No abstract

The blood-brain barrier (BBB) poses a challenge for the treatment of cerebrovascular diseases including cerebral ischemia-reperfusion injury, Parkinson's syndrome, and cerebral tumors. Nanotechnology has developed as a promising strategy for drug delivery applications to the brain, especially liposomes (Lps) that have shown an intrinsic ability to cross the BBB. Angiopep-2 (ANG), a ligand for low-density lipoprotein receptor-related protein-1 (LRP1), is a good prospect for use as a targeting ligand for brain delivery using Lps. It was also reported that Polysorbate 80 (Tween 80, T80) plays a special role in brain targeting. Moreover, the nasal drug delivery method has attracted increased attention with its brain targeting capability in the clinical treatment of cerebrovascular diseases. The aim of this work was to evaluate the capability of Angiopep-conjugated Polysorbate 80-Coated Liposomes in the delivery of cyclovirobuxine D across the BBB in vitro and in vivo. For this purpose, we first synthesized DSPE-PEG2000-Angiopep-2 then cyclovirobuxine D was encapsulated in Angiopep-conjugated Polysorbate 80-Coated Liposomes (T80-An2-CVB-D-Lps) prepared by thin film evaporation and an ultrasonic technique. Formulations were characterized in terms of encapsulation efficiency, transmission electron microscope (TEM) morphology, size distribution, and zeta potential. Angiopep-conjugated Polysorbate 80-Coated Liposomes enhanced in vitro BBB transport of CVB-D compared to the nontargeted liposomes and the CVB-D solution in the BBB model consisting of brain microvascular endothelial (bEnd.3) cells. To evaluate the brain targeting of T80-An2-CVB-D-Lps in vivo, microdialysis samples were collected from the striatum and blood simultaneously. Rats were dosed with brain-targeting liposomes, CVB-D liposomes and CVB-D solution by intranasal administration and with brain-targeting liposomes by intravenous injection. The results showed that T80-An2-CVB-D-Lps were spherical, small (approximately 80 nm), homogeneously dispersed, negatively charged and possessed a high encapsulation efficiency. T80-An2-CVB-D-Lps crossed the BBB model better than the other treatments did. In addition, in a pharmacodynamic study, there was a higher AUC in the brain after T80-An2-CVB-D-Lps by intranasal administration. In conclusion, T80-An2-Lps can enhance the BBB permeability and improve the transport of CVB-D to the brain. This coadministration strategy can be utilized to enhance the brain accumulation in other cerebrovascular diseases.

The blood-brain barrier (BBB) restricts the delivery of most drugs to the brain. In our previous study, the feasibility of cyclovirobuxine D delivery to the brain by a non-invasive nasal route was evaluated. In this study, a suitable drug delivery system by way of intranasal administration was developed, which could improve brain targeting. First, a formulation of cyclovirobuxine D (CVB-D) based on chitosan nanoparticles (CS-CVB-D-NPs) was prepared by the modified ionotropic gelation method through single-factor screening experiment. The CS-CVB-D-NPs with a entrapment efficiency (EE) of (62.82±2.59)% were found to be of a narrow polydispersity index (PI) (0.19±0.01) and (235.37± 12.71) nm in size, with a zeta potential of (33.9 ± 1.7) mV. The NPs possessed a sustained release characterization with in vitro release of 88.03 ± 2.30% at 24 h. In vivo, the higher AUC0-t(brain) of CS-CVB-D-NPs by intranasal administration revealed the development of a novel brain-targeting delivery method of CVB-D.

oxidative stress is a pathophysiological condition resulting in neurotoxicity, which is possibly associated with neurodegenerative disorders. in this study, the antioxidative effects of the antioxidant astaxanthin (aXT) in combination with huperzine a (Hupa), which is used as a cholinesterase inhibitor for the treatment of alzheimer's disease, were investigated. Pc12 cells were treated with either tert-butyl hydroperoxide (TBHP), or with the toxic version of β-amyloid, aβ 25-35 , to induce oxidative stress and neurotoxicity. cell viability, morphology, lactate dehydrogenase (ldH) release, intracellular accumulation of reactive oxygen species (roS), superoxide dismutase (Sod) activity and malondialdehyde (Mda) content were determined, while neuroprotection was also monitored using an MTT assay. it was found that combining AXT with HupA significantly increased the viability of PC12 cells, prevented membrane damage (as measured by ldH release), attenuated intracellular roS formation, increased Sod activity and decreased the level of Mda after TBHP exposure when compared to these drugs administered alone. Pretreatment with Hupa and aXT decreased toxic damage produced by aβ 25-35. These data indicated that combining an antioxidant with a cholinesterase inhibitor increases the degree of neuroprotection; with future investigation this could be a potential therapy used to decrease neurotoxicity in the brain.