title: Optimization of rate-controlled 17beta-estradiol nanoparticles for cerebral ischemia therapy.
abstract: The objective of this study was to prepare and evaluate rate-controlled 17beta-estradiol nanoparticles (E2-NPs), and then optimize them by central composite design (CCD) using a response surface methodology (RSM). The E2-NPs were designed for cerebral ischemia therapy and prepared by oil-in-water (o/w) emulsion by mixing E2 and phosphatidylcholine, cross-linking of the bovine serum albumin (BSA) wall material with glutaraldehyde, and subsequently creating a biodegradable coating shell with L-arginine. In two-factor, five-level CCD, the independent variables were the pH value of the aqueous phase (X1) and the amount of glutaraldehyde (X2). The optimal formulation of the E2-NPs was developed from the response equations of each fitted model. The optimal E2-NPs particle size was 92.4 +/- 1.4 nm, and its cumulative release in 4.0 h (therapeutic window for stroke) was 71.17 +/- 0.24%, with a zero-order release model of 24 h. The preparation and testing of the optimal formulation showed a good correlation between the predicted and observed values. In addition, a brain microdialysis study demonstrated that the E2-NPs had the ability to penetrate the blood-brain barrier and clearly increase and maintain the drug concentration in the brain over 12 h. Furthermore, the E2-NPs reduced brain infarct size in rats with middle cerebral artery occlusion (MCAO)-induced stroke. These results suggest that rate-controlled E2-NPs increase the efficacy of E2 for ischemic stroke therapy.
authors.affiliation: Department of Occupational Therapy, I-Shou University, Kaohsiung 82445, Taiwan.
authors.forename: Li-Ching
authors.initials: LC
authors.lastname: Chang
authors.forename: Chun-Jen
authors.initials: CJ
authors.lastname: Cheng
authors.forename: Tung-Hu
authors.initials: TH
authors.lastname: Tsai
authors.forename: Ching-Wen
authors.initials: CW
authors.lastname: Liu
authors.forename: Tong-Rong
authors.initials: TR
authors.lastname: Tsai
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology*; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000737:chemistry*; D004958:Estradiol / Q000008:administration & dosage* / Q000737:chemistry*; D008297:Male; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry* / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000737:chemistry; D051381:Rats; D016896:Treatment Outcome
chemical_list: D003692:Delayed-Action Preparations; D053769:Nanocapsules; D018696:Neuroprotective Agents; D004958:Estradiol