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In Vivo Quantitative Understanding of PEGylated Liposome’s Influence on Brain Delivery of Diphenhydramine
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 Med BV, Leiden, Netherlands.
Nanomi BV, Oldenzaal, Netherlands.
Leiden Univ, Leiden Acad Ctr Drug Res, Div Syst Biomed & Pharmacol, Predict Pharmacol Grp, Leiden, Netherland.
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2018 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 15, no 12, p. 5493-5500Article in journal (Refereed) Published
Abstract [en]

Despite the promising features of liposomes as brain drug delivery vehicles, it remains uncertain how they influence the brain uptake in vivo. In order to gain a better fundamental understanding of the interaction between liposomes and the blood–brain barrier (BBB), it is indispensable to test if liposomes affect drugs with different BBB transport properties (active influx or efflux) differently. The aim of this study was to quantitatively evaluate how PEGylated (PEG) liposomes influence brain delivery of diphenhydramine (DPH), a drug with active influx at the BBB, in rats. The brain uptake of DPH after 30 min intravenous infusion of free DPH, PEG liposomal DPH, or free DPH + empty PEG liposomes was compared by determining the unbound DPH concentrations in brain interstitial fluid and plasma with microdialysis. Regular blood samples were taken to measure total DPH concentrations in plasma. Free DPH was actively taken up into the brain time-dependently, with higher uptake at early time points followed by an unbound brain-to-plasma exposure ratio (Kp,uu) of 3.0. The encapsulation in PEG liposomes significantly decreased brain uptake of DPH, with a reduction of Kp,uu to 1.5 (p < 0.05). When empty PEG liposomes were coadministered with free drug, DPH brain uptake had a tendency to decrease (Kp,uu 2.3), and DPH was found to bind to the liposomes. This study showed that PEG liposomes decreased the brain delivery of DPH in a complex manner, contributing to the understanding of the intricate interactions between drug, liposomes, and the BBB.

Place, publisher, year, edition, pages
2018. Vol. 15, no 12, p. 5493-5500
Keywords [en]
nanocarrier, liposome, blood-brain barrier, brain uptake, microdialysis, diphenhydramine
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science; Pharmacokinetics and Drug Therapy
Identifiers
URN: urn:nbn:se:uu:diva-365857DOI: 10.1021/acs.molpharmaceut.8b00611ISI: 000452344600006PubMedID: 30376346OAI: oai:DiVA.org:uu-365857DiVA, id: diva2:1263252
Available from: 2018-11-14 Created: 2018-11-14 Last updated: 2019-01-22Bibliographically 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)
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Available from: 2018-12-20 Created: 2018-11-20 Last updated: 2019-01-21

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Hu, YangHammarlund-Udenaes, Margareta

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