Pluronic P85-coated poly(butylcyanoacrylate) nanoparticles overcome phenytoin resistance in P-glycoprotein overexpressing rats with lithium-pilocarpine-induced chronic temporal lobe epilepsy

• Published in: Biomaterials Vol. 97; pp. 110 - 121
• Main Authors: Fang, Ziyan, Chen, Shuda, Qin, Jiaming, Chen, Bao, Ni, Guanzhong, Chen, Ziyi, Zhou, Jueqian, Li, Ze, Ning, Yuping, Wu, Chuanbin, Zhou, Liemin
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.08.2016
• Subjects: Advanced Basic Science; Animals; Anticonvulsants; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; blood-brain barrier; Brain; Chronic Disease; Dentistry; Disease Models, Animal; Drug Resistance; Drugs; Enbucrilate - chemistry; Epilepsy; Epilepsy, Temporal Lobe - chemically induced; Epilepsy, Temporal Lobe - drug therapy; Female; Hippocampus - metabolism; kidneys; Lithium; liver; Lobes; Microdialysis; Nanoparticles; Nanoparticles - chemistry; Obstacles; P-glycoprotein; P-glycoproteins; Phenytoin; Phenytoin - pharmacokinetics; Phenytoin - therapeutic use; Pilocarpine; Poloxalene - chemistry; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Seizures - drug therapy; Tariquidar; therapeutics; Tissue Distribution; P-glycoprotein; Nanoparticles; Microdialysis; Drug resistance; Tariquidar; Phenytoin
• ISSN: 0142-9612; 1878-5905; 1878-5905
• DOI: 10.1016/j.biomaterials.2016.04.021

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.