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Use of nanoparticles to deliver therapeutics to the CNS

Jörg Kreuter1*
  • 1 Goethe-Universität Frankfurt, Institut für Pharmazeutische Technologie, Germany

INTRODUCTION
For most drugs including anticancer agents, antibiotics, peptides, and oligo- and macromolecules the bloodbrain barrier (BBB) represents an insurmountable barrier. The limited access of these drugs to the brain is due to the tight junctions between the endothelial cells lining the brain blood vessels as well as to the existence of very active drug efflux systems, e.g. the ABC (ATP-binding cassette) transporters, such as Pgp, in the luminal cell membranes of these cells1.
EMPLOYMENT OF NANOPARTICLES
One of the most promising strategies to overcome this problem is the binding of the active compounds to the nanoparticles coated with surfactants such as polysorbate 80 (Tween®80)2,3 or poloxamer 188 (Puronic®F 68)4 or the attachment of targeting ligands such as apolipoprotein A-1 or E, transferrin or antibodies against certain receptors located on the brain capillary endothelial cells. The polymers used for brain delivery have to be rapidly biodegradable and include poly(butyl cyanoacrylate) (PBCA), human serum albumin (HSA), and poly(lactic-coglycolic acid) (PLGA). A number of drugs were transported into the brain using these carrier systems and yielded significant pharmacological effects after intravenous injection. These include doxorubicin, the hexapeptide dalargin, nerve growth factor (NGF), loperamide, tubocurarine, the NMDA receptor antagonists MRZ 2/576 and MRZ 2/596, and others. All these substances normally cannot cross the BBB at all or only in very limited amounts2,3.
Whereas normally the transport across the BBB is increased with increasing lipophilicity of the drugs, this property appears to be of no importance for the nanoparticle-mediated delivery to the brain: After binding to the polysorbate 80-coated particles, both, the rather hydrophilic peptide dalargin as well as the lipophilic compound loperamide, exhibited a dose-dependent antinociceptive effect after i.v. injection as demonstrated by the tail-flick as well as by the hot plate test. This effect was accompanied by a Straub reaction and was totally inhibited by pretreatment with naloxone, indicating that it was a central effect and not peripheral analgesia2,3.
Another very exciting result was obtained with nerve growth factor (NGF)4. After binding of NGF to PBCA nanoparticles coated with polysorbate 80, their potential to reverse scopolamine-induced amnesia was investigated in rats using the passive avoidance reflex (PAR) test and in the 1-methyl-4-phentl-1,2,3,6- tetrahydropyridine (MPTP)-induced Parkinsonian syndrome model. Intravenous injection of NGF bound to PBCA nanoparticles coated with polysorbate 80 successfully reversed the scopolamine-induced amnesia and improved recognition and memory in an acute amnestic mouse model and demonstrated a significant reduction of the basic symptoms of Parkinsonism (oligokinesia, rigidity, tremor). In addition, increased NGF concentrations in brain were observed after i.v. injection of the nanoparticle-bound NGF. These results demonstrate that the PBCA nanoparticles coated with polysorbate 80 are an effective carrier system for the transport of NGF to the central nervous system across the BBB after i.v. injection that could improve the therapy of age-related neurodegenerative diseases.
In order to achieve a significant drug transport across the BBB, for PBCA nanoparticles the coating with polysorbate 80 or poloxamer 188 is required5. The PLGA nanoparticles require the coating with poloxamer 188 whereas polysorbate appears to be less effective. The HSA nanoparticles also can be coated with polysorbate 80. Even more efficient is the attachment of targeting ligands such as apolipoprotein A-1 (apo A-1) or E (apo E), transferrin, or antibodies against the transferrin receptor such as OX26 or R17217 to the HSA nanoparticles6,7.
BRAIN TUMOURS
The intravenous injection of polysorbate 80-coated nanoparticles loaded with doxorubicin (5 mg/kg) yielded very high brain levels of 6 μg/g doxorubicin in the brain of rats8. Experiments with the extremely aggressive orthotopic glioblastoma 101/8 transplanted intracranially led to a long term survival for 6 months of up to 40 % of the rats after intravenous injection of the polysorbate 80-coated nanoparticle preparation using a dose of 1.5 mg/kg on days 2, 5, and 8 after tumour transplantation9 (Fig. 1). The morphological as well as the histological features of this tumour model closely resemble human glioblastomas10. After 6 months, the surviving animals were sacrificed and showed a total remission by histological investigation. The untreated controls died within 10 - 20 days, the animals in the doxorubicin control and uncoated doxorubicin nanoparticle groups died between 10 – 50 days. Similar, slightly lower effects were observed after coating with poloxamer 188, whereas the overcoating of PLGA nanoparticles with the latter surfactant appeared to yield even better anti-tumour effects11.
No increase in drug-related toxicity was observed for the nanoparticle formulations12
MECHANISM OF DRUG TRANSPORT
The mechanism of the nanoparticle-mediated transport of the drugs across the BBB appears to be endocytotic uptake of the nanoparticles by brain capillary endothelial cells. This uptake was first shown in tissue cultures. In animal experiments, similar antinociceptive effects as with polysorbate or poloxamer 188-coating were obtained after pre-adsorption of apolipoproteins B or E (apo B or apo E) on PBCA nanoparticles prior to injection or after the covalent binding of these apolipoproteins to HSA nanoparticles. As shown by 2-D PAGE, after i.v. injection the polysorbate 80 or poloxamer 188 coating enhances adsorption of plasma apolipoproteins A-1, B, or E on the nanoparticle surface4.The adsorbed apolipoproteins then could promote the interaction of the particles with receptors of the LDL family or scavenger receptors followed by their endocytotic uptake. This uptake after i.v. injection recently was visualized in mice using transmission electron microscopy13 (Fig. 2). The nanoparticles appear to mimic naturally occurring lipoprotein particles, thus acting as Trojan horses. After the uptake into the endothelial cells, the drugs either may be released within these cells and then diffuse freely into the brain or may be transported by transcytosis. The electron microscopical pictures showed that at least some nanoparticles were transcytosed after 30 min.
In vitro a large peptide, rhoGin, a GTPase, produced neurite outgrowth and differentiation in PC12 cells after binding to nanoparticles showing that it fully retained its functionality. LDL blockade inhibited the nanoparticle uptake into the neurons14.

CONCLUSIONS
The nanoparticles represent very promising carrier systems for the transport of drugs across the BBB that even can transport large molecules and retain their functionality.

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References

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Conference: Pharmacology and Toxicology of the Blood-Brain Barrier: State of the Art, Needs for Future Research and Expected Benefits for the EU, Brussels, Belgium, 11 Feb - 12 Feb, 2010.

Presentation Type: Oral Presentation

Topic: Presentations

Citation: Kreuter J (2010). Use of nanoparticles to deliver therapeutics to the CNS. Front. Pharmacol. Conference Abstract: Pharmacology and Toxicology of the Blood-Brain Barrier: State of the Art, Needs for Future Research and Expected Benefits for the EU. doi: 10.3389/conf.fphar.2010.02.00024

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Received: 11 Mar 2010; Published Online: 11 Mar 2010.

* Correspondence: Jörg Kreuter, Goethe-Universität Frankfurt, Institut für Pharmazeutische Technologie, Frankfurt, Germany, kreuter@em.uni-frankfurt.de