title: Small-Sized mPEG-PLGA Nanoparticles of Schisantherin A with Sustained Release for Enhanced Brain Uptake and Anti-Parkinsonian Activity.
abstract: Schisantherin A (SA) is a promising anti-Parkinsonism natural product. However, its poor water solubility and rapid serum clearance impose significant barriers to delivery of SA to the brain. This work aimed to develop SA in a nanoparticle formulation that extended SA circulation in the bloodstream and consequently an increased brain uptake and thus to be potentially efficacious for the treatment of Parkinson's disease (PD). Spherical SA nanoparticles with a mean particle size of 70 nm were prepared by encapsulating SA into methoxy poly(ethylene glycol)-block-poly(d,l)-lactic-co-glycolic acid (mPEG-PLGA) nanoparticles (SA-NPs) with an encapsulation efficiency of ∼91% and drug loading of ∼28%. The in vitro release of the SA-NPs lasted for 48 h with a sustained-release pattern. Using the Madin-Darby canine kidney (MDCK) cell model, the results showed that first intact nanoparticles carrying hydrophobic dyes were internalized into cells, then the dyes were slowly released within the cells, and last both nanoparticles and free dyes were externalized to the basolateral side of the cell monolayer. Fluorescence resonance energy transfer (FRET) imaging in zebrafish suggested that nanoparticles were gradually dissociated in vivo with time, and nanoparticles maintained intact in the intestine and brain at 2 h post-treatment. When SA-NPs were orally administrated to rats, much higher Cmaxand AUC0-twere observed in the plasma than those of the SA suspension. Furthermore, brain delivery of SA was much more effective with SA-NPs than with SA suspension. In addition, the SA-NPs exerted strong neuroprotective effects in zebrafish and cell culture models of PD. The protective effect was partially mediated by the activation of the protein kinase B (Akt)/glycogen synthase kinase-3β (Gsk3β) pathway. In summary, this study provides evidence that small-sized mPEG-PLGA nanoparticles may improve cross-barrier transportation, oral bioavailability, brain uptake, and bioactivity of this Biopharmaceutics Classification System (BCS) Class II compound, SA.
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau , Macau, China.
authors.forename: Tongkai
authors.initials: T
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau , Macau, China.
authors.forename: Chuwen
authors.initials: C
authors.lastname: Li
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau , Macau, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27516, United States.
authors.forename: Xiang
authors.initials: X
authors.lastname: Yi
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau , Macau, China.
authors.forename: Ruibing
authors.identifier: http://orcid.org/0000-0001-9489-4241
authors.initials: R
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau , Macau, China.
authors.forename: Simon Ming-Yuen
authors.initials: SM
authors.lastname: Lee
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau , Macau, China.
authors.forename: Ying
authors.identifier: http://orcid.org/0000-0003-4555-2143
authors.initials: Y
authors.lastname: Zheng
mesh_terms: D000818:Animals; D001921:Brain; D034242:Cyclooctanes; D003692:Delayed-Action Preparations; D004149:Dioxoles; D004285:Dogs; D004337:Drug Carriers; D017705:Lignans; D053758:Nanoparticles; D010316:Particle Size; D011091:Polyesters; D011092:Polyethylene Glycols; D051381:Rats
chemical_list: D034242:Cyclooctanes; D003692:Delayed-Action Preparations; D004149:Dioxoles; D004337:Drug Carriers; D017705:Lignans; D011091:Polyesters; C558447:methoxypolyethyleneglycol-poly(lactic-co-glycolic acid); D011092:Polyethylene Glycols; C034557:schizandrer A
keywords: Schisantherin A; brain delivery; cellular uptake; fluorescence resonance energy transfer (FRET); mPEG−PLGA nanoparticles; oral bioavailability