title: Functionalized nanocarrier combined seizure-specific vector with P-glycoprotein modulation property for antiepileptic drug delivery.
abstract: Despite optimal therapeutic regimen with currently available antiepileptic drugs (AEDs), approximately a third of epilepsy patients remain drug refractory. Region-specific overexpression of multidrug efflux transporters at the blood-brain barrier, such as P-glycoprotein (P-gp), might contribute to multidrug resistance (MDR) by reducing target concentrations of AEDs. Therefore, development of nanomedicine that can modulate P-gp function as well as facilitate targeted AEDs delivery represents a promising strategy for epilepsy intervention. To achieve this, we sought to exploit the possibility of combination of active targeting function of tryptophan by transporter-mediated endocytosis and overcoming MDR by Pluronic block copolymers. Herein, a tryptophan derivate (TD) functionalized Pluronic P123/F127 mixed micelles encapsulating LTG (TD-PF/LTG) was developed to promote AEDs delivery to epileptogenic focus. TD-PF/LTG was about 20 nm in diameter with a spherical shape and high encapsulation efficiency. A rat epilepsy model with pilocarpine was established to evaluate the brain penetration efficiency of the LTG-incorporated polymeric micellar formulation, compared with free LTG formulations. Studies showed that TD-PF/LTG was more efficient than PF/LTG as well as free LTG in delivering the drug to the brain, especially the hippocampus. The enhanced targeted delivery could be ascribed to the increased tryptophan uptake at epileptogenic focus as well as P-gp modulation property of the nanomaterial. Taken together, TD-conjugated Pluronic micelles showed promising potential as a nanoplatform for the delivery of AEDs in refractory epilepsy.
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai 200040, PR China; Department of Neurology, The Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, 600 Yishan Road, Shanghai 200233, China.
authors.forename: Jiansheng
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutics, Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Yajing
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Radiology, Huashan Hospital, Fudan University, 12 Wulumuqi Middle Road, Shanghai 200040, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutics, Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Jiajia
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Radiology, Huashan Hospital, Fudan University, 12 Wulumuqi Middle Road, Shanghai 200040, China.
authors.forename: Xiangrong
authors.initials: X
authors.lastname: Yu
authors.affiliation: Instrumental Analysis Center, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Zhonglian
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Department of Pharmaceutics, Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Fanmin
authors.initials: F
authors.lastname: Meng
authors.affiliation: Department of Neurology, The Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, 600 Yishan Road, Shanghai 200233, China.
authors.forename: Yuwu
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai 200040, PR China. Electronic address: mythstory@126.com.
authors.forename: Xunyi
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Pharmaceutics, Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China. Electronic address: shenteng@fudan.edu.cn.
authors.forename: Teng
authors.initials: T
authors.lastname: Shen
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai 200040, PR China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Hong
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004337:Drug Carriers; D004827:Epilepsy / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D053758:Nanoparticles; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D004337:Drug Carriers
keywords: Antiepileptic drug; Epilepsy; Lamotrigine; P-glycoprotein; Polymeric micelles; Tryptophan