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 C and AUC were 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.

Multifunctional Polymeric Nanoplatforms for Brain Diseases Diagnosis, Therapy and Theranostics

“…The high antitumor effect against glioblastomas, as well as considerable analgesia, revealed that these NP systems can cross the BBB and release the drug at a specific site. Similar results were also observed by Chen et al [118]. Block copolymers were also used for the preparation of NPs [194].…”

“…Decreased amyloid-beta (Aβ) plaques and related inflammation characteristics [117] mPEG-PLGA Schisantherin A Improved oral bioavailability, increased brain uptake, and enhanced the bioactivity of this drug [118] Rabies virus glycoprotein 29-modified deferoxamine-loaded PLGA…”

“…It was found that these NPs containing memantine decrease Aβ plaques and related inflammation characteristics of AD. Chen et al designed small mPEG-PLGA NPs for the delivery of schisantherin A in PD (Figure 3) [118]. It was demonstrated that these NPs promote the delivery of schisantherin A into the brain, improve the oral bioavailability, increase the brain uptake, and enhance the bioactivity of this drug.…”

Investigating the Influence of Aromatic Moieties on the Formulation of Hydrophobic Natural Products and Drugs in Poly(2-oxazoline)-Based Amphiphiles

“…[45,46] The formation of nanoparticles and nanocrystals to formulate schisantherin A, a related dibenzo[a,c]cyclooctadiene lignan, was described by Cheng et al The drug/carrier aggregates could pass the hemato-encephalic barrier and showed effects potentially useful for the treatment of Parkinson´s disease. [47,48] Several strategies for the development of drug specific drug delivery platforms have been followed, lately. In particular, Luo, Nangia and co-workers backed the synthetic work with extensive modeling and achieved very high drug loadings paired with excellent therapeutic efficacy.…”

Recent Advancements of Nanomedicine in Neurodegenerative Disorders Theranostics

“…Another study using PLGA NP mediated Puerarin or Schisantherin A delivery showed enhanced brain uptake and anti‐Parkinsonian activity. [ 96 ] Several other types of nanovehicles which showed promising results in preclinical studies in PD are summarized in Table 2 . [ 97 ]…”