title: Pluronic P85-coated poly(butylcyanoacrylate) nanoparticles overcome phenytoin resistance in P-glycoprotein overexpressing rats with lithium-pilocarpine-induced chronic temporal lobe epilepsy.
abstract: P-glycoprotein (Pgp) overexpression in the blood brain barrier (BBB) is hypothesized to lower brain drug concentrations and thus inhibit anticonvulsant effects in drug-resistant epilepsy. Recently, the poly(butylcyanoacrylate) (PBCA) nanoparticle system was shown to overcome the obstacle of the BBB to deliver drugs into the brain. To determine whether pluronic P85-coated phenytoin poly(butylcyanoacrylate) nanoparticles (P85-PHT-PBCA-NPs) target PHT to the brain, PHT-resistant rats overexpressing Pgp in the BBB were screened by response to PHT treatment after chronic temporal lobe epilepsy induced by lithium-pilocarpine, followed by direct verification of PHT transport via measurement of brain PHT concentrations using microdialysis. Thereafter, the PHT-resistant rats were divided into three groups, which were treated with PHT, PHT + tariquidar (TQD), or P85-PHT-PBCA-NPs. PHT + TQD and P85-PHT-PBCA-NPs showed anticonvulsant activity in the PHT-resistant rats and increased the ratio of the area under the curve of the PHT concentrations in the brain/plasma in comparison with that observed in animals subjected to PHT treatment. However, the ratios of the PHT concentrations in the liver/plasma and kidney/plasma following P85-PHT-PBCA-NPs treatment were much lower than those measured following PHT + TQD treatment. Thus, Pgp overexpression decreases therapeutic drug concentrations in the brains of subjects with drug-resistant epilepsy and P85-PHT-PBCA-NPs could increase these drug concentrations.
authors.affiliation: Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, 58th Zhongshan 2nd Road, Guangzhou, Guangdong, 510080, PR China; Department of Neurology, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou Huiai Hospital, Guangzhou, Guangdong, 510370, PR China.
authors.forename: Ziyan
authors.initials: Z
authors.lastname: Fang
authors.affiliation: Department of Neurology, Guangzhou First People's Hospital, 1st Panfu Road, Guangzhou, Guangdong, 510180, PR China.
authors.forename: Shuda
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, 58th Zhongshan 2nd Road, Guangzhou, Guangdong, 510080, PR China.
authors.forename: Jiaming
authors.initials: J
authors.lastname: Qin
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510006, PR China.
authors.forename: Bao
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, 58th Zhongshan 2nd Road, Guangzhou, Guangdong, 510080, PR China.
authors.forename: Guanzhong
authors.initials: G
authors.lastname: Ni
authors.affiliation: Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, 58th Zhongshan 2nd Road, Guangzhou, Guangdong, 510080, PR China.
authors.forename: Ziyi
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, 58th Zhongshan 2nd Road, Guangzhou, Guangdong, 510080, PR China.
authors.forename: Jueqian
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Neurology, Guangzhou First People's Hospital, 1st Panfu Road, Guangzhou, Guangdong, 510180, PR China.
authors.forename: Ze
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Neurology, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou Huiai Hospital, Guangzhou, Guangdong, 510370, PR China.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Ning
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510006, PR China. Electronic address: chuanbinwu@126.com.
authors.forename: Chuanbin
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, 58th Zhongshan 2nd Road, Guangzhou, Guangdong, 510080, PR China. Electronic address: lmzhou56@163.com.
authors.forename: Liemin
authors.initials: L
authors.lastname: Zhou
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D002908:Chronic Disease; D004195:Disease Models, Animal; D004351:Drug Resistance; D004659:Enbucrilate / Q000737:chemistry*; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced* / Q000188:drug therapy*; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D008094:Lithium; D053758:Nanoparticles / Q000737:chemistry*; D010672:Phenytoin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010862:Pilocarpine; D011060:Poloxalene / Q000737:chemistry*; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D012640:Seizures / Q000188:drug therapy; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C422648:pluronic block copolymer p85; D010862:Pilocarpine; D010672:Phenytoin; D011060:Poloxalene; D008094:Lithium; D004659:Enbucrilate
keywords: Drug resistance; Microdialysis; Nanoparticles; P-glycoprotein; Phenytoin; Tariquidar