Rational Design of Thermosensitive Hydrogel to Deliver Nanocrystals with Intranasal Administration for Brain Targeting in Parkinson's Disease.

Yun Tan,Chuntai Liu,Rui Ma,Yi Zhang,Yao Liu,Jingshan Luo,Tongkai Chen,Xiaojia Chen,Huijie Hong,Yujing Liu,Shengpeng Wang

doi:10.34133/2021/9812523

Abstract

Mitochondrial dysfunction is commonly detected in individuals suffering from Parkinson's disease (PD), presenting within the form of excessive reactive oxygen species (ROS) generation as well as energy metabolism. Overcoming this dysfunction within brain tissues is an effective approach to treat PD, while unluckily, the blood-brain barrier (BBB) substantially impedes intracerebral drug delivery. In an effort to improve the delivery of efficacious therapeutic drugs to the brain, a drug delivery platform hydrogel (MAG-NCs@Gel) was designed by complexing magnolol (MAG)-nanocrystals (MAG-NCs) into the noninvasive thermosensitive poly(N-isopropylacrylamide) (PNIPAM) with self-gelation. The as-prepared MAG-NCs@Gel exhibited obvious improvements in drug solubility, the duration of residence with the nasal cavity, and the efficiency of brain targeting, respectively. Above all, continuous intranasal MAG-NCs@Gel delivery enabled MAG to cross the BBB and enter dopaminergic neurons, thereby effectively alleviating the symptoms of MPTP-induced PD. Taking advantage of the lower critical solution temperature (LCST) behavior of this delivery platform increases its viscoelasticity in nasal cavity, thus improving the efficiency of MAG-NCs transit across the BBB. As such, MAG-NCs@Gel represented an effective delivery platform capable of normalizing ROS and adenosine triphosphate (ATP) in the mitochondria of dopaminergic neurons, consequently reversing the mitochondrial dysfunction and enhancing the behavioral skills of PD mice without adversely affecting normal tissues.

Highlights

Parkinson’s disease (PD) is one of the most severe neurodegenerative diseases which affects approximately 2% of individuals over the age of 65, resulting in motor and nonmotor dysfunction because of the degenerating the dopaminergic neurons in the substantia nigra [1,2,3]
The dynamic light scattering (DLS) was initially used to assess the hydrated particle size of MAGcontaining NCs (MAG-NCs), which exhibited a mean diameter of 81:57 ± 1:48 nm and the mean particle distribution index (PDI) of 0:11 ± 0:02 (Figure S3a), and the mean hydrated MAG-NC particle size for storage one month was still 81-84 nm with PDI of 0.1-0.2 (Figure S3b), these indicating that MAG-NC remained stable for a month or more
Relative to the sizes of hydrated particles detected via DLS, TEM imaging suggested MAG-NCs to be somewhat smaller about 30 nm (Figure S3c), because TEM images revealed the true size of the drug NCs without accounting for the PVP-K30 coating or the electric double layer

Summary

Introduction

Parkinson’s disease (PD) is one of the most severe neurodegenerative diseases which affects approximately 2% of individuals over the age of 65, resulting in motor and nonmotor dysfunction because of the degenerating the dopaminergic neurons in the substantia nigra [1,2,3]. The exposure of these hydrogels to warmer temperatures within the nasal cavity can result in increased hydrogel viscoelasticity, thereby reducing the rate of mucociliary clearance and ensuring gradual sustained drug release Such a thermosensitive hydrogel delivery system has offered great potential to improve drug potency and to absorb significant amounts of water or biological fluids [41, 42]. As a self-gelation process, it is wonderful that the MAG-NCs@emulsion polymer changed from a fluid to a solid-like state during natural cooling, yielding the transparent polymer network MAG-NCs@Gel (Movie S1) This MAG-NCs@Gel preparation was intranasally injected into experimental model mice, whereupon it was able to penetrate the BBB to achieve effective drug release, thereby targeting mitochondria within neurons to reduce ROS generation and increase ATP levels as a treatment for PD (Figure 1(b)). Encapsulated MAG-NCs were able to efficiently transit across the BBB, improving their cerebral bioavailability and enabling the targeted treatment of PD

Results

Discussion

Conflicts of Interest