Pharmaceutical Research

, Volume 18, Issue 3, pp 323–328 | Cite as

Novel Polymeric Micelles Based on the Amphiphilic Diblock Copolymer Poly(N-vinyl-2-pyrrolidone)-block-poly(D,L-lactide)

  • Amina Benahmed
  • Maxime Ranger
  • Jean-Christophe Leroux

Abstract

Purpose. The purpose of this work was to synthesize a new amphiphilic diblock copolymer of poly(N-vinyl-2-pyrrolidone and poly(D,L-lactide) (PVP-b-PDLLA) capable of self-assembling into polymeric micelles with multiple binding sites and high entrapment efficiency.

Methods. The copolymer was synthesized by ring-opening polymerization of D,L-lactide initiated by potassium PVP hydroxylate. It was characterized by gel permeation chromatography, 1H- and 13C-NMR spectroscopy. The ability of the copolymer to self-assemble was demonstrated by dynamic and static light scattering, spectrofluorimetry and 1H-NMR. The hydrophobic model drug indomethacin was incorporated into the polymeric micelles by a dialysis procedure.

Results. A series of amphiphilic diblock copolymers based on PVP-b-PDLLA were successfully synthesized. The critical association concentrations in water were low, always below 15 mg/L. Micellar size was generally bimodal with a predominant population between 40 and 100 nm. PVP-b-PDLLA micelles were successfully loaded with the poorly water-soluble drug indomethacin and demonstrated an entrapment efficiency higher than that observed with control poly(ethylene glycol)-b-PDLLA micelles. It was hypothesized that specific interactions with the hydrophilic outer shell could contribute to the increase in drug loading.

Conclusion. PVP-b-PDLLA micelles appear to exhibit multiple binding sites and thus represent a promising strategy for the delivery of a variety of drugs.

poly(N-vinyl-2-pyrrolidone) (PVP) poly(D,L-lactide) (PDLLA) colloids diblock copolymer polymeric micelles drug carrier, indomethacin 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

