title: Enhanced brain delivery of lamotrigine with Pluronic(®) P123-based nanocarrier.
abstract: BACKGROUND
  P-glycoprotein (P-gp) mediated drug efflux across the blood-brain barrier (BBB) is an important mechanism underlying poor brain penetration of certain antiepileptic drugs (AEDs). Nanomaterials, as drug carriers, can overcome P-gp activity and improve the targeted delivery of AEDs. However, their applications in the delivery of AEDs have not been adequately investigated. The objective of this study was to develop a nano-scale delivery system to improve the solubility and brain penetration of the antiepileptic drug lamotrigine (LTG).
  
  
  METHODS
  LTG-loaded Pluronic(®) P123 (P123) polymeric micelles (P123/LTG) were prepared by thin-film hydration, and brain penetration capability of the nanocarrier was evaluated.
  
  
  RESULTS
  The mean encapsulating efficiency for the optimized formulation was 98.07%; drug-loading was 5.63%, and particle size was 18.73 nm. The solubility of LTG in P123/LTG can increase to 2.17 mg/mL, making it available as a solution. The in vitro release of LTG from P123LTG presented a sustained-release property. Compared with free LTG, the LTG-incorporated micelles accumulated more in the brain at 0.5, 1, and 4 hours after intravenous administration in rats. Pretreatment with systemic verapamil increased the rapid brain penetration of free LTG but not P123/LTG. Incorporating another P-gp substrate (Rhodamine 123) into P123 micelles also showed higher efficiency in penetrating the BBB in vitro and in vivo.
  
  
  CONCLUSIONS
  These results indicated that P123 micelles have the potential to overcome the activity of P-gp expressed on the BBB and therefore show potential for the targeted delivery of AEDs. Future studies are necessary to further evaluate the appropriateness of the nanocarrier to enhance the efficacy of AEDs.
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Jian-Sheng
authors.initials: JS
authors.lastname: Liu
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Jian-Hong
authors.initials: JH
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Xing-Hua
authors.initials: XH
authors.lastname: Tang
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Lan
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, People's Republic of China.
authors.forename: Teng
authors.initials: T
authors.lastname: Shen
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Xun-Yi
authors.initials: XY
authors.lastname: Wu
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Hong
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry; D002460:Cell Line; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics*; D000077213:Lamotrigine; D008297:Male; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D011060:Poloxalene / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014227:Triazines / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D004337:Drug Carriers; D008823:Micelles; D014227:Triazines; C464484:pluronic block copolymer P123; D011060:Poloxalene; D000077213:Lamotrigine
keywords: P-glycoprotein; antiepileptic drug; lamotrigine; nanocarrier; pluronic; polymeric micelles