Skip to main content
SpringerLink
Log in

Long-Circulating PEGylated Polycyanoacrylate Nanoparticles as New Drug Carrier for Brain Delivery

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose. The aim of this study was to evaluate the ability of long-circulating PEGylated cyanoacrylate nanoparticles to diffuse into the brain tissue.

Methods. Biodistribution profiles and brain concentrations of [14C]-radiolabeled PEG-PHDCA, polysorbate 80 or poloxamine 908-coated PHDCA nanoparticles, and uncoated PHDCA nanoparticles were determined by radioactivity counting after intravenous administration in mice and rats. In addition, the integrity of the blood-brain barrier (BBB) after nanoparticles administration was evaluated by in vivo quantification of the diffusion of [14C]-sucrose into the brain. The location of fluorescent nanoparticles in the brain was also investigated by epi-fluorescent microscopy.

Results. Based on their long-circulating characteristics, PEGylated PHDCA nanoparticles penetrated into the brain to a larger extent than all the other tested formulations. Particles were localized in the ependymal cells of the choroid plexuses, in the epithelial cells of pia mater and ventricles, and to a lower extent in the capillary endothelial cells of BBB. These phenomena occurred without any modification of BBB permeability whereas polysorbate 80-coated nanoparticles owed, in part, their efficacy to BBB permeabilization induced by the surfactant. Poloxamine 908-coated nanoparticles failed to increase brain concentration probably because of their inability to interact with cells.

Conclusions. This study proposes PEGylated poly (cyanoacrylate) nanoparticles as a new brain delivery system and highlights two requirements to design adequate delivery systems for such a purpose: a) long-circulating properties of the carrier, and b) appropriate surface characteristics to allow interactions with BBB endothelial cells.

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

Access this article

Log in via an institution

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. S. I. Rapoport. Blood-Brain Barrier in Physiology and Medicine, Raven Press, New York, 1976.

    Google Scholar 

  2. D. J. Begley. The blood-brain barrier: principles for targeting peptides and drugs to the central nervous system. J. Pharm. Pharmacol. 48:136-146 (1996).

    Google Scholar 

  3. R. A. Kroll and E. A. Neuwelt. Outwitting the blood-brain barrier for therapeutic purposes: osmotic opening and other means. Neurosurgery 42:1083-1099 (1998).

    Google Scholar 

  4. W. M. Pardridge. Vector mediated drug delivery the brain. Adv. Drug Deliv. Rev. 36:299-321 (1999).

    Google Scholar 

  5. J. Huwyler, D. Wu, and W. M. Pardridge. Brain drug delivery of small molecules using immunoliposomes. Proc. Natl. Acad. Sci. USA 93:14164-14169 (1996).

    Google Scholar 

  6. M. Naoi and Y. Eto. Liposome targeting to mouse brain: mannose as a recognition marker. Biochem. Biophys. Res. Commun. 153:1038-1044 (1988).

    Google Scholar 

  7. P. Couvreur, C. Dubernet, and F. Puisieux. Controlled drug delivery with nanoparticles: Current possibilities and future trends. Eur. J. Pharm. Biopharm. 41:2-13 (1995).

    Google Scholar 

  8. S. D. Troster, U. Müller, and J. Kreuter. Modification of the body distribution of poly(methylmethacrylate) nanoparticles in rats by coating with surfactants. Int. J. Pharm. 61:85-100 (1990).

    Google Scholar 

  9. S. M. Moghimi. Mechanisms regulating body distribution of nanospheres conditioned with pluronic and tetronic block copolymers. Adv. Drug Deliv. Rev. 16:183-193 (1995).

    Google Scholar 

  10. S. Stolnik, L. Illum, and S. S. Davis. Long circulating microparticulate drug carriers. Adv. Drug Deliv. Rev. 16:195-214 (1995).

