uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Targeted Brain Delivery of Methotrexate by Glutathione PEGylated Liposomes: How can the Formulation Make a Difference?
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab. (Translational PKPD)ORCID iD: 0000-0002-8702-6654
2-BBB Medicine B.V..
Leiden University.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab. (Translational PKPD)ORCID iD: 0000-0002-9181-1321
2019 (English)In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 139, p. 197-204Article in journal (Refereed) Published
Abstract [en]

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-toplasma concentration ratio (K-p,K-uu) of 0.10, PEG-HSPC liposomes did not affect the brain uptake of MTX, while PEG-EYPC liposomes improved the uptake (K-p,(uu) 1.5, p < 0.05). Compared to PEG control formulations, GSHPEG-HSPC liposomes increased brain delivery of MTX by 4-fold (K-p,(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 GSHPEG-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.

Place, publisher, year, edition, pages
2019. Vol. 139, p. 197-204
Keywords [en]
Brain delivery, Brain-targeting, Liposomes, Glutathione, Formulation, Methotrexate, Microdialysis
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science; Pharmacokinetics and Drug Therapy
Identifiers
URN: urn:nbn:se:uu:diva-365858DOI: 10.1016/j.ejpb.2019.04.004ISI: 000468711400021PubMedID: 30951819OAI: oai:DiVA.org:uu-365858DiVA, id: diva2:1263255
Available from: 2018-11-14 Created: 2018-11-14 Last updated: 2019-06-19Bibliographically approved
In thesis
1. Drug Delivery to the Brain by Liposomes: Understanding Factors Governing Delivery Outcomes In Vivo
Open this publication in new window or tab >>Drug Delivery to the Brain by Liposomes: Understanding Factors Governing Delivery Outcomes In Vivo
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The blood-brain barrier (BBB) is the primary obstacle for efficient drug delivery to the central nervous system (CNS). One promising strategy to enhance brain delivery is to utilize nanocarriers (NC), e.g., liposomes, encapsulating CNS drugs. However, there is still a lack of understanding of how carrier- and payload-associated factors with liposomal brain delivery may influence brain drug uptake and ultimately therapeutic performance. In this thesis, the impact of factors including the liposomal formulation, the addition of a BBB-targeting ligand and the BBB transport properties of the payload itself on brain drug delivery were quantitatively investigated in vivo with microdialysis. Furthermore, by using a model-based approach, the benefits of NCs with different properties to increase the therapeutic index of CNS drugs were studied and key parameters influencing the therapeutic performance were identified.

The formulation of PEGylated (PEG) liposomes could significantly influence brain delivery of methotrexate (MTX). Compared to free MTX, PEG liposomes based on egg-yolk phosphatidylcholine (EYPC) increased brain uptake of MTX by 3-fold, while the formulation based on hydrogenated soy phosphatidylcholine (HSPC) did not affect the uptake at all. Also, PEG liposomes could influence the BBB transport of payloads differently, depending on if the payload itself show active uptake or efflux at the BBB. For diphenhydramine (DPH), a drug with active uptake at the BBB, PEG-EYPC liposomes significantly reduced its uptake into the brain. Moreover, the brain-targeting effect of glutathione (GSH)-tagged PEG liposomal MTX was highly dependent on the liposomal formulation that is combined with GSH. Compared to the PEG control formulations, GSH-PEG-HSPC liposomes increased brain delivery of MTX 4-fold, while GSH-coating on PEG-EYPC liposomes did not further enhance the uptake. In the last simulation study, two independent processes of nanodelivery to the brain were identified. A NC only prolonging circulation time increases the therapeutic index by reducing peripheral toxicity, while a NC with increased circulation time and brain uptake improves the therapeutic index due to both elevated central effect and decreased peripheral toxicity. Faster in vivo drug release and faster systemic elimination of the intact NC reduce the therapeutic performance. A drug with shorter half-life will obtain more therapeutic benefit from NC-encapsulation.

In summary, this thesis work contributes to a better understanding of factors governing the success of liposomal brain delivery and gives important insights on what needs to be considered and how to optimize the properties of a NC when developing NC-based strategies for treating CNS diseases.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 60
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 263
Keywords
nanocarrier, liposome, blood-brain barrier, brain delivery, formulation, methotrexate, diphenhydramine, microdialysis, pharmacokinetics, model-based approach
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science; Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-366375 (URN)978-91-513-0511-0 (ISBN)
Public defence
2019-01-11, Room B21, Biomedicinskt centrum (BMC), Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2018-12-20 Created: 2018-11-20 Last updated: 2019-01-21

Open Access in DiVA

No full text in DiVA

Other links

Publisher's full textPubMed

Authority records BETA

Hu, YangHammarlund-Udenaes, Margareta

Search in DiVA

By author/editor
Hu, YangHammarlund-Udenaes, Margareta
By organisation
Department of Pharmaceutical BiosciencesScience for Life Laboratory, SciLifeLab
In the same journal
European journal of pharmaceutics and biopharmaceutics
Pharmaceutical Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 93 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf