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Pharmaceutical Research

, Volume 13, Issue 1, pp 38–43 | Cite as

Pharmacokinetics and Biodistribution of Oligonucleotide Adsorbed onto Poly(isobutylcyanoacrylate) Nanoparticles After Intravenous Administration in Mice

  • Yuichiro Nakada
  • Elias Fattal
  • Monique Foulquier
  • Patrick Couvreur
Article

Abstract

Purpose. The goal of this study was to evaluate the ability of nanoparticles to be used as a targeted delivery system for oligonucleotides.

Methods. Pharmacokinetic and tissue distribution were carried out in mice by measuring the radioactivity associated to the model oligothymidylate 33P-pdT16 loaded to poly(isobutylcyanoacryrate) (PIBCA) nanoparticles. In addition, we have used a TLC linear analyzer to measure quantitatively on a polyacrylamide gel electrophoresis, the amount of non degraded pdT16

Results. Organ distribution study has shown that nanoparticles deliver 33P-pdT16 specifically to the liver reducing its distribution in the kidney and in the bone marrow. Nanoparticles could partially protect pdT16 against degradation in the plasma and in the liver 5 min after administration, whereas free oligonucleotide was totally degraded at the same time.

Conclusions. Nanoparticles protect oligonucleotides in vivo against degradation and deliver them to the liver.

oligonucleotides nanoparticles pharmacokinetics poly(isobutylcyanoacrylate) tissue distribution stability 

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REFERENCES

  1. 1.
    Y. C. Cheng and C. A. Stein. Antisense oligonucleotides as therapeutic agents-is the bullet really magical?. Science 261:1004–1012(1993).Google Scholar
  2. 2.
    P. S. Eder, R. J. Devine, J. M. Dagle and J. A. Walder. Substrate specificity and kinetics of degradation of antisense oligo-nucleotides by a 3′ exonuclease in plasma. Antisense Res. Dev. 1:141–151(1991).Google Scholar
  3. 3.
    J. Goodchild, B. Kim and P. C. Zamecnik. The clearance and degradation of oligonucleotides following intravenous injection into rabbits. Antisense Res. Dev. 1:153–160(1991).Google Scholar
  4. 4.
    C. Ropert, C. Malvy and P. Couvreur. Inhibition of the friend retrovirus by antisense oligonucleotides encapsulated in liposomes: Mechanism of action. Pharm. Res. 10:1427–1433(1993).Google Scholar
  5. 5.
    C. Chavany, T. L. Doan, P. Couvreur, F. Puisieux and C. Hélène. Polyalkylcyanoacrylate nanoparticles as polymeric carriers. Pharm. Res. 9:441–449(1992).Google Scholar
  6. 6.
    C. Chavany, T. Saison-Behmoaras, T. L. Doan, F. Puisieux, P. Couvreur and C. Hélène. Adsorption of oligonucleotides onto polyisohexylcyanoacrylate nanoparticles protects them against nucleases and increases their cellular uptake. Pharm. Res. 11:1370–1378(1994).Google Scholar
  7. 7.
    G. Schwab, C. Chavany, I. Duroux, G. Goubin, J. Lebeau, C. Helene and T. S. Behmoaras. Antisense oligonucleotides adsorbed to polyalkylcyanoacrylate nanoparticles specifically inhibit mutated Ha-ras-mediated cell proliferation and tumorigenicity in nude mice. Proc. Natl. Acad. Sci. USA.. 91:10460–10464 (1994).Google Scholar
  8. 8.
    J. Sambrook, E.F. Fritsch, T. Maniatis. Molecular Cloning, a laboratory manual 2nd edition, Cold Spring Harbor Laboratory Press, 1989.Google Scholar
  9. 9.
    T. Chem, P. S. Miller, P. O P. T s'o and O. M. Colvin. Disposition and metabolism of oligodeoxynucleoside methylphosphonate following a single iv injection in mice. Drug Metab. Dispos. 18:815–818 (1990).Google Scholar
  10. 10.
    S. Agrawal, J. Temsamani and J. Y. Tang. Pharmacokinetics, biodistribution, and stability of oligodeoxynucleotide phospho-rothioates in mice. Proc. Natl. Acad. Sci. USA.. 88:7595–7599 (1991).Google Scholar
  11. 11.
    P.L. Iverson, J. Mata, W.G. Tracewell and G. Zon. Pharmacokinetics of an antisense phosphorothioate oligodeoxynucleotide against rev from human immunodeficiency virus type 1 in adult male rat following single injections and continuous infusion. Antisense Res. Dev. 4:43–52 (1994).Google Scholar
  12. 12.
    J. Temsamani, J. Y. Yang, A. Padmapriya, M. Kubert and S. Agrawal. Pharmacokinetics, biodistribution and stability of capped oligodeoxynucleotide phosphorothioates in mice. Antisense Res. Dev. 3:277–284 (1993).Google Scholar
  13. 13.
    V. Lenaerts, J.F. Nagerlkerke, T.J.C. VanBerkel, P. Couvreur,, L. Grislain, M. Roland and P. Speiser. In vivo uptake of polyisobutylcyanoacrylate nanoparticles by the rat liver Kupffer, endothelial and parenchymal cells. J. Pharm. Sci. 73:980–982 (1984).Google Scholar
  14. 14.
    C. Vauthier, I. Aynie, M. Foulquier, E. Fattal, C. Malvy and P. Couvreur. Development of multi-channel radioactivity counter PAGE analysis for oligonucleotide drug carrier evaluation. Proceedings of the 22nd International Symposium on Controlled release of Bioactive Materials, Seattle, pp. 590–591, 1995.Google Scholar
  15. 15.
    V. Lenaerts, P. Couvreur, D. Christiams-Leyh, E. Joiris, M. Roland, B. Rollman and P. Speiser. Degradation of poly(isobutylcyanoacrylate) nanoparticles. Biomaterials 5:65–68 (1984).Google Scholar

Copyright information

© Plenum Publishing Corporation 1996

Authors and Affiliations

  • Yuichiro Nakada
    • 1
    • 2
  • Elias Fattal
    • 2
  • Monique Foulquier
    • 2
  • Patrick Couvreur
    • 2
  1. 1.Pharmaceuticals Research CenterKanebo, LTD., 5-90OsakaJapan
  2. 2.Laboratoire de Physico-chimie-Pharmacotechnie-Biopharmacie, URA CNRS 1218Université Paris-Sud, Faculté de PharmacieChatenay-Malabry, CedexFrance

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