title: Electroresponsive Nanoparticles Improve Antiseizure Effect of Phenytoin in Generalized Tonic-Clonic Seizures.
abstract: Previously, we developed electroresponsive hydrogel nanoparticles (ERHNPs) modified with angiopep-2 (ANG) to facilitate the delivery of the antiseizure drug phenytoin sodium (PHT). However, the electroresponsive characteristics were not verified directly in epileptic mice and the optimal preparation formula for electroresponsive ability is still unclear. Here, we further synthesized PHT-loaded ANG-ERHNPs (ANG-PHT-HNPs) and PHT-loaded nonelectroresponsive hydrogel nanoparticles (ANG-PHT-HNPs) by changing the content of sodium 4-vinylbenzene sulfonate in the preparation formulae. In vivo microdialysis analysis showed that ANG-PHT-ERHNPs not only have the characteristics of a higher distribution in the central nervous system, but also have electroresponsive ability, which resulted in a strong release of nonprotein-bound PHT during seizures. In both electrical- (maximal electrical shock) and chemical-induced (pentylenetetrazole and pilocarpine) seizure models, ANG-PHT-ERHNPs lowered the effective therapeutic doses of PHT and demonstrated the improved antiseizure effects compared with ANG-PHT-HNPs or PHT solution. These results demonstrate that ANG-ERHNPs are able to transport PHT into the brain efficiently and release them when epileptiform activity occurred, which is due to the content of sodium 4-vinylbenzene sulfonate in formula. This may change the therapeutic paradigm of existing drug treatment for epilepsy into a type of on-demand control for epilepsy in the future.
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, China.|Institute of Pharmaceutics, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Ying
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Liying
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Liang
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Cenglin
authors.initials: C
authors.lastname: Xu
authors.affiliation: Epilepsy Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Epilepsy Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Hu
authors.affiliation: Institute of Pharmaceutics, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Yongzhong
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, China. chenzhong@zju.edu.cn.|Epilepsy Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. chenzhong@zju.edu.cn.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. chenzhong@zju.edu.cn.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D004830:Epilepsy, Tonic-Clonic / Q000188:drug therapy* / Q000503:physiopathology; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D008297:Male; D053758:Nanoparticles / Q000737:chemistry / Q000627:therapeutic use*; D010672:Phenytoin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000927:Anticonvulsants; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D010672:Phenytoin
keywords: Electroresponsive; Epilepsy; Microdialysis; Nanoparticle; Sodium 4-vinylbenzene sulfonate