Skip to main content
Log in

Disposition Characteristics of Macromolecules in Tumor-Bearing Mice

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

As part of the strategy for the design of macromolecular carriers for drug targeting, the disposition characteristics of macromolecules were studied in mice bearing tumors that served as target tissues. Eight kinds of macromolecules including four polysaccharides and four proteins with different molecular weights and electric charges were used; tissue distribution and tumor localization after intravenous injection were studied. Pharmacokinetic analysis revealed that the tissue radioactivity uptake rate index calculated in terms of clearance was different among the tested compounds; especially, the urinary radioactivity excretion clearances and the total hepatic radioactivity uptake clearances varied widely. Compounds with low molecular weights (approximately 10 kD) or positive charges showed lower tumor radioactivity accumulation; radioactivity was rapidly eliminated from the plasma via rapid urinary excretion or extensive hepatic uptake, respectively. On the other hand, large and negatively charged compounds, carboxymethyl dextran, bovine serum albumin, and mouse immunoglobulin G, showed higher radioactivity accumulation in the tumor (calculated total amounts were 15.6, 10.8, and 20.8% of the dose, respectively) and prolonged retention in the circulation. These results demonstrated that the total systemic exposure rather than the uptake rate index was correlated with total tumor uptake. Molecular weight and electric charge of the macromolecules significantly affected their disposition characteristics and, consequently, determined radioactivity accumulation in the tumor. It was concluded that a drug–carrier complex designed for systemic tumor targeting should be polyanionic in nature and larger than 70,000 in molecular weight.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. E. Tomlinson. In E. Tomlinson and S. S. Davis (eds.), Site-Specific Drug Delivery, John Wiley & Sons, Chichester, 1986, pp. 1–26.

    Google Scholar 

  2. H. Sezaki, Y. Takakura, and M. Hashida. Adv. Drug Deliv. Rev. 3:247–266 (1989).

    Google Scholar 

  3. C.-W. Vogel. In C.-W. Vogel (ed.), Immunoconjugates: Antibody Conjugates in Radioimaging and Therapy of Cancer, Oxford University Press, New York, 1988, pp. 3–7.

    Google Scholar 

  4. H. Sezaki and M. Hashida. CRC Crit. Rev. Ther. Drug Carrier Syst. 1:1–38 (1984).

    Google Scholar 

  5. T. Kojima, M. Hashida, S. Muranishi, and H. Sezaki. J. Pharm. Pharmacol. 32:30–34 (1980).

    Google Scholar 

  6. M. Hashida, A. Kato, T. Kojima, S. Muranishi, H. Sezaki, N. Tanigawa, K. Satomura, and Y. Hikasa. Gann 72:226–234 (1981).

    Google Scholar 

  7. M. Hashida, Y. Takakura, S. Matsumoto, H. Sasaki, A. Kato, T. Kojima, S. Muranishi, and H. Sezaki. Chem. Pharm. Bull. 31:2055–2063 (1983).

