Abstract
Drug delivery to the brain is becoming more and more important but is severely restricted by the blood-brain barrier. Nanoparticles coated with polysorbates have previously been shown to enable the transport of several drugs across the blood-brain barrier, which under normal circumstances is impermeable to these compounds. Apolipoprotein E was suggested to mediate this drug transport across the blood-brain barrier. In the present study, apolipoprotein E was coupled by chemical methods to nanoparticles made of human serum albumin (HSA-NP). Loperamide, which does not cross the blood-brain barrier but exerts antinociceptive effects after direct injection into the brain, was used as model drug. Apolipoprotein E was chemically bound via linkers to loperamide-loaded HSA-NP. This preparation induced antinociceptive effects in the tail-flick test in ICR mice after i.v. injection. In contrast, nanoparticles linked to apolipoprotein E variants that do not recognize lipoprotein receptors failed to induce these effects. These results indicate that apolipoprotein E attached to the surface of nanoparticles facilitates transport of drugs across the blood-brain barrier, probably after interaction with lipoprotein receptors on the brain capillary endothelial cell membranes.
Footnotes
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This work was supported by LTS Lohmann Therapiesysteme, Andernach, Germany, the society Hilfe für krebskranke Kinder Frankfurt e.V. (M.M.), and the Forschungskommission Freiburg (M.M.H.).
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doi:10.1124/jpet.105.097139.
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ABBREVIATIONS: LDL-R, low-density lipoprotein receptor; HSA-NP, nanoparticle(s) made of human serum albumin; PBS, phosphate-buffered saline; TEA, triethanolamine; HPLC, high-performance liquid chromatography; PEG, polyethylene glycol; P-gp, P-glycoprotein; %MPE, percentage maximal possible effect; LRP, low-density lipoprotein receptor-related protein.
- Received October 14, 2005.
- Accepted March 17, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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