Oral Delivery of Puerarin Nanocrystals To Improve Brain Accumulation and Anti-Parkinsonian Efficacy

Abstract

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.

Preparation of Puerarin Chitosan Oral Nanoparticles by Ionic Gelation Method and Its Related Kinetics

“…It has a variety of biological functions and is widely used in various clinical fields. The ingredient can relieve coronary heart disease angina pectoris, provide adjuvant treatment for myocardial [1,2] and cerebral infarction, and promote the recovery of neurological functions [3][4][5]. However, Pur is a BCS IV drug with low oral bioavailability [6].…”

Zebrafish Models for the Safety and Therapeutic Testing of Nanoparticles with a Focus on Macrophages

“…Both studies demonstrated that nanosilica acted on the retina and dopaminergic neurons to change color preference and to cause PD-like behavior [ 62 , 214 ]. Puerarin has emerged as a promising herb-derived anti-Parkinsonism compound and puerarin nanocristals (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 [ 215 , 216 ]. Moreover, other NPs with alleged neuroprotective effects for treating PD, such as polymeric NPs of Ginkgolide B, have shown correct bioavailability and cerebral accumulation in zebrafish models [ 217 ].…”

Nanotechnology-Based Drug Delivery Strategies to Repair the Mitochondrial Function in Neuroinflammatory and Neurodegenerative Diseases

“…In order to increase bioavailability of natural compounds in determined organs, other nanosystems containing plant chemicals have been associated with targeting moieties (Table 3). Puerarin (PUE), an isoflavone able to revert mitochondrial dysfunction and promote mitochondrial biogenesis [223], with poor water solubility and permeability across the BBB, and short half-life [224,225]. PUE has been loaded on GO nanosheets linked to lactoferrin to bind to the vascular endothelial receptor on the BBB and to promote brain access of the therapeutic agent.…”