Pharmaceutical Research

, Volume 17, Issue 5, pp 607–611

Methotrexate Esters of Poly(Ethylene Oxide)-Block-Poly(2-Hydroxyethyl-L-Aspartamide). Part I: Effects of the Level of Methotrexate Conjugation on the Stability of Micelles and on Drug Release

  • Yu Li
  • Glen S. Kwon

Abstract

Purpose. To study the effects of hydrophobicity of the micelle-formingblock copolymeric drug conjugate, methotrexate (MTX) esters ofpoly-(ethylene oxide)-block-poly(2-hydroxyethyl-L-aspartamide) (MTXesters of PEO-b-PHEA), on the stability of micelles and on drug release.

Methods. MTX esters of PEO-b-PHEA with three levels of MTXconjugation were synthesized. Size distribution of the micelles wasmeasured by dynamic light scattering (DLS). The critical micelleconcentration (CMC) was determined by a light scattering study. Sizeexclusion high performance liquid chromatography (SEC-HPLC) wasused to study the equilibrium between unimers and micelles, and releaseof MTX at pH 7.4.

Results. MTX esters of PEO-b-PHEA with MTX substitution of 7.4%,22%, and 54% were prepared. The conjugates formed micelles basedon DLS. The stability of the micelles correlated with the level of MTXconjugation. The conjugate with 54% MTX had a lower CMC (0.019mg/mL) than the conjugates with 22% MTX (0.081 mg/mL) or 7.4%MTX (0.14 mg/mL). Micelle dissociation was significantly slower forthe conjugate with 54% MTX than that with 22% and 7.4% MTX.Slower release of MTX from the micelles was also observed for theconjugate with the higher MTX attachment.

Conclusions. MTX esters of PEO-b-PHEA can be structurallymodulated by varying the degree of MTX substitution, which in turn changesthe hydrophobicity of the conjugate, thereby modifying micelle stabilityand controlling drug release.

methotrexate block copolymer polymeric conjugate micelles unimers drug delivery 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

REFERENCES

  1. 1.
    C. Allen, Y. Yu, D. Maysinger, and A. Eisenberg. Polycaprolactone-b-poly(ethylene oxide) block copolymer micelles as a novel drug delivery vehicle for neurotrophic agents FK506 and L-685,818. Bioconjugate Chem. 9:564–572 (1998).Google Scholar
  2. 2.
    K. Kataoka, G. S. Kwon, M. Yokoyama, T. Okano, and Y. Sakurai. Block copolymer micelles as vehicles for drug delivery. J. Controlled Release. 24:119–132 (1993).Google Scholar
  3. 3.
    X. Zhang, J. K. Jackson, and H. M. Burt. Development of amphiphilic diblock copolymers as micellar carriers of taxol. Int. J. Pharm. 132:195–206 (1996).Google Scholar
  4. 4.
    G. S. Kwon, M. Naito, M. Yokoyama, T. Okano, Y. Sakurai, and K. Kataoka. Micelles based on ab block copolymers of poly(ethylene oxide) and poly(β-benzyl l-aspartate). Langmuir 9:945–949 (1993).Google Scholar
  5. 5.
    K. Kataoka. Targetable polymeric drugs. In K. Park (ed.) Controlled Drug Delivery: Challenges and Strategies, American Chemical Society, Washington, D.C., 1997, pp. 49–71 (1997).Google Scholar
  6. 6.
    M. Y. Gorshkova and L. L. Stotskaya. Micelle-like macromolecular systems for controlled release of daunomycin. Polymers for Advanced Technologies 9:362–367 (1998).Google Scholar
  7. 7.
    M. Yokoyama, T. Sugiyama, T. Okano, Y. Sakurai, M. Naito, and K. Kataoka. Analysis of micelle formation of an adriamycin-conjugated poly(ethylene glycol)-poly(aspartic acid) block copolymer by gel permeation chromatography. Pharm. Res. 10:895–899 (1993).Google Scholar
  8. 8.
    R. Nagarajan, M. Barry, and E. Ruckenstein. Unusual selectivity in solubilization by block copolymer micelles. Langmuir 2:210–215 (1986).Google Scholar
  9. 9.
    G. S. Kwon, M. Y. Suwa, T. Okano, Y. Sakurai, and K. Kataoka. Physical entrapment of adriamycin in ab block copolymer micelles. Pharm. Res. 12:192–195 (1995).Google Scholar
  10. 10.
    M. Yokoyama, T. Okano, Y. Sakurai, H. Ekimoto, C. Skibazaki, 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. 29:17–23 (1991).Google Scholar
  11. 11.
    Y. Li and G. S. Kwon. Micelle-like structures of poly(ethylene oxide)-block-poly(2-hydroxyethyl aspartamide)-methotrexate conjugates. Colloids Surf. B: Biointerfaces 16:217–226 (1999).Google Scholar
  12. 12.
    M. Yokoyama, S. Inoue, K. Kataoka, N. Yui, and Y. Sakurai. Preparation of adriamycin-conjugated poly(ethylene glycol)-poly-(aspartic acid) block copolymer: a new type of polymeric anticancer drug. Macromol. Chem. Rapid Commun. 8:431–435 (1987).Google Scholar
  13. 13.
    L. Zhang, H. Shen, and A. Eisenberg. Phase separation behavior and crew cut micelle formation of polystyrene-b-poly(acrylic acid) copolymer in solutions. Macromolecules 30:1001–1011 (1997).Google Scholar
  14. 14.
    P. Tancrede, J. Barwicz, S. Jutras, and I. Gruda. The effect of surfactants on the aggregation state of amphotericin B. Biochim.-Biophys. Acta 1030:289–295 (1990).Google Scholar
  15. 15.
    N. J. Yurro, M. Gratzel, and A. M. Braun. Photochemical processes in micellar system Angew. Chem. Int. Ed. Engl. 19:675–696 (1980).Google Scholar

Copyright information

© Plenum Publishing Corporation 2000

Authors and Affiliations

  • Yu Li
    • 1
  • Glen S. Kwon
    • 2
  1. 1.School of PharmacyUniversity of Wisconsin-MadisonMadison
  2. 2.School of PharmacyUniversity of Wisconsin-MadisonMadison

Personalised recommendations