Direct Evidence That Polysorbate-80-Coated Poly(Butylcyanoacrylate) Nanoparticles Deliver Drugs to the CNS via Specific Mechanisms Requiring Prior Binding of Drug to the Nanoparticles
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
Purpose. It has recently been suggested that the poly(butylcyanoacrylate) (PBCA) nanoparticle drug delivery system has a generalized toxic effect on the blood-brain barrier (BBB) (8) and that this effect forms the basis of an apparent enhanced drug delivery to the brain. The purpose of this study is to explore more fully the mechanism by which PBCA nanoparticles can deliver drugs to the brain.
Methods. Both in vivo and in vitro methods have been applied to examine the possible toxic effects of PBCA nanoparticles and polysorbate-80 on cerebral endothelial cells. Human, bovine, and rat models have been used in this study.
Results. In bovine primary cerebral endothelial cells, nontoxic levels of PBCA particles and polysorbate-80 did not increase paracellular transport of sucrose and inulin in the monolayers. Electron microscopic studies confirm cell viability. In vivo studies using the antinociceptive opioid peptide dalargin showed that both empty PBCA nanoparticles and polysorbate-80 did not allow dalargin to enter the brain in quantities sufficient to cause antinociception. Only dalargin preadsorbed to PBCA nanoparticles was able to induce an antinociceptive effect in the animals.
Conclusion. At concentrations of PBCA nanoparticles and polysorbate-80 that achieve significant drug delivery to the brain, there is little in vivo or in vitro evidence to suggest that a generalized toxic effect on the BBB is the primary mechanism for drug delivery to the brain. The fact that dalargin has to be preadsorbed onto nanoparticles before it is effective in inducing antinociception suggests specific mechanisms of delivery to the CNS rather than a simple disruption of the BBB allowing a diffusional drug entry.
- R. Alyautdin, D. Gothier, V. Petrov, D. Kharkevich, and J. Kreuter. Analgesic activity of the hexapeptide dalargin adsorbed on the surface of polysorbate 80-coated poly(butyl cyanoacrylate) nanoparticles. Eur. J. Pharm. Biopharm. 41:44-48 (1995).
- 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 poly-sorbate 80-coated polybutylcyanoacrylate nanoparticles. Pharm. Res. 14:325-328 (1997).
- R. N. Alyautdin, E. B. Tezikov, P. Ramge, D. A. Kharkevich, D. J. Begley, and J. Kreuter. Significant entry of tubocurarine into the brain of rats by absorption to polysorbate 80-coated polybutyl-cyanoacrylate nanoparticles: an in situ brain perfusion study. J. Microencapsul. 15:67-74 (1998).
- 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).
- A. Friese, E. Seiler, G. Quack, B. Lorenz, and J. Kreuter. Enhancement of the duration of the anticonvulsive activity of a novel NMDA receptor antagonist using poly(butylcyanoacylate) nanoparticles as a parenteral controlled release delivery system. Eur. J. Pharm. Biopharm. 49:103-109 (2000).
- D. J. Begley, M. W. Bradbury, and J. Kreuter (eds.). The Blood-Brain Barrier and Drug Delivery to the CNS, Marcel Dekker, New York, 2000.
- A. Minn, R. D. S. El-BachÁ, C. Bayol-Denizot, P. Lagrange, and F. G. Suleman. Drug metabolism in the brain: Benefits and risks. In D. J. Begley, M. W. Bradbury, and J. Kreuter (eds.) The Blood-Brain Barrier and Drug Delivery to the CNS, Marcel Dekker, New York, 2000, pp. 145-170.
- 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).
- E. I. Kalenikova, O. F. Dimittriekova, S. V. Zhukova, and V.A. Tishenko. Farmokinetica dalargina. Vopr. Med. Khim. 34:75-83 (1988).
- P. Ramge, J. Kreuter, and B. Lemmer. Circadian phase-dependent antinociceptive reaction in mice after i. v. injection of dalargin-loaded nanoparticles determined by the hot-plate test and the tail-flick test. Chronobiol. Int. 17:767-777 (1999).
- R. Cecchelli, B. Dehouck, L. Descamps, L. Fenart, V. BuÉe-Scherrer, C. Duhem, S. Lundquist, M. Rentfel, G. Torpier, and M. P. Dehouck. In vitro model for evaluating drug transport across the blood-brain barrier. Adv. Drug Deliv. Rev. 36:165-178 (1999).
