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Eur J Pharm Biopharm. 2019 Jun;139:197-204. doi: 10.1016/j.ejpb.2019.04.004. Epub 2019 Apr 2.

Targeted brain delivery of methotrexate by glutathione PEGylated liposomes: How can the formulation make a difference?

Author information

1
Translational PKPD Research Group, Department of Pharmaceutical Biosciences, Associate Member of SciLife Lab, Uppsala University, Uppsala, Sweden.
2
2-BBB Medicines B.V., J.H. Oortweg 19, 2333CH Leiden, the Netherlands.
3
Predictive Pharmacology Group, Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands.
4
Translational PKPD Research Group, Department of Pharmaceutical Biosciences, Associate Member of SciLife Lab, Uppsala University, Uppsala, Sweden. Electronic address: mhu@farmbio.uu.se.

Abstract

The purpose of this study was to quantitatively investigate how conjugation of GSH to different liposomal formulations influence the brain delivery of methotrexate (MTX) in rats. GSH-PEG liposomal MTX based on hydrogenated soy phosphatidylcholine (HSPC) or egg yolk phosphatidylcholine (EYPC) and their corresponding PEG control liposomes were prepared. The brain delivery of MTX after intravenously administering free MTX, four liposomal formulations or free MTX + empty GSH-PEG-HSPC liposomes was evaluated by performing microdialysis in brain interstitial fluid and blood. Compared to free MTX with a steady-state unbound brain-to-plasma concentration ratio (Kp,uu) of 0.10, PEG-HSPC liposomes did not affect the brain uptake of MTX, while PEG-EYPC liposomes improved the uptake (Kp,uu 1.5, p < 0.05). Compared to PEG control formulations, GSH-PEG-HSPC liposomes increased brain delivery of MTX by 4-fold (Kp,uu 0.82, p < 0.05), while GSH-coating on PEG-EYPC liposomes did not result in a further enhancement in uptake. The co-administration of empty GSH-PEG-HSPC liposomes with free MTX did not influence the uptake of MTX into the brain. This work showed that the brain-targeting effect of GSH-PEG liposomal MTX is highly dependent on the liposomal formulation that is combined with GSH, providing insights on formulation optimization of this promising brain delivery platform.

KEYWORDS:

Brain delivery; Brain-targeting; Formulation; Glutathione; Liposomes; Methotrexate; Microdialysis

PMID:
30951819
DOI:
10.1016/j.ejpb.2019.04.004
[Indexed for MEDLINE]

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