REFERENCES

  1. 1.
    M. Yokoyama, T. Okano, Y. Sakurai, S. Fukushima, K. Okamoto, and K. Kataoka. Selective delivery of adriamycin to a solid tumor using a polymeric micelle carrier system. J. Drug Target. 7:171-186 (1999).Google Scholar
  2. 2.
    S. V. Vinogradov, T. K. Bronich, and A. V. Kabanov. Self-assembly of polyamine-poly(ethylene glycol) copolymers with phosphorothioate oligonucleotides. Bioconjugate Chem. 9:805-812 (1998).Google Scholar
  3. 3.
    K. Kataoka, H. Togawa, A. Harada, K. Yasugi, T. Matsumoto, and S. Katayose. Spontaneous formation of polyion complex micelles with narrow distribution from antisense oligonucleotide and cationic block copolymer in physiological saline. Macromolecules 29:8556-8557 (1996).Google Scholar
  4. 4.
    M. Jones and J. Leroux. Polymeric micelles—A new generation of colloidal drug carriers. Eur. J. Pharm. Biopharm. 48:101-111 (1999).Google Scholar
  5. 5.
    G. S. Kwon, S. Suwa, M. Yokoyama, T. Okano, Y. Sakurai, and K. Kataoka. Enhanced tumor accumulation and prolonged circulation times of micelles-forming poly(ethylene oxide-aspartate) block copolymer-adriamycin conjugate. J. Control. Release 29:17-23 (1994).Google Scholar
  6. 6.
    K. Kataoka, G. S. Kwon, M. Yokoyama, T. Okano, and Y. Sakurai. Block copolymer micelles as vehicles for drug delivery. J. Control. Release 24:119-132 (1993).Google Scholar
  7. 7.
    K. Yasugi, Y. Nagasaki, M. Kato, and K. Kataoka. Preparation and characterization of polymer micelles from poly(ethylene glycol)-poly(D,L-lactide) block copolymers as potential drug carrier. J. Control. Release 62:89-100 (1999).Google Scholar
  8. 8.
    C. Allen, D. Maysinger, and A. Eisenberg. Nano-engineering block copolymer aggregates for drug delivery. Colloids and Surfaces B: Biointerfaces 16:3-28 (1999).Google Scholar
  9. 9.
    F. De Jaeghere, E. Alleman, J.-C. Leroux, W. Stevels, J. Feijen, E. Doelker, and R. Gurny. Formulation and lyoprotection of poly(lactic acid-co-ethylene oxide) nanoparticles: Influence on physical stability and in vitro cell uptake. Pharm. Res. 16:859-866 (1999).Google Scholar
  10. 10.
    W. G. Rothschild. Binding of hydrogen donors by peptide groups of lactams. Identity of interaction sites. J. Am. Chem. Soc. 94:8676-8683 (1972).Google Scholar
  11. 11.
    M. Otagiri, T. Imai, H. Koinuma, and U. Matsumoto. Spectroscopic study of the interaction of coumarin anticoagulant drugs with polyvinylpyrrolidone. J. Pharm. Biomed. Anal. 7:929-935 (1989).Google Scholar
  12. 12.
    R. J. Mumper, J. G. Duguid, K. Anwer, M. K. Barron, H. Nitta, and A. P. Rolland. Polyvinyl derivatives as novel interactive polymers for controlled gene delivery to muscle. Pharm. Res. 13:701-709 (1996).Google Scholar
  13. 13.
    G. F. Doebbler. Cryoprotective compounds. Cryobiology 3:2-11 (1966).Google Scholar
  14. 14.
    M. Townsend and P. P. DeLuca. Use of lyoprotectants in the freeze-drying of a model protein, Ribonuclease A. J. Parent. Sci. Technol. 37:190-199 (1988).Google Scholar
  15. 15.
    W. R. Gombotz, S. C. Pankey, R. Phan, R. Drager, K. Donaldson, K. P. Antonsen, A. S. Hoffman, and H. V. Raff. The stabilization of a human IgM monoclonal antibody with poly(vinylpyrrolidone). Pharm. Res. 11:624-632 (1994).Google Scholar
  16. 16.
    H. Kamada, Y. Tsutsumi, S. Tsunoda, T. Kihira, Y. Kaneda, Y. Yamamoto, S. Nakagawa, Y. Horisawa, and T. Mayumi. Molecular design of conjugated tumor necrosis factor-a: Synthesis and characteristics of polyvinyl pyrrolidone modified tumor necrosis factor-a. Biochem. Biophys. Res. Comm. 257:448-453 (1999).Google Scholar
  17. 17.
    V. P. Torchilin. Polymer-coated long-circulating microparticulate pharmaceuticals. J. Microencapsulation 15:1-19 (1998).Google Scholar
  18. 18.
    G. P. Bettinetti, P. Mura, A. Liguori, G. Bramanti, and F. Giordano. Solubilization and interaction of naproxen with polyvinylpyrrolidone in aqueous solution and the solid state. Farmaco 43:331-343 (1988).Google Scholar
  19. 19.
    M. C. Tros de llarduya, C. Martin, M. M. Goni, and M. C. Martinez-Oharriz. Solubilisation and interaction of sulindac with polyvinylpyrrolidone K30 in the solid state and aqueous solution. Drug Dev. Ind. Pharm. 24:295-300 (1998).Google Scholar
  20. 20.
    J. L. Eguiburu, M. J. Fernandez-Berridi, and J. M. Roman. Graft copolymers for biomedical applications prepared by free radical polymerization of poly(L-lactide) macromonomers with vinyl and acrylic monomers. Polymer 37:3615-3622 (1996).Google Scholar
  21. 21.
    E. Ranucci, G. Spagnoli, F. Bignotti, P. Ferruti, O. Schiavon, P. Caliciceti, and F. M. Veronese. Synthesis and molecular weight characterization of end-functionalized N-vinyl-2-pyrrolidone oligomers. Macromol. Chem. Phys. 196:763-774 (1995).Google Scholar
  22. 22.
    Z. Jedlinski, P. Kurcok, W. Walach, H. Janeczek, and I. Radecka. Synthesis of ethylene glycol-L-lactide block copolymers. Makromol. Chem. 194:1681-1689 (1993).Google Scholar
  23. 23.
    Y. Wang, S. Chen, and J. Huang. Synthesis and characterization of a novel macroinitiator of poly(ethylene oxide) with a 4-hydoxy-2,2,6,6-tetramethylpiperidinyloxy end group: Initiation of the polymerization of styrene by a “living” radical mechanism. Macromolecules 32:2480-2483 (1999).Google Scholar
  24. 24.
    I. Astafieva, X. F. Zhong, and A. Eisenberg. Critical micellization phenomena in block polyelectrolyte solutions. Macromolecules 26:7339-7352 (1993).Google Scholar
  25. 25.
    Y.G. Takei, T. Aoki, K. Sanui, N. Ogata, T. Okano, and Y. Sakurai. Temperature-responsive bioconjugates. 1. Synthesis of temperature-responsive oligomers with reactive end groups and their coupling to biomolecules. Bioconjugate Chem. 4:42-46 (1993).Google Scholar
  26. 26.
    S. A. Hagan, G. A. Coombes, M. C. Garnett, S. E. Dunn, M. C. Davies, L. Illum, S. S. Davis, S. E. Harding, S. Purkiss, and P. R. Gellert. Polylactide-poly(ethylene glycol) copolymers as drug delivery systems. 1. Characterization of water dispersible micelle-forming systems. Langmuir 12:2153-2161 (1996).Google Scholar
  27. 27.
    F. Kohori, K. Sakai, T. Aoyagi, M. Yokoyama, Y. Sakurai, and T. Okano. Preparation and characterization of thermally reponsive block copolymer micelles comprising poly(N-isopropylacryl-amide-b-DL-lactide). J. Control. Release 55:87-98 (1998).Google Scholar
  28. 28.
    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
  29. 29.
    L. S. Taylor and G. Zografi. Spectroscopic characterization of interactions between PVP and indomethacin in amorphous molecular dispersions. Pharm. Res. 14:1691-1698 (1997).Google Scholar
  30. 30.
    J. F. G. A. Jansen, E. M. M. de Brabander-van den Berg, and E. W. Meijer. Encapsulation of guest molecules into a dendritic box. Science 266:1226-1229 (1994).Google Scholar

Copyright information

© Plenum Publishing Corporation 2001

Authors and Affiliations

  • Amina Benahmed
    • 1
  • Maxime Ranger
    • 1
  • Jean-Christophe Leroux
    • 1
  1. 1.Faculty of PharmacyUniversity of MontrealSucc. Centre-ville, Montréal (Canada

Personalised recommendations