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A brain-targeted drug delivery nanoplatform based on graphene oxide could overcome the blood–brain barrier for the treatment of Parkinson's disease.

Recent work has highlighted the potential of puerarin (PU) as a valuable compound to treat Parkinson’s disease (PD), but its undesirable water solubility and bioavailability have constrained its utility. In this study, we sought to develop nanoparticles (NPs) that could be used to encapsulate PU, thereby extending its in vivo half-life and improving its bioavailability and accumulation in the brain to treat the symptoms of PD. We prepared spherical NPs (88.36 ± 1.67 nm) from six-armed star-shaped poly­(lactide-co-glycolide) (6-s-PLGA) NPs that were used to encapsulate PU (PU-NPs) with 89.52 ± 1.74% encapsulation efficiency, 42.97 ± 1.58% drug loading, and a 48 h sustained drug release. NP formation and drug loading were largely mediated by hydrophobic interactions, while changes in the external environment led these NPs to become increasingly hydrophilic, thereby leading to drug release. Relative to PU alone, PU-NPs exhibited significantly improved cellular internalization, permeation, and neuroprotective effects. Upon the basis of Förster resonance energy transfer (FRET) of NPs-administered zebrafish, we were able to determine that these NPs were rapidly absorbed into circulation whereupon they were able to access the brain. We further conducted oral PU-NPs administration to rats, revealing significant improvements in PU accumulation within the plasma and brain relative to rats administered free PU. In MPTP-mediated neurotoxicity in mice, we found that PU-NPs treatment improved disease-associated behavioral deficits and depletion of dopamine and its metabolites. These findings indicated that PU-NPs represent a potentially viable approach to enhancing PU oral absorption, thus improving its delivery to the brain wherein it can aid in the treatment of PD.

Puerarin (PU) has emerged as a promising herbderived anti-Parkinsonism compound. However, the undesirable water solubility as well as the unwanted bioavailability of PU limit its application. Therefore, this study aimed to develop and characterize PU nanocrystals (PU-NCs) with enhanced oral bioavailability and improved brain accumulation for the treatment of Parkinson's disease (PD). The fabricated PU-NCs were approximately spherical, with a mean size of 83.05 ± 1.96 nm, a PDI of 0.047 ± 0.009, a drug loading of 72.7%, and a rapid dissolution rate in vitro. Molecular dynamics simulation of PU and Pluronic F68 demonstrated the interaction energy and binding energy of −88.1 kJ/mol and −40.201 ± 0.685 kJ/mol, respectively, indicating a spontaneous binding with van der Waals interactions. In addition, the cellular uptake and permeability of PU-NCs were significantly enhanced as compared to PU alone (p < 0.01). Moreover, PU-NCs exerted a significant neuroprotective effect against the cellular damage induced by the 1-methyl-4phenylpyridinium ion (MPP + ). Besides, PU-NCs demonstrated no obvious toxic effects on zebrafish, as evidenced by the unaltered morphology, hatching, survival rate, body length, and heart rate. Fluorescence resonance energy transfer (FRET) imaging revealed that intact nanocrystals were found in the intestine and brain of adult zebrafish gavaged with DiO/DiI/PU-NCs. Increased values of C max and AUC 0−t were observed in the plasma of rats following oral administration of PU-NCs compared to PU suspension. Likewise, brain accumulation of PU-NCs was higher than that of PU suspension. Furthermore, PU-NCs attenuated dopamine depletion, ameliorated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral deficits, and enhanced the levels of dopamine and its metabolites. Taken altogether, this study provides evidence that PU-NCs could be exploited as a potential oral delivery system to treat PD, by improving the poor bioavailability of PU and enhancing their delivery into the brain.