- P. Ramge, R. E. Unger, J. B Oltrogge, D. Zenker, D. Begley, J. Kreuter, and H. von Briesen. Polysorbate-80 coating enhances uptake of polybutylcyanoacrylate (PBCA)-nanoparticles by human and bovine primary brain capillary endothelial cells. Eur. J. Neurosci. 12:1931-1940 (2000).
- K. R. Dorovini-Zis, R. Prameya, and P. D. Bowman. Culture and characterisation of microvascular endothelial cells derived from human brain. Lab. Invest. 64:425-436 (1991).
- S. MÉeresse, M. P. Dehouck, P. Delorme, M. Bensaid, J. P. Tauber, C. Delbart, J. C. Fruchard, and R. Cecchelli. Bovine brain endothelial cells express tight junctions and monoamine oxidase activity in long-term culture. J. Neurochem. 53:1363-1371 (1989).
- J. Boother and M. Sensenbrenner. Growth and cultivation of dissociated neurons and glial cells from embryonic #x03A7;ck, rat and human brain in flask cultures. Neurobiology 2:97-105 (1972).
- A. Siflinger-Birnboim, P. J. Del Vecchio, J. A. Cooper, F. A. Blumenstock, J. N. Shepard, and A. B. Mailk. Molecular sieving characteristics of the cultured endothelial monolayer. J. Cell. Physiol. 132:111-117 (1987).
- M.-P. Dehouck, S. MÉeresse, P. Delorme, J. C. Fruchart, and R. Cecchelli. An easier, reproducible, and mass-production method to study the blood-brain barrier in vitro. J. Neurochem. 54:1798-1801 (1990).
- M.-P. Dehouck, P. Jolliet-Riant, F. Bree, J.-C. Fruchart, R. Cecchelli, and J.-P. Tillement. Drug transfer across the blood-brain barrier: correlation between in vitro and in vivo models. J. Neurochem. 58:1790-1797 (1992).
- T. J. Raub, S. L. Kuentzel, and G.A Sawada. Permeability of bovine brain microvessel endothelial cells in vitro: barrier tightening by a factor released from astroglioma cells. Exp. Cell Res. 199:330-340 (1992).
- 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).
- J. Kreuter and R. N. Alyautdin. Using nanoparticles to target drugs to the central nervous system. In D. J. Begley, M. W. Bradbury, and J. Kreuter (eds.), The Blood-Brain Barrier and Drug Delivery to the CNS, Marcel Dekker, New York, 2000, pp. 205-223.
- R. N. Alyautdin, A. Reichel, R. LÖbenberg, P. Ramge, J. Kreuter, and D. J. Begley. Interaction of poly(butylcyanoacrylate) nanoparticles with the blood-brain barrier in vivo and in vitro. J. Drug Target. 9:209-221 (2001).
- B. Kante. G Couvreur, C. Dubois-Krack, P. De Meester, M. Guiot, M. Roland, and P. Spieser. Toxicity of polyalkylcyanoacrylate nanoparticles 1: free nanoparticles. J. Pharm. Sci. 71:786-790 (1982).
- S. E Gelperina, A. S. Khalansky, I. N. Skidan, Z. S. Smirnova, A. I. Bobruskin, S. E. Severin, B. Turowski, F. E. Zanella, and J. Kreuter. Toxicological studies of doxorubicin bound to polysorbate 80-coated poly(butyl cyanoacrylate nanoparticles in healthy rats and rats with intracranial glioblastoma. Toxicol. Lett. 126:131-141 (2002).
- U. Schroeder 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).
- Direct Evidence That Polysorbate-80-Coated Poly(Butylcyanoacrylate) Nanoparticles Deliver Drugs to the CNS via Specific Mechanisms Requiring Prior Binding of Drug to the Nanoparticles
Volume 20, Issue 3 , pp 409-416
- Cover Date
- Print ISSN
- Online ISSN
- Kluwer Academic Publishers-Plenum Publishers
- Additional Links
- CNS drug delivery
- blood-brain barrier
- Industry Sectors
- Author Affiliations
- 1. Institut für Pharmazeutische Technologie, Biozentrum, J.W.Goethe-Universität, Frankfurt, Germany
- 2. Department of Pharmacology, Moscow Medical Academy, Russia
- 3. Max-Planck-Institut für physiologische und klinische Forschung, W.G.Kerckhoff-Institut, Bad Nauheim, Germany
- 4. Center of Molecular Diagnostics and Therapy, Moscow Institute of Medical Ecology, Moscow, Russia
- 5. Georg-Speyer-Haus, Frankfurt, Germany
- 6. Centre for Neuroscience Research, Guy's Campus, King's College London, London, SE1 1UL, United Kingdom