Investigation of glucose-modified liposomes using polyethylene glycols with different chain lengths as the linkers for brain targeting

Abstract

Background An intimidating challenge to transporting drugs into the brain parenchyma is the presence of the blood–brain barrier (BBB). Glucose is an essential nutritional substance for brain function sustenance, which cannot be synthesized by the brain. Its transport primarily depends on the glucose transporters on the brain capillary endothelial cells. In this paper, the brain-targeted properties of glucose-modified liposomes using polyethylene glycols with different chain lengths as the linkers were compared and evaluated to establish an optimized drug-delivery system. Methods Coumarin 6-loaded liposomes (GLU200-LIP, GLU400-LIP, GLU1000-LIP, and GLU2000-LIP) composed of phospholipids and glucose-derived cholesterols were prepared by thin-film dispersion-ultrasound method. The BBB model in vitro was developed to evaluate the transendothelial ability of the different liposomes crossing the BBB. The biodistribution of liposomes in the mice brains was identified by in vivo and ex vivo nearinfrared fluorescence imaging and confocal laser scanning microscopy and further analyzed quantitatively by high-performance liquid chromatography. Results Glucose-derived cholesterols were synthesized and identified, and coumarin 6-loaded liposomes were prepared successfully. The particle sizes of the four types of glucose-modified liposomes were around or smaller than 100 nm with a polydispersity index less than 0.300. GLU400-LIP, GLU1000-LIP, and GLU2000-LIP achieved higher cumulative cleared volumes on BBB model in vitro after 6 hours compared with GLU200-LIP ( P < 0.05) and were significantly higher than that of the conventional liposome ( P < 0.001). The qualitative and quantitative biodistribution results in the mice showed that the accumulation of GLU1000-LIP in the brain was the highest among all the groups ( P < 0.01 versus LIP). Conclusion The data indicated that GLU400-LIP, GLU1000-LIP, and GLU2000-LIP all possess the potential of brain targeting, among which GLU1000-LIP, as a promising drug-delivery system, exhibited the strongest brain delivery capacity.

Glycosylated Sertraline-Loaded Liposomes for Brain Targeting: QbD Study of Formulation Variabilities and Brain Transport

“…Qin and coworkers have utilized N-acetyl glucosamine (NAG) as a ligand for the GLUT1 to deliver Coumarin-6, as fluorescent probe, to brain cells (11). Moreover, Xie and coworkers demonstrated that the water solubility of NAG led to greater cellular internalization capacity of the pegylated-glycosylated liposomes (12). They have also reported that high PEG surface modification may retard the targeting capacity of the liposome to endothelial cells due to the steric hindrance, whereas low content of PEG may obstruct the exposure to GLUT receptors (12).…”

In vitro screening of nanomedicines through the blood brain barrier: A critical review

“…To this end, a plethora of techniques has been used to verify in vivo the preliminary results obtained with the cellbased assays, namely scintigraphy [324][325][326], near-infrared in vivo imaging [327][328][329][330][331][332][333], ex vivo optical imaging [301,334], confocal microscopy [309,317], chromatographic quantification [307,312,315,335] and pharmacodynamics studies [281,285,336]. In all cases, the consistency between the results from in vitro and in vivo studies was evidenced.…”

“…The main conclusions from the results of the studies presented in Table 7, include the fact that an increase in the size of the nanocarrier yields a decrease in the BBB permeability coefficient [297][298][299][300][301][302][303][304][305] and that nanoparticle surface plays a key role in BBB permeability (in terms of surface coating [306] and surface charge, with enhanced permeability values for cationic charges [302,307,308]). Overall, drug loading onto nanocarriers enhances BBB permeability and this enhancement often follows a timedependent pattern [309][310][311][312][313][314][315].…”

Current approaches to enhance CNS delivery of drugs across the brain barriers

“…Its transport primarily depends on the glucose transporters on the brain capillary endothelial cells. Xie et al 62 showed that the glucosemodified liposomes GLU1000-LIP exhibit a strong brain delivery capacity.…”