Intranasal Administration of Self-Oriented Nanocarriers Based on Therapeutic Exosomes for Synergistic Treatment of Parkinson's Disease.

The treatment of Parkinson's disease (PD) has been hindered by the complex pathologies and multiple membrane barriers during drug delivery. Although exosomes derived from mesenchymal stem cells (MSCs) have great potential for PD, MSC-derived exosomes alone could not fully meet the therapeutic requirements due to their limitation in therapy and delivery. Here, we develop a self-oriented nanocarrier called PR-EXO/PP@Cur that combines therapeutic MSC-derived exosomes with curcumin. PR-EXO/PP@Cur can be self-oriented across the multiple membrane barriers and directly release drugs into the cytoplasm of target cells after intranasal administration. With enhanced accumulation of drugs in the action site, PR-EXO/PP@Cur achieves three-pronged synergistic treatment to deal with the complex pathologies of PD by reducing α-synuclein aggregates, promoting neuron function recovery, and alleviating the neuroinflammation. After treatment with PR-EXO/PP@Cur, the movement and coordination ability of PD model mice are significantly improved. These results show that PR-EXO/PP@Cur has great prospects in treatment of PD or other neurodegenerative diseases.

Osthole-Loaded Nanoemulsion Enhances Brain Target in the Treatment of Alzheimer's Disease via Intranasal Administration.

Osthole (OST) is a natural coumarin compound that exerts multiple pharmacologic effects. However, the poor water solubility and the low oral absorption of OST limit its clinical application for the treatment of neurologic diseases. A suitable preparation needs to be tailored to evade these unfavourable properties of OST. In this study, an OST nanoemulsion (OST-NE) was fabricated according to the pseudoternary phase diagram method, which was generally used to optimize the prescription in light of the solubility of OST in surfactants and cosurfactants. The final composition of OST-NE was 3.6% of ethyl oleate as oil phase, 11.4% of the surfactant (polyethylene glycol ester of 15-hydroxystearic acid: polyoxyethylene 35 castor oil = 1 : 1), 3% of polyethylene glycol 400 as cosurfactant, and 82% of the aqueous phase. The pharmacokinetic study of OST-NE showed that the brain-targeting coefficient of OST was larger by the nasal route than that by the intravenous route. Moreover, OST-NE inhibited cell death, decreased the apoptosis-related proteins (Bax and caspase-3), and enhanced the activity of antioxidant enzymes (superoxide dismutase and glutathione) in L-glutamate-induced SH-SY5Y cells. OST-NE improved the spatial memory ability, increased the acetylcholine content in the cerebral cortex, and decreased the activity of acetylcholinesterase in the hippocampus of Alzheimer's disease model mice. In conclusion, this study indicates that the bioavailability of OST was improved by using the OST-NE via the nasal route. A low dose of OST-NE maintained the neuroprotective effects of OST, such as inhibiting apoptosis and oxidative stress and regulating the cholinergic system. Therefore, OST-NE can be used as a possible alternative to improve its bioavailability in the prevention and treatment of Alzheimer's disease.