Delivery to the Brain Across the Blood Brain Barrier

The BBB represents an unsurmountable obstacle for a large number of drugs, including anticancer drugs, antibiotics, and a variety of central nervous system-active drugs, especially neuropeptides [352]. Nanoparticles coated with polysorbate 80 were shown to enable the delivery of a number of drugs across the BBB and to induce a significant pharmacological action [30, 66-68, 304, 305, 353-355]. Besides polysorbate 80, polysorbate 20, 40, and 60 also enabled this delivery, whereas with a variety of other surfactants no drug transport across the BBB was detectable [356]. The drugs that were delivered across the BBB with the polysorbate-coated nanoparticles include the hexapaptide dalargin [30, 66, 353] and another peptide, kytorphin [354], loperamide [67], tubocurarine [355], doxorubicin [304], and the NMDA-receptor antagonist MRZ 2/576 (8-chloro-4-hydroxy-1-oxo-1,2-dihydropyridazino[4,5-fo]quinoline-5-oxide choline salt)

[305]. Especially the results with the last two compounds are very promising: Doxorubicin seems to be very active against brain tumors but is not able to cross the BBB. After binding to polysorbate 80-coated nanoparticles drug concentrations in the brain were 60 times above the detection limit whereas all controls were below this limit [304]. No increase in doxorubicin toxicity appeared with these nanoparticles [69]. MRZ 2/576 is a potent but short acting anticonvulsant. Binding to the polysorbate-coated nanoparticles prolonged its action from 15 min up to almost 5 hours.

The mechanism for this drug delivery is not totally elucidated. In vitro an uptake of the polysorbate 80-coated nanoparticles but not of uncoated nanoparticles by endo-cytosis was observed in cultured human, bovine, rat, and mouse brain capillary endothelial cells [68, 357]. Only the polysorbate-coated nanoparticles adsorbed apolipoprotein E after incubation in plasma but not uncoated nanoparticles or those coated with the other surfactants. This apolipopro-tein as well as apolipoprotein B but not other apolipopro-teins also enabled a transport of significant amounts of the model hexapeptide drug dalargin across the BBB into the brain [312]. Both apolipoproteins are present in lipoprotein particles that are taken up by the lipoprotein receptors on the blood capillary endothelial cells of the brain. It is conceivable that the nanoparticles after injection into the bloodstream adsorb these apolipoproteins and thus mimic natural lipopro-tein particles, leading to the uptake by these cells followed by drug delivery to the brain interior. Thus the polysorbate-coated nanoparticles would act as "Trojan horses." An alternative delivery mechanism, opening of the tight junctions between the endothelial cells, seems to be less likely since no major increase in the so-called inulin spaces was observed after intravenous injection [357], and no drug transport into the brain was observable with the other surfactants [54].

Transport of drugs across the BBB with nanoparticles was reviewed comprehensively in [352].

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