between drug derivative hydroxyl and polymer carboxyl None N/A N/T Anticancer activity of conjugate was comparable to free drug against L1210 leukemia bearing mice 58... 

Although the Diels-Alder reaction of a conjugated diene, such as butadiene or isoprene, with maleic anhydride, has been known to yield tetrahydrophthalic anhydride, it has recently been shown (81, 85) that alternating copolymers are prepared under the influence of ionizing radiation (81) or free radical initiators (81, 85). The participation of the charge transfer complex as a common intermediate in both adduct... 

Kaneda Y, Yamamoto Y, Kamada H, Tsunoda S, Tsutsumi Y, Hirano T, Mayumi Y (1998) Antitumor activity of tumor necrosis factor alpha conjugated with divinyl ether and maleic acid anhydride copolymer on solid tumors in mice. Cancer Res 58 290-295... 

The reaction of a conjugated diene such as butadiene or iso-prene and an electron acceptor monomer such as maleic anhydride proceeds through a ground state complex which undergoes cycliza-tion to yield the Diels-Alder adduct. However, under UV light, in air or in the presence of sensitizers, the adduct is accompanied by the equimolar, alternating copolymer which results from excitation of the ground state complex, followed by homopolymerization of the excited complex (13)> as shown in Eq. (I8). 

The thermal reaction of a conjugated diene and maleic anhydride yields the cyclic Diels-Alder adduct. However, alternating copolymers are readily formed when the reaction is carried out in the presence of a free-radical precursor at a temperature where the catalyst half-life is one hour or less, or the catalyst addition time is less than one hour (2, 13). 

Another polyvinylic prodrug, SMANCS (Fig. 34.3), is a conjugate of a low molecular weight styrene maleic anhydride copolymer (SMA, 1.6 kDa) and neocarzinostatin (NCS). It is already marketed in Japan for the treatment of hepatocellular carcinoma. 

Hirano T, Ohashi S, Morimoto S, Tsukada K, Kobayashi T, Tsukagoshi S. Synthesis of antitumor-active conjugates of adriamycin or daunomycin with the copolymer of divinyl ether maleic anhydride. Makromol Chem 1986 187 2815-2824. 

Initially, Maeda et al. conjugated an antitumor protein neocarzinostatin (NCS, MW 12 kDa) with copolymer of styrene-maleic acid half-w-butylate (SMA) [59-61]. The eonjugation of protein (NCS) with SMA called SMANCS... 

Oda T, Maeda H. Binding to and internalization by cultured cells of neocarzinostatin and enhancement of its actions by conjugation with hpophihc styrene-maleic acid copolymer. Cancer Res 1987 47 3206 3211. 

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