title: The role of apolipoprotein E in uptake of atovaquone into the brain in murine acute and reactivated toxoplasmosis.
abstract: We investigated whether coating of atovaquone nanosuspensions (ANSs) with apolipoprotein E (apoE) peptides improves the uptake of atovaquone into the brain. The passage across the blood-brain barrier (BBB) of ANSs stabilized by polysorbate 80 (Tween 80), poloxamer 184 (P184), or poloxamer 338 (P338) and the same formulations coated with apoE peptides were analyzed in vitro and in vivo. Passage through a rat coculture model of the BBB did not differ between individual atovaquone formulations, and the addition of apoE peptides did not enhance the transport. Following the induction of toxoplasmic encephalitis (TE) in mice, treatment with all atovaquone formulations reduced the number of parasites and inflammatory foci compared with untreated mice. Uptake of atovaquone into the brain did not depend on coating with apoE. Finally, incubation of apoE peptide-coated ANSs with brain endothelial cells for 30 min did result in the accumulation of nanoparticles on the cell surface but not in their uptake into the cells. In conclusion, ANSs coated with Tween 80 or poloxamers showed therapeutic efficacy in murine toxoplasmosis. ApoE- and apoE-derived peptides do not induce the uptake of ANSs into the brain. Alternative mechanisms seem to be in operation, thereby mediating the passage of atovaquone across the BBB.
authors.affiliation: Institute of Microbiology and Hygiene, Charité-University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Hend M
authors.initials: HM
authors.lastname: Shubar
authors.forename: Ildiko R
authors.initials: IR
authors.lastname: Dunay
authors.forename: Sabrina
authors.initials: S
authors.lastname: Lachenmaier
authors.forename: Margitta
authors.initials: M
authors.lastname: Dathe
authors.forename: Faris Nadiem
authors.initials: FN
authors.lastname: Bushrab
authors.forename: Rachmat
authors.initials: R
authors.lastname: Mauludin
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Müller
authors.forename: Rudolf
authors.initials: R
authors.lastname: Fitzner
authors.forename: Klaus
authors.initials: K
authors.lastname: Borner
authors.forename: Oliver
authors.initials: O
authors.lastname: Liesenfeld
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D001057:Apolipoproteins E / Q000737:chemistry*; D053626:Atovaquone / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000469:parasitology; D018920:Coculture Techniques; D051379:Mice; D020442:Poloxamer / Q000737:chemistry; D011136:Polysorbates / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D013501:Surface-Active Agents / Q000737:chemistry; D014018:Tissue Distribution; D014124:Toxoplasmosis, Animal / Q000188:drug therapy*; D016781:Toxoplasmosis, Cerebral / Q000188:drug therapy* / Q000469:parasitology
chemical_list: D000981:Antiprotozoal Agents; D001057:Apolipoproteins E; D011136:Polysorbates; D013501:Surface-Active Agents; D020442:Poloxamer; D053626:Atovaquone