Abstract
Chemical conjugation of poly(styrene-co-maleic acid) to an antitumor protein (neocarzinostatin) yielded an entirely new derivative designated as smancs (polystyrene-maleic acid conjugated neocarzinostatin). The purpose of the modification was to improve its pharmacological properties; the resulting conjugate exhibited much higher tumoritropism and lymphotropism, enhancedin vivo stability (about ten times), higher chemotherapeutic index (lower toxicity), and decreased antigenicity. Another advantage associated with this molecular engineering was an increased hydrophobicity. By this character it was solubilized in lipid contrast medium LipiodolR, which facilitated highly sensitive detection under x-ray-accompanying selective anticancer effectin situ. Three factors were responsible for such improvements: molecular size, hydrophobicity, and polyanionic nature. Most of the known drugs so far used as therapeutic agents are less than 1000 daltons, and those with larger molecular weights have been explored much less extensively. By polymer conjugation, the size of the drug can be extended to about 15,000 daltons (macromolecular therapeutics). The most outstanding characteristic of smancs (16,000 daltons) was the tumoritropicity, which may be a result of the highly developed neovasculature of solid tumors. Smancs as a prototype drug thus appears to lead the way in cancer drug targeting.
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References
Amoss, M. S., Jr., Monahan, M. W., and Verlander, M. S. (1974).J. Clin. Endocrinol. Metab. 39, 187–190.
Ashihara, Y., Kono, T., Yamazaki, S., and Inada, Y. (1978).Biochem. Biophys. Res. Commun. 83, 385–391.
Bartholeyns, J., and Moore, S. (1974).Science 186, 444–445.
Billiau, A. (1981).Arch. Virol. 67, 121–133.
Carraher, C. E., Jr., and Gebelein, C. G., eds. (1982).Biological Activity of Polymers (Adv. Chem. Ser. No. 186), American Chemical Society, Washington, D.C.
Courtice, F. C. (1963). InLymph and the Lymphatic System (Mayersen, H. S., ed.), C. C. Thomas, Springfield, Illinois, pp. 89–126.
Hilfenhaus, J., Damm, H., Hofstaetter, T., Mauler, R., Ronneberger, H., and Weinmann, E. (1981).J. Interferon. Res. 1, 424–436.
Iwai, K., Maeda, H., and Konno, T. (1984).Cancer Res. 44, 2115–2121.
Kamisaki, Y., Wada, H., Yagura, T., Matsushima, A., and Inada, Y. (1981).J. Pharmacol. Exp. Therap. 216, 410–414.
Konno, T., Maeda, H., Iwai, K., Tashiro, S., Morinaga, T., Mochinaga, H., Hiraoka, R., and Yokoyama, I. (1983).Eur. J. Cancer 19, 1053–1065.
Konno, T., Maeda, H., Iwai, K., Maki, S., and Tashiro, S. (1984).Cancer, in press.
Maeda, H. (1981).Anticancer Res. 1, 175–186.
Maeda, H., and Takeshita, J. (1976).J. Antibiot. 29, 111–112.
Maeda, H., Sakamoto, S., and Ogata, J. (1977).Antimicrob. Agents Chemotherap. 11, 941–945.
Maeda, H., Takeshita, J., and Kanamaru, R. (1979a).Int. J. Protein Peptide Res. 14, 81–86.
Maeda, H., Takeshita, J., Kanamaru, R., Sato, H., Katoh, J., and Sato, H. (1979b).Gann 70, 601–606.
Maeda, H., Takeshita, J., and Yamashita, A. (1980).Eur. J. Cancer. 16, 723–731.
Matsushima, A., Nishimura, H., Ashihara, Y., Yokota, Y., and Inada, Y. (1980).Chem. Lett. 1980, 773–776.
Meares, C. F., DeRiemer, L. H., Leung, C. S.-H., Yeh, S. M., Miura, M., Sherman, D. G., Goodwin, D. A., and Diamanti, C. I. (1982). InModification of Proteins (Adv. Chem. Ser. No. 198), American Chemical Society, Washington, D.C., pp. 369–387.
Nishimura, K., and Hayashi, H. (1970).Kumamaoto Igaku Z. 44, 298–318.
Nishimura, H., Ashihara, Y., Matsushima, A., and Inada, Y. (1979).Enzyme 24, 261–264.
Nishimura, H., Matsushima, A., and Inada, Y. (1981).Enzyme 26, 49–53.
Oda, T., and Maeda, H. (1983). InProceedings Japanese Cancer Association, 42nd Annual Meeting, October, Abstract 939.
Peterson, H. I., Appelgren, K. L., and Rosengren, B. H. O. (1972).Eur. J. Cancer 8, 677–681.
Peterson, H. I., and Appelgren, K. L. (1973).Eur. J. Cancer 9, 543–547.
Peterson, H. I.,et al. (1982).
Sakamoto, S., Maeda, H., Matsumoto, T., and Ogata, J. (1978).Cancer Treat. Rep. 62, 2063–2070.
Seneger, D. R., Galli, S. J., Dvorak, A. M., Perruzzi, C. A., Harrey, V. S., and Dvorak, H. F. (1983).Science 219, 983–985.
Shibata, K., Okubo, H., Ishibashi, H., Tsuda-Kawamura, K., and Yanashe, T. (1978).Br. J. Exp. Pathol. 59, 601–608.
Takeshita, J., Maeda, H., and Kanamaru, R. (1982).Gann 73, 278–284.
Trouet, A., Masquelier, M., Baurain, R., and Deprese-De Compeneere, D. (1982).Proc. Natl. Acad. Sci. USA 79.
Ulmer, K. M. (1983).Science 219, 666–671.
Vilcek, J., Sulea, I. T., Zerebeckyj, I. L., and Yip, Y. K. (1980).J. Clin. Microbiol. 11, 102–105.
Wang, D., Wilson, G., and Moore, S. (1976).Biochemistry 15, 660–665.
Yamasaki, N., Hayashi, K., and Funatsu, M. (1968).Agric. Biol. Chem. 32, 55–63.
Zunino, F., Gambetta, R., Vigevani, A., Penco, S., Geroni, C., and Di Marco, A. (1981).Tumori 67, 521–524.
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Maeda, H., Matsumoto, T., Konno, T. et al. Tailor-making of protein drugs by polymer conjugation for tumor targeting: A brief review on smancs. J Protein Chem 3, 181–193 (1984). https://doi.org/10.1007/BF01040499
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DOI: https://doi.org/10.1007/BF01040499