    Google Scholar 

  8. M. Hashida, A. Kato, Y. Takakura, and H. Sezaki. Drug Metab. Dispos. 12:492–499 (1984).

    Google Scholar 

  9. Y. Takakura, S. Matsumoto, M. Hashida, and H. Sezaki. Cancer Res. 44:2505–2510 (1984).

    Google Scholar 

  10. S. Matsumoto, A. Yamamoto, Y. Takakura, H. Hashida, N. Tanigawa, and H. Sezaki. Cancer Res. 46:4463–4468 (1986).

    Google Scholar 

  11. Y. Takakura, K. Mori, H. Hashida, and H. Sezaki. Chem. Pharm. Bull. 34:1775–1783 (1986).

    Google Scholar 

  12. Y. Takakura, R. Atsumi, M. Hashida, and H. Sezaki. Int. J. Pharm. 37:145–154 (1987).

    Google Scholar 

  13. Y. Takakura, M. Kitajima, S. Matsumoto, M. Hashida, and H. Sezaki. Int. J. Pharm. 37: 135–143 (1987).

    Google Scholar 

  14. Y. Takakura, A. Takagi, M. Hashida, and H. Sezaki. Pharm. Res. 4:293–300 (1987).

    Google Scholar 

  15. R. Atsumi, K. Endo, T. Kakautani, Y. Takakura, M. Hashida, and H. Sezaki. Cancer Res. 47:5546–5551 (1987).

    Google Scholar 

  16. S. Nakane, S. Matsumoto, Y. Takakura, M. Hashida, and H. Sezaki. J. Pharm. Pharmacol. 40: 1–6 (1988).

    Google Scholar 

  17. K. Sato, K. Itakura, K. Nishida, Y. Takakura, M. Hashida, and H. Sezaki. J. Pharm. Sci. 78:11–16 (1989).

    Google Scholar 

  18. Y. Takakura, Y. Kaneko, T, Fujita, M. Hashida, H. Maeda, and H. Sezaki. J. Pharm. Sci. 78:117–121 (1989).

    Google Scholar 

  19. Y. Takakura, T. Fujita, M. Hashida, H. Maeda, and H. Sezaki. J. Pharm. Sci. 78:219–222 (1989).

    Google Scholar 

  20. T. Fujita, Y. Takakura, M. Hashida, and H. Sezaki. J. Control. Release (in press) (1989).

  21. W. M. Mckerman and C. R. Rickettes. Biochem. J. 76:117–120 (1960).

    Google Scholar 

  22. E. A. Peterson and H. S. Sober. J. Am. Chem. Soc. 78:751–755 (1956).

    Google Scholar 

  23. W. M. Pardridge, A. K. Kumagai, and J. B. Eisenberg. Biochem. Biophys. Res. Commun. 146: 307–313 (1987).

    Google Scholar 

  24. A. K. Kumagai, J. B. Eisenberg, and W. M. Pardridge. J. Biol. Chem. 262:15214–15219 (1987).

    Google Scholar 

  25. H. S. Isbel, H. L. Frush, and J. D. Moyer. Tech. Assoc. Pulp Paper Ind. 40:739–742 (1957).

    Google Scholar 

  26. D. J. Hnatowich, W. W. Layne, and R. L. Childs. Int. J. Appl. Isot. 33:327–332 (1982).

    Google Scholar 

  27. D. T. Mahin and R. T. Roftberg. Anal. Biochem. 16:500–509 (1966).

    Google Scholar 

  28. R. W. Mowry and R. C. Millican. Am. J. Pathol. 29:523–545 (1953).

    Google Scholar 

  29. R. G. Melton, C. N. Wiblin, A. Baskerville, R. L. Foster, and R. F. Sherwood. Biochem. Pharmacol. 36:113–121 (1987).

    Google Scholar 

  30. B. A. Brown, R. D. Comeau, P. L. Jones, F. A. Liberatore, W. P. Neacy, H. Sands, and B. M. Gallagher. Cancer Res. 47:1149–1154 (1987).

    Google Scholar 

  31. J. Munniksma, M. Noteborn, T. Kooistra, S. Steinstra, J. M. W. Bouma, M. Gruber, A. Brouwer, D. P. U. Dalen, and D. L. Knook, Biochem. J. 192:613–621 (1980).

    Google Scholar 

  32. A. E. Taylor and N. D. Granger. In E. M. Renkin and C. C. Michel (eds), Handbook of Physiology: The Cardiovascular System IV, American Physiological Society, Bethesda, Md., 1984, pp. 467–520.

    Google Scholar 

  33. B. M. Brenner, T. H. Hostetter, and H. D. Humes. Am. J. Physiol. 234:F455–F460 (1978).

    Google Scholar 

  34. R. L. Dedrick. J. Pharmacokin. Biopharm. 1:435–461 (1973).

    Google Scholar 

  35. J. N. Purtell, A. J. Pesce, D. H. Clyne, W. C. Miller, and V. E. Pollak. Kid. Int. 16: 366–376 (1979).

    Google Scholar 

  36. E. I. Christensen, H. G. Rennke, and F. A. Carone. Am. J. Physiol. 244:F436–F441 (1983).

    Google Scholar 

  37. R. K. Jain. Cancer Metas. Rev. 6:559–593 (1987).

    Google Scholar 

  38. C. W. Song and S. H. Levitt. Cancer Res. 31:587–589 (1971).

    Google Scholar 

  39. S. W. O'Conor and W. F. Bale. Cancer Res. 44:3719–3723 (1984).

    Google Scholar 

  40. D. Trigueo, J. B. Buciak, J. Yang, and W. M. Pardridge. Proc. Natl. Acad. Sci. 86:4761–4765 (1989).

    Google Scholar 

  41. K. B. Bischoff, R. L. Dedrick, and D. S. Zaharko. J. Pharm. Sci. 59:149–154 (1970).

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Takakura, Y., Fujita, T., Hashida, M. et al. Disposition Characteristics of Macromolecules in Tumor-Bearing Mice. Pharm Res 7, 339–346 (1990). https://doi.org/10.1023/A:1015807119753

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1015807119753

Navigation