Glutathione PEGylated liposomes: pharmacokinetics and delivery of cargo across the blood–brain barrier in rats

Abstract

Partly due to poor blood–brain barrier drug penetration the treatment options for many brain diseases are limited. To safely enhance drug delivery to the brain, glutathione PEGylated liposomes (G-Technology®) were developed. In this study, in rats, we compared the pharmacokinetics and organ distribution of GSH-PEG liposomes using an autoquenched fluorescent tracer after intraperitoneal administration and intravenous administration. Although the appearance of liposomes in the circulation was much slower after intraperitoneal administration, comparable maximum levels of long circulating liposomes were found between 4 and 24 h after injection. Furthermore, 24 h after injection a similar tissue distribution was found. To investigate the effect of GSH coating on brain delivery in vitro uptake studies in rat brain endothelial cells (RBE4) and an in vivo brain microdialysis study in rats were used. Significantly more fluorescent tracer was found in RBE4 cell homogenates incubated with GSH-PEG liposomes compared to non-targeted PEG liposomes (1.8-fold, p < 0.001). In the microdialysis study 4-fold higher (p < 0.001) brain levels of fluorescent tracer were found after intravenous injection of GSH-PEG liposomes compared with PEG control liposomes. The results support further investigation into the versatility of GSH-PEG liposomes for enhanced drug delivery to the brain within a tolerable therapeutic window.

In vivo Functional Evaluation of Increased Brain Delivery of the Opioid Peptide DAMGO by Glutathione-PEGylated Liposomes

“…These results are not in line with previous studies where a benefit of GSH coating was shown using the brain microdialysis technique studying ribavirin (J. Rip, unpublished observations) and carboxyfluorescein (13). A beneficial influence from the GSH-PEG liposomes was also indicated when a different approach with cerebral open-flow microperfusion (cOFM) was used to study doxorubicin (16).…”

“…Maybe even more importantly, the hydrophilic nature of DAMGO affected the choice of liposomal composition. The liposomal formulation of DAMGO contained a different phospholipid from that used in the formulations of the other molecules (EYPC vs hydrogenated soy phosphatidylcholine; HSPC) (13)(14)(15). EYPC results in a less stable liposomal formulation, which is required to enable in vivo release of the more hydrophilic DAMGO from the liposomes.…”

“…GSH-PEG liposomes have shown advantageous properties in both in vitro and in vivo studies in addition to ours. The uptake of GSH-PEG liposomes was significantly greater than the uptake of control liposomes in brain endothelial cells in one in vitro study (13). Encapsulation of methylprednisolone in the GSHcoated PEG liposomes improved its therapeutic efficacy in acute experimental autoimmune encephalomyelitis (EAE) in mice compared to that of the drug in non-coated PEG liposomes (14).…”

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

“…Several mechanisms and strategies were proposed to mediate this targeting potential and improve drug bioavailability in the brain. Surfacemodified liposomes with polyethylene glycol (PEG) are widely used to thwart their recognition by the reticuendothelial system (RES), hence extends their residence time in blood (2,3). The specificity of liposomes toward an endothelial target can be accomplished by modifying the vesicular surface with certain homing devices, namely receptor agonists, antagonists, or antibodies (4).…”

Liposomes Containing Phytochemicals for Cancer Treatment-an Update

“…They usually cause due to abnormal proliferation of glial cells which provide support and protection to neurons. Glioma is accounts for 29% of all primary brain tumors and 80% of malignant tumors [38].…”