A Novel Delivery System of Cyclovirobuxine D for Brain Targeting: Angiopep-Conjugated Polysorbate 80-Coated Liposomes via Intranasal Administration

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.

Cyclovirobuxine D inhibits cell proliferation and migration and induces apoptosis in human glioblastoma multiforme and low‑grade glioma

“…In addition, CVB-D could regulate calcium levels inside the cells (23). Previous studies have suggested that calcium levels play an important role in tumor growth, apoptosis and differentiation (24)(25)(26). The hypothesis that CVB-D can promote tumor apoptosis by affecting calcium ion channels can be further explored in future studies and can aid the investigation of the antitumor activity of this compound.…”

Targeted Delivery of Intranasally Administered Cyclovirobuxine D Liposomes to Brain for Treatment Cerebral Ischemia-Reperfusion Injury via Anti-oxidative Stress and Activating Autophagy

“…Besides, there was a better targeting and higher AUC of CVBD in the brain after T80-An2-CVBD-Lps by intranasal administration. [15][16][17] Based on the superiority of nasal administration and nano preparations, therefore, this study focused on the protection of CVBD brain-targeted liposomes in CIRI to clarify the target and molecular mechanism of CVBD in treating CIRI, which can lay a foundation for innovative research and development of TNCM.…”

<p>Rhynchophylline Loaded-mPEG-PLGA Nanoparticles Coated with Tween-80 for Preliminary Study in Alzheimer’s Disease</p>

“…18,19 Nanotechnology-based drug delivery systems with good solubility, high bioavailability, less patient variability and prolonged circulation time provide new therapeutic strategy for AD with brain targeting TCM delivery across through the BBB. [20][21][22] A substance assisting in targeting drug delivery into the brain is Tween 80 (polysorbate 80), which is commonly coating the surfaces of nanoparticles for drug load and delivery. 23 Tween 80 can adsorb apolipoprotein E and enable the binding to the lipoprotein receptor-related proteins (LRPs).…”