Pharmaceutical Research

, Volume 10, Issue 7, pp 970–974 | Cite as

Biodistribution of Micelle-Forming Polymer–Drug Conjugates

  • Glen S. Kwon
  • Masayuki Yokoyama
  • Teruo Okano
  • Yasuhisa Sakurai
  • Kazunori Kataoka
Article

Abstract

Polymeric micelles have potential utility as drug carriers. To this end, polymeric micelles based on AB block copolymers of polyethylene oxide (PEG) and poly(aspartic acid) [p(Asp)] with covalently bound Adriamycin (ADR) were prepared. The micelle forming polymer–drug conjugates [PEO-p(Asp(ADR)] were radiolabeled and their biodistribution was investigated after intravenous injection in mice. Long circulation times in blood for some compositions of PEO-p[Asp(ADR)] conjugates were evident, which are usually atypical of colloidal drug carriers. This was attributed to the low interaction of the PEO corona region of the micelles with biocomponents (e.g., proteins, cells). Low uptake of the PEO-p(Asp(ADR)] conjugates in the liver and spleen was determined. The biodistribution of the PEO-p[Asp(ADR)] conjugates was apparently dependent on micelle stability; stable micelles could maintain circulation in blood, while unstable micelles readily formed free polymer chains which rapidly underwent renal excretion. Long circulation times in blood of PEO-p(Asp(ADR)] conjugates are thought to be prerequisite for enhanced uptake at target sites (e.g., tumors).

polymeric micelles drug delivery systems cancer therapy Adriamycin 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

REFERENCES

  1. 1.
    M. Yokoyama, M. Miyauchi, N. Yamada, T. Okano, Y. Sakurai, K. Kataoka, and S. Inoue. Polymeric micelle as novel carrier: Adriamycin-conjugated poly(ethylene glycol)-poly(aspartic acid) block copolymer. J. Control. Release 11:269–278 (1990).Google Scholar
  2. 2.
    M. Yokoyama, M. Miyauchi, N. Yamada, T. Okano, Y. Sakurai, K. Kataoka, and S. Inoue. Characterization and anticancer activity of micelle-forming polymeric anticancer drug adriamycin-conjugated poly(ethylene glycol)-poly(aspartic acid) block copolymer. Cancer Res. 50:1693–1700 (1990).Google Scholar
  3. 3.
    M. Yokoyama, T. Okano, Y. Sakurai, H. Ekimoto, C. Shibazaki, and K. Kataoka. Toxicity and antitumor activity against solid tumors of micelle-forming polymeric anticancer drug and its extremely long circulation in blood. Cancer Res. 51:3229–3236 (1991).Google Scholar
  4. 4.
    M. Yokoyama, G. Kwon, T. Okano, Y. Sakurai, T. Seto, and K. Kataoka. Preparation of micelle-forming polymer-drug conjugates. Bioconjug. Chem. 3:295–301 (1992).Google Scholar
  5. 5.
    M. Yokoyama, G. Kwon, T. Okano, Y. Sakurai, H. Ekimoto, K. Okamoto, T. Seto, and K. Kataoka. Optimization of micelle-forming polymeric drug. Drug Target. Deliv. (in press).Google Scholar
  6. 6.
    E. W. Merrill and E. W. Salzman. Polyethylene oxide as a biomaterial. ASAIO J. 6:60–64 (1983).Google Scholar
  7. 7.
    A. Abuchowski, T. van Es, N. C. Palczuk, and F. F. Davis. Alteration of the immunological properties of bovine serum albumin by covalent attachment of polyethylene glycol. J. Biol. Chem. 252:3578–3581 (1977).Google Scholar
  8. 8.
    A. L. Klibanov, K. Maruyama, V. P. Torchilin, and L. Huang. Amphipathic polyethylene glycols effectively prolong the circulation time of liposomes. FEBS Lett. 268:235–237 (1990).Google Scholar
  9. 9.
    M. C. Woodle, G. Storm, M. S. Newman, J. J. Jekot, L. R. Collins, F. J. Martin, and F. C. Szoka. Prolonged systemic delivery of peptide drugs by long-circulating liposomes: Illustration with vasopressin in the brattleboro rat. Pharm Res. 9:260–265 (1992).Google Scholar
  10. 10.
    L. Illum and S. S. Davis. The organ uptake of intravenously administered colloidal particles can be altered using a non-ionic surfactant (poloxamer 338). FEBS Lett. 167:79–82 (1984).Google Scholar
  11. 11.
    R. Duncan and J. Kopechek. Soluble synthetic polymers as potential drug carriers. Adv. Polym. Sci. 57:51–101 (1984).Google Scholar
  12. 12.
    L. B. Wingard, T. R. Tritton, and K. A. Egler. Cell surface effects of adriamycin and carminomycin immobilized on crosslinked poly vinyl alcohol. Cancer Res. 45:3529–3536 (1985).Google Scholar
  13. 13.
    C. Zhao, M. A. Winnik, G. Riess, and M. D. Croucher. Fluorescence probe technique used to study micelle formation in water-soluble block copolymers. Langmuir 6:514–516 (1990).Google Scholar
  14. 14.
    K. Prochazka, D. Kiserow, C. Ramireddy, Z. Tuzar, P. Munk, and S. E. Webber. Time-resolved fluorescence studies of the chain dynamics of naphthalene-labeled polystyrene-block-poly(methacrylic acid) micelles in aqueous media. Macromolecules 25:454–460 (1992).Google Scholar
  15. 15.
    A. Gabizon and D. Papahadjopoulos. Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors. Proc. Natl. Acad. Sci. 85:6949–6953 (1988).Google Scholar

Copyright information

© Plenum Publishing Corporation 1993

Authors and Affiliations

  • Glen S. Kwon
    • 1
    • 2
  • Masayuki Yokoyama
    • 1
    • 2
  • Teruo Okano
    • 1
    • 2
  • Yasuhisa Sakurai
    • 1
    • 2
  • Kazunori Kataoka
    • 1
    • 3
  1. 1.International Center for Biomaterials Science, Research Institute for BioscienceScience University of TokyoNoda-shiJapan
  2. 2.Institute of Biomedical EngineeringTokyo Women's Medical CollegeShinjuku-kuJapan
  3. 3.Department of Materials Science and Technology and Research Institute for BioscienceScience University of TokyoNoda-shiJapan

Personalised recommendations