A biophysical insight of Camptothecin biodistribution: towards a molecular understanding of its pharmacokinetic issues
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Outros Autores: | , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/1822/74221 |
Resumo: | Camptothecin (CPT) is a potent anticancer drug, and its putative oral administration is envisioned although difficult due to physiological barriers that must be overcome. A comprehensive biophysical analysis of CPT interaction with biointerface models can be used to predict some pharmacokinetic issues after oral administration of this or other drugs. To that end, different models were used to mimic the phospholipid composition of normal, cancer, and blood–brain barrier endothelial cell membranes. The logD values obtained indicate that the drug is well distributed across membranes. CPT-membrane interaction studies also confirm the drug’s location at the membrane cooperative and interfacial regions. The drug can also permeate membranes at more ordered phases by altering phospholipid packing. The similar logD values obtained in membrane models mimicking cancer or normal cells imply that CPT has limited selectivity to its target. Furthermore, CPT binds strongly to serum albumin, leaving only 8.05% of free drug available to be distributed to the tissues. The strong interaction with plasma proteins, allied to the large distribution (VD<sub>SS</sub> = 5.75 ± 0.932 L·Kg<sup>−1</sup>) and tendency to bioaccumulate in off-target tissues, were predicted to be pharmacokinetic issues of CPT, implying the need to develop drug delivery systems to improve its biodistribution. |
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A biophysical insight of Camptothecin biodistribution: towards a molecular understanding of its pharmacokinetic issuesCamptothecinDrug distributionDrug-membrane interactionBiophysical profilingBiomimetic modelsPartition coefficientADMET/PK predictionSmall and wide-angle X-ray diffractionFluorescence spectroscopyHuman serum albumin (HSA)ADMETPK predictionScience & TechnologyCamptothecin (CPT) is a potent anticancer drug, and its putative oral administration is envisioned although difficult due to physiological barriers that must be overcome. A comprehensive biophysical analysis of CPT interaction with biointerface models can be used to predict some pharmacokinetic issues after oral administration of this or other drugs. To that end, different models were used to mimic the phospholipid composition of normal, cancer, and blood–brain barrier endothelial cell membranes. The logD values obtained indicate that the drug is well distributed across membranes. CPT-membrane interaction studies also confirm the drug’s location at the membrane cooperative and interfacial regions. The drug can also permeate membranes at more ordered phases by altering phospholipid packing. The similar logD values obtained in membrane models mimicking cancer or normal cells imply that CPT has limited selectivity to its target. Furthermore, CPT binds strongly to serum albumin, leaving only 8.05% of free drug available to be distributed to the tissues. The strong interaction with plasma proteins, allied to the large distribution (VD<sub>SS</sub> = 5.75 ± 0.932 L·Kg<sup>−1</sup>) and tendency to bioaccumulate in off-target tissues, were predicted to be pharmacokinetic issues of CPT, implying the need to develop drug delivery systems to improve its biodistribution.This work was supported by Fundação para a Ciência e Tecnologia (FCT) in the framework of the Strategic Funding [UID/FIS/04650/2019], and by the project CONCERT [POCI-01- 0145-FEDER-032651 and PTDC/NAN-MAT/326512017], co-financed by the European Regional Development Fund (ERDF), through COMPETE 2020, under Portugal 2020, and FCT I.P. The authors thank Elettra Sincrotone and Sigrid Bernstorff, Trieste, Italy, for beam time and support through the project 20155321. Marlene Lúcio thanks FCT and ERDF for doctoral position [CTTI-150/18-CF (1)] in the ambit of the project CONCERT. Andreia Almeida (SFRH/BD/118721/2016) and Eduarda Fernandes (SFRH/BD/147938/2019) grants are supported by FCT, POPH and FEDER/COMPETE.Multidisciplinary Digital Publishing Institute (MDPI)Universidade do MinhoAlmeida, AndreiaFernandes, EduardaSarmento, BrunoLúcio, M.2021-06-122021-06-12T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/1822/74221engAlmeida, A.; Fernandes, E.; Sarmento, B.; Lúcio, M. A Biophysical Insight of Camptothecin Biodistribution: Towards a Molecular Understanding of Its Pharmacokinetic Issues. Pharmaceutics 2021, 13, 869. https://doi.org/10.3390/pharmaceutics130608691999-492310.3390/pharmaceutics13060869https://www.mdpi.com/1999-4923/13/6/869info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-21T11:56:12Zoai:repositorium.sdum.uminho.pt:1822/74221Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:45:49.495632Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
A biophysical insight of Camptothecin biodistribution: towards a molecular understanding of its pharmacokinetic issues |
title |
A biophysical insight of Camptothecin biodistribution: towards a molecular understanding of its pharmacokinetic issues |
spellingShingle |
A biophysical insight of Camptothecin biodistribution: towards a molecular understanding of its pharmacokinetic issues Almeida, Andreia Camptothecin Drug distribution Drug-membrane interaction Biophysical profiling Biomimetic models Partition coefficient ADMET/PK prediction Small and wide-angle X-ray diffraction Fluorescence spectroscopy Human serum albumin (HSA) ADMET PK prediction Science & Technology |
title_short |
A biophysical insight of Camptothecin biodistribution: towards a molecular understanding of its pharmacokinetic issues |
title_full |
A biophysical insight of Camptothecin biodistribution: towards a molecular understanding of its pharmacokinetic issues |
title_fullStr |
A biophysical insight of Camptothecin biodistribution: towards a molecular understanding of its pharmacokinetic issues |
title_full_unstemmed |
A biophysical insight of Camptothecin biodistribution: towards a molecular understanding of its pharmacokinetic issues |
title_sort |
A biophysical insight of Camptothecin biodistribution: towards a molecular understanding of its pharmacokinetic issues |
author |
Almeida, Andreia |
author_facet |
Almeida, Andreia Fernandes, Eduarda Sarmento, Bruno Lúcio, M. |
author_role |
author |
author2 |
Fernandes, Eduarda Sarmento, Bruno Lúcio, M. |
author2_role |
author author author |
dc.contributor.none.fl_str_mv |
Universidade do Minho |
dc.contributor.author.fl_str_mv |
Almeida, Andreia Fernandes, Eduarda Sarmento, Bruno Lúcio, M. |
dc.subject.por.fl_str_mv |
Camptothecin Drug distribution Drug-membrane interaction Biophysical profiling Biomimetic models Partition coefficient ADMET