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The Impact of Liposomal Formulations on the Release and Brain Delivery of Methotrexate: An In Vivo Microdialysis Study
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab. (Translationell PKPD)
Eyesiu Med BV, JH Oortweg 19, NL-2333 Leiden, Netherlands..
Eyesiu Med BV, JH Oortweg 19, NL-2333 Leiden, Netherlands.;2 BBB Med BV, JH Oortweg 19, NL-2333 Leiden, Netherlands..
Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Cluster Syst Pharmacol, Leiden, Netherlands..
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2017 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 106, no 9, p. 2606-2613Article in journal (Refereed) Published
Abstract [en]

The impact of liposomal formulations on the in vivo release and brain delivery of methotrexate (MTX) was quantitatively assessed in rats. Two PEGylated liposomal MTX formulations based on hydrogenated soy phosphatidylcholine (HSPC) or egg-yolk phosphatidylcholine (EYPC) were prepared. The drug release and uptake into the brain after intravenous administration of both formulations were compared with unformulated MTX by determining the released, unbound MTX in brain and plasma using microdialysis. Total MTX concentrations in plasma were determined using regular blood sampling. The administration of both high-and low-dose EYPC liposomes resulted in 10 times higher extent of MTX release in plasma compared to that obtained from HSPC liposomes (p < 0.05). MTX itself possessed limited brain uptake with steady-state unbound brain-to-plasma concentration ratio (K-p,K-uu) of 0.10 +/- 0.06. Encapsulation in HSPC liposomes did not affect MTX brain uptake (K-p,K-uu 0.11 +/- 0.05). In contrast, EYPC liposomes significantly improved MTX brain delivery with a 3-fold increase of Kp, uu (0.28 +/- 0.14 and 0.32 +/- 0.13 for high-and low-dose EYPC liposomal MTX, respectively, p < 0.05). These results provide unique quantitative evidence that liposomal formulations based on different phospholipids can result in very different brain delivery of MTX.

Place, publisher, year, edition, pages
2017. Vol. 106, no 9, p. 2606-2613
Keywords [en]
liposome, nanocarrier, blood-brain barrier, brain delivery, in vivo release, microdialysis, methotrexate
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-344533DOI: 10.1016/j.xphs.2017.03.009ISI: 000417339900053PubMedID: 28322936OAI: oai:DiVA.org:uu-344533DiVA, id: diva2:1188431
Funder
Swedish Research Council, 521-2011-4339Available from: 2018-03-07 Created: 2018-03-07 Last updated: 2018-03-07Bibliographically approved

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