Nanoparticles to Permit Transfer across the BBB

In recent years Kreuter et al. [59, 60] and Schroeder et al. [61-64] applied a special procedure to permit brain targeting of nanoparticles. This was accomplished by altering their surface with surfactants. Specifically, polymeric nano-particles are coated with different hydrophilic surfactants. So far only poly(butylcyanoacrylate) nanoparticles possess the potential to transport drugs across the blood-brain barrier in vivo [99].

The most common method is to first fabricate the nano-particles; then the drug is bound by adsorption on the surface of the nanoparticles or by forming a solid solution or dispersion. Thereafter, a surfactant is added to the nano-particle/drug complex.

Poly(butylcyanoacrylate) nanoparticles have an average diameter size of about 200-300 nm and are very rapidly biodegraded [97, 100]. Figure 7 shows the two pathways of biodegradation of these nanoparticles. The main pathway consists of enzymatic cleavage of the butylester group of the polymer. The polymeric acid is then formed, and butanol is formed as well. Both metabolites are water soluble and will be excreted by the kidneys. During the other minor pathway, the polymer chain is degraded and formaldehyde is formed in traces, too low to be of physiological concern [101].

The first drug that was successfully delivered to the brain with this approach was the hexapeptide enkephalin, dalargin (Tyr-D-Ala-Gly-Phe-Leu-Arg). These studies were carried out first in the laboratory of Kreuter and subsequently and independently in the laboratory of Sabel.

Figure 7. Biodegradation of PBCA-nanoparticles.

Reaction times of rats in hot-plate-tests after . administration of Dalargin with & without nanoparticles latency period [sec]

latency period [sec]

Figure 8. Central analgesic effect of dalargin-loaded nanoparticles coated with polysorbate 80 after i.v. injection.

Dalargin on coated PBCA-Nps Dalargin adsorbed on PBCA-Nps Dalargin alone nanoparticles alone

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Figure 8. Central analgesic effect of dalargin-loaded nanoparticles coated with polysorbate 80 after i.v. injection.

Figure 7. Biodegradation of PBCA-nanoparticles.

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