    Google Scholar 

  11. R. Gref, Y. Minamitake, M. T. Peracchia, V. S. Trebetskoy, V. P. Torchilin, and R. Langer. Biodegradable long-circulating polymeric nanospheres. Science 263:1600-1603 (1994).

    Google Scholar 

  12. M. T. Peracchia, E. Fattal, D. Desmaële, M. Besnard, J. P. Noël, J. M. Gomis, M. Appel, J. D'Angelo, and P. Couvreur. Stealth® PEGylated polycyanoacrylate nanoparticles for intravenous administration and splenic targeting. J. Control. Release 60:121-128 (1999).

    Google Scholar 

  13. J. Kreuter, R. N. Alyautdin, D. A. Kharkevich, and A. A. Ivanov. Passage of peptides through the blood-brain barrier with colloidal polymer particles (nanoparticles). Brain Res. 674:171-174 (1995).

    Google Scholar 

  14. U. Schröder and B. A. Sabel. Nanoparticles, a drug carrier system to pass the blood-brain barrier, permit central analgesic effects of i.v. dalargin injections. Brain Res. 710:121-124 (1996).

    Google Scholar 

  15. R. N. Alyautdin, V. E. Petrov, K. Langer, A. Berthold, D. A. Kharkevich, and J. Kreuter. Delivery of loperamide across the blood-brain barrier with polysorbate 80-coated polybutylcyanoacrylate nanoparticles. Pharm. Res. 14:325-328 (1997).

    Google Scholar 

  16. R. N. Alyautdin, E. B. Tezikov, P. Ramges, D. A. Kharkebich, D. J. Begley, and J. Kreuter. Significant entry of tubocurarine into the brain of rats by adsorption to polysorbate 80-coated polyisobutylcyanoacrylate nanoparticles: an in situ brain perfusion study. J. Microencapsul. 15:67-74 (1998).

    Google Scholar 

  17. A. Friese, E. Seiller, G. Quack, B. Lorenz, and J. Kreuter. Increase of the duration of the anticonvulsive activity of a novel NMDA receptor antagonist using poly(butylcyanoacrylate) nanoparticles as a parenteral controlled release system. Eur. J. Pharm. Biopharm. 49:103-109 (2000).

    Google Scholar 

  18. A. E. Gulyaev, S. E. Gelperina, I. N. Skidan, A. S. Antropov, G. Y. Kivman, and J. Kreuter. Significant transport of doxorubicin into the brain with polysorbate 80-coated nanoparticles. Pharm. Res. 16:1564-1569 (1999).

    Google Scholar 

  19. J. C. Olivier, L. Fenart, R. Chauvet, C. Pariat, R. Cecchelli, and W. Couet. Indirect evidence that drug brain targeting using polysorbate 80-coated polybutylcyanoacrylate nanoparticles is related to toxicity. Pharm. Res. 16:1836-1842 (1999).

    Google Scholar 

  20. I. Brigger, P. Chaminade, D. Desmaële, M. T. Peracchia, J. D'Angelo, R. Gurny, M. Renoir, and P. Couvreur. Near infrared with principal component analysis as a novel analytical approach for nanoparticle technology. Pharm. Res. 17:1124-1132 (2000).

    Google Scholar 

  21. H. Fessi, F. Puisieux, J. P. Devissaguet, N. Ammoury, and S. Benita. Nanocapsule formation by interfacial polymer deposition following solvent displacement. Int. J. Pharm. 55:R1-R4 (1989).

    Google Scholar 

  22. L. Illum, I. M. Hunneyball, and S. S. Davis. The effect of hydrophilic coatings on the uptake of colloidal particles by the liver and peritoneal macrophages. Int. J. Pharm. 29:53-67 (1986).

    Google Scholar 

  23. M. T. Peracchia, C. Vauthier, D. Desmaële, A. Gulik, J. C. Dedieu, M. Demoy, J. D'Angelo, and P. Couvreur. Pegylated nanoparticles from a novel methoxypolyethylene glycol cyanoacrylate-hexadecyl cyanoacrylate amphiphilic copolymer. Pharm. Res. 15:550-556 (1998).

