Quantitative Aspects of Nanodelivery Across the Blood-Brain Barrier : Exemplified with the Opioid Peptide DAMGO
The use of nanocarriers is an intriguing approach in the development of efficacious treatment for brain disorders. The aim of the conducted research was to evaluate and quantify the impact of a liposomal nanocarrier formulation on the brain drug delivery. A novel approach for investigating the blood...
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Uppsala universitet, Institutionen för farmaceutisk biovetenskap
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ndltd-UPSALLA1-oai-DiVA.org-uu-2675992016-01-14T04:52:24ZQuantitative Aspects of Nanodelivery Across the Blood-Brain Barrier : Exemplified with the Opioid Peptide DAMGOengLindqvist, AnnikaUppsala universitet, Institutionen för farmaceutisk biovetenskapUppsala2015blood-brain barrierliposomesnanocarriersbrain deliverypharmacokineticsmodeling and simulationmicrodialysisopioid peptideDAMGOLC-MS/MSThe use of nanocarriers is an intriguing approach in the development of efficacious treatment for brain disorders. The aim of the conducted research was to evaluate and quantify the impact of a liposomal nanocarrier formulation on the brain drug delivery. A novel approach for investigating the blood-brain barrier transport of liposomal DAMGO is presented, including in vivo microdialysis in rat, a high quality LC-MS/MS bioanalytical method and pharmacokinetic model analysis of the data. Factors limiting the brain distribution of the free peptide DAMGO were also investigated. Microdialysis, in combination with plasma sampling, made it possible to separate the released drug from the encapsulated and to quantify the active substance in both blood and brain interstitial fluid over time. The opioid peptide DAMGO entered the brain to a limited extent, with a clearance out of the brain 13 times higher than the clearance into the brain. The brain to blood ratio of unbound drug was not affected when the efflux transporter inhibitors cyclosporine A and elacridar were co-administered with DAMGO. Nor was the transport affected in the in vitro Caco-2 assay using the same inhibitors. This indicates that DAMGO is not transported by P-glycoprotein (Pgp) or breast cancer resistant protein (Bcrp). The blood-brain barrier transport was significantly increased for DAMGO when formulated in liposomes, resulting in 2-3 fold higher brain to blood ratio of unbound DAMGO. The increased brain delivery was seen both for glutathione tagged PEGylated liposomes, as well as for PEGyalted liposomes without specific brain targeting. The improvement in brain delivery was observed only when DAMGO was encapsulated into the liposomes, thus excluding any effect of the liposomes themselves on the integrity of the blood-brain barrier. Modeling of the data provided additional mechanistic understanding of the brain uptake, showing that endocytosis or transcytosis of intact liposomes across the endothelial cell membranes were unlikely. A model describing fusion of the liposomes with the luminal membrane described the experimental data the best. In conclusion, the studies presented in this thesis all contribute to an increased understanding of how to evaluate and improve brain delivery of CNS active drugs and contribute with important insights to the nanocarrier field. Doctoral thesis, comprehensive summaryinfo:eu-repo/semantics/doctoralThesistexthttp://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-267599urn:isbn:978-91-554-9428-5Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, 1651-6192 ; 208application/pdfinfo:eu-repo/semantics/openAccess |
collection |
NDLTD |
language |
English |
format |
Doctoral Thesis |
sources |
NDLTD |
topic |
blood-brain barrier liposomes nanocarriers brain delivery pharmacokinetics modeling and simulation microdialysis opioid peptide DAMGO LC-MS/MS |
spellingShingle |
blood-brain barrier liposomes nanocarriers brain delivery pharmacokinetics modeling and simulation microdialysis opioid peptide DAMGO LC-MS/MS Lindqvist, Annika Quantitative Aspects of Nanodelivery Across the Blood-Brain Barrier : Exemplified with the Opioid Peptide DAMGO |
description |
The use of nanocarriers is an intriguing approach in the development of efficacious treatment for brain disorders. The aim of the conducted research was to evaluate and quantify the impact of a liposomal nanocarrier formulation on the brain drug delivery. A novel approach for investigating the blood-brain barrier transport of liposomal DAMGO is presented, including in vivo microdialysis in rat, a high quality LC-MS/MS bioanalytical method and pharmacokinetic model analysis of the data. Factors limiting the brain distribution of the free peptide DAMGO were also investigated. Microdialysis, in combination with plasma sampling, made it possible to separate the released drug from the encapsulated and to quantify the active substance in both blood and brain interstitial fluid over time. The opioid peptide DAMGO entered the brain to a limited extent, with a clearance out of the brain 13 times higher than the clearance into the brain. The brain to blood ratio of unbound drug was not affected when the efflux transporter inhibitors cyclosporine A and elacridar were co-administered with DAMGO. Nor was the transport affected in the in vitro Caco-2 assay using the same inhibitors. This indicates that DAMGO is not transported by P-glycoprotein (Pgp) or breast cancer resistant protein (Bcrp). The blood-brain barrier transport was significantly increased for DAMGO when formulated in liposomes, resulting in 2-3 fold higher brain to blood ratio of unbound DAMGO. The increased brain delivery was seen both for glutathione tagged PEGylated liposomes, as well as for PEGyalted liposomes without specific brain targeting. The improvement in brain delivery was observed only when DAMGO was encapsulated into the liposomes, thus excluding any effect of the liposomes themselves on the integrity of the blood-brain barrier. Modeling of the data provided additional mechanistic understanding of the brain uptake, showing that endocytosis or transcytosis of intact liposomes across the endothelial cell membranes were unlikely. A model describing fusion of the liposomes with the luminal membrane described the experimental data the best. In conclusion, the studies presented in this thesis all contribute to an increased understanding of how to evaluate and improve brain delivery of CNS active drugs and contribute with important insights to the nanocarrier field. |
author |
Lindqvist, Annika |
author_facet |
Lindqvist, Annika |
author_sort |
Lindqvist, Annika |
title |
Quantitative Aspects of Nanodelivery Across the Blood-Brain Barrier : Exemplified with the Opioid Peptide DAMGO |
title_short |
Quantitative Aspects of Nanodelivery Across the Blood-Brain Barrier : Exemplified with the Opioid Peptide DAMGO |
title_full |
Quantitative Aspects of Nanodelivery Across the Blood-Brain Barrier : Exemplified with the Opioid Peptide DAMGO |
title_fullStr |
Quantitative Aspects of Nanodelivery Across the Blood-Brain Barrier : Exemplified with the Opioid Peptide DAMGO |
title_full_unstemmed |
Quantitative Aspects of Nanodelivery Across the Blood-Brain Barrier : Exemplified with the Opioid Peptide DAMGO |
title_sort |
quantitative aspects of nanodelivery across the blood-brain barrier : exemplified with the opioid peptide damgo |
publisher |
Uppsala universitet, Institutionen för farmaceutisk biovetenskap |
publishDate |
2015 |
url |
http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-267599 http://nbn-resolving.de/urn:isbn:978-91-554-9428-5 |
work_keys_str_mv |
AT lindqvistannika quantitativeaspectsofnanodeliveryacrossthebloodbrainbarrierexemplifiedwiththeopioidpeptidedamgo |
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