Polymeric Nanoparticles-Based Brain Delivery with Improved Therapeutic Efficacy of Ginkgolide B in Parkinson’s Disease

Abstract

Purpose Ginkgolide B (GB) is a terpene lactone derivative of Ginkgo biloba that is believed to function in a neuroprotective manner ideal for treating Parkinson’s disease (PD). Despite its promising therapeutic properties, GB has poor bioavailability following oral administration and cannot readily achieve sufficient exposure in treated patients, limiting its clinical application for the treatment of PD. In an effort to improve its efficacy, we utilized poly(ethylene glycol)-co-poly(ε-caprolactone) (PEG-PCL) nanoparticles as a means of encapsulating GB (GB-NPs). These NPs facilitated the sustained release of GB into the blood, thereby improving its ability to accumulate in the brain and to treat PD. Methods and Results Using Madin-Darby canine kidney (MDCK) cells, we were able to confirm that these NPs could be taken into cells via multiple nonspecific mechanisms including micropinocytosis, clathrin-dependent endocytosis, and lipid raft/caveolae-mediated endocytosis. Once internalized, these NPs tended to accumulate in the endoplasmic reticulum and lysosomes. In zebrafish, we determined that these NPs were readily able to undergo transport across the chorion, gastrointestinal, blood–brain, and blood-retinal barriers. In a 1-methyl-4-phenylpyridinium ion (MPP + )-induced neuronal damage model system, we confirmed the neuroprotective potential of these NPs. Following oral administration to rats, GB-NPs exhibited more desirable pharmacokinetics than did free GB, achieving higher GB concentrations in both the brain and the blood. Using a murine PD model, we demonstrated that these GB-NPs achieved superior therapeutic efficacy and reduced toxicity relative to free GB. Conclusion In conclusion, these results indicate that NPs encapsulation of GB can significantly improve its oral bioavailability, cerebral accumulation, and bioactivity via mediating its sustained release in vivo.

Therapeutic Applications of Terpenes on Inflammatory Diseases

“…Furthermore, Ginkgo-biloba-derived have nanoencapsulated and demonstrated anti-inflammatory effects in Parkinson´s disease and arthritis models (Han, 2005;Zhao et al, 2020). Similarly, lycopeneloaded nanoparticles could reduce the knee-joint thickness, and inhibit the total leukocyte infiltration, the mononuclear cells, and the neutrophils in the inflammation site in arthritis in vivo models (Meira et al, 2020).…”

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

“…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 ].…”

Neuroregulatory role of ginkgolides

“…Ginkgolide B achieves very poor water solubility, and oral administration exhibits low brain penetration and blood bioavailability. As for now, one of the improvements of oral absorption of ginkgolide B is an encapsulation of Ginkgolide B [52]. Interestingly other than EGB 761 Biloba extracts like 2 G or GBDP show even better effects against PD.…”