    Google Scholar 

  24. K. Ohno, K. D. Pettigrew, and S. I. Rapoport. Lower limits of cerebrovascular permeability to nonelectrolytes in the conscious rat. Am. J. Physiol. 235:H299-H307 (1978).

    Google Scholar 

  25. R. D. Broadwell and M. V. Sofroniew. Serum proteins bypass the blood-brain barrier for extracellular entry to the central nervous system. Exp. Neurol. 120:245-263 (1993).

    Google Scholar 

  26. J. C. Neal, S. Stolnik, E. Schacht, E. R. Kenawy, M. C. Garnett, S. S. Davis, and L. Illum. In vitro displacement by rat serum of adsorbed radiolabeled poloxamer and poloxamine copolymers from model and biodegradable nanospheres. J. Pharm. Sci. 87: 1242-1248 (1998).

    Google Scholar 

  27. H. Harashima, S. Komatsu, S. Kojima, C. Yanagi, Y. Morioka, M. Naito and H. Kiwada. Species difference in the disposition of liposomes among mice, rats, and rabbits: allometric relationship and species dependent hepatic uptake mechanism. Pharm. Res. 13:1049-1054 (1996).

    Google Scholar 

  28. M. Demoy, J. P. Andreux, C. Weingarten, B. Gaouritin, V. Guilloux, and P. Couvreur. Spleen capture of nanoparticles: influence of animal species and surface characteristics. Pharm. Res. 16:37-41 (1999).

    Google Scholar 

  29. S. I. Rapoport, W. R. Fredericks, K. Ohno, and K. D. Petrigrew. Quantitative aspects of reversible osmotic opening of the blood-brain barrier. Am. J. Physiol. 238:R421-R431 (1980).

    Google Scholar 

  30. S. M. Moghimi, I. S. Muir, L. Illum, S. S. Davis, and V. Kolb-Bachofen. Coating particles with a block co-polymer (poloxamine-908) suppresses opsonization but permits the activity of dysopsonins in the serum. Biochim. Biophys. Acta 1179:157-165 (1993).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Physico-Chimie, Pharmacotechnie, Biopharmacie, Université Paris-Sud XI, UMR CNRS 8612, 5, rue Jean Baptiste Clément, 92296, Châtenay-Malabry, France

    Pilar Calvo, Hélène Chacun & Elias Fattal

  2. Université Paris-Sud XI, UPRES/EA 2706, 5, rue Jean Baptiste Clément, 92296, Châtenay-Malabry, France

    Bruno Gouritin & Jean P. Andreux

  3. Chimie Organique, Université Paris-Sud XI, URA CNRS 1843, 5, rue Jean Baptiste Clément, 92296, Châtenay-Malabry, France

    Didier Desmaële & Jean D'Angelo

  4. Service des Molecules Marquées, CEA/Saclay bat, 547, 91191, Gif sur Yvette, France

    Jean-Pierre Noel & Dominique Georgin

  5. Physico-Chimie, Pharmacotechnie, Biopharmacie, Université Paris-Sud XI, UMR CNRS 8612, 5, rue Jean Baptiste Clément, 92296, Châtenay-Malabry, France

    Patrick Couvreur

Authors
  1. Pilar Calvo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bruno Gouritin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hélène Chacun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Didier Desmaële
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jean D'Angelo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jean-Pierre Noel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dominique Georgin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Elias Fattal
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jean P. Andreux
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Patrick Couvreur
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Calvo, P., Gouritin, B., Chacun, H. et al. Long-Circulating PEGylated Polycyanoacrylate Nanoparticles as New Drug Carrier for Brain Delivery. Pharm Res 18, 1157–1166 (2001). https://doi.org/10.1023/A:1010931127745

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1010931127745

Search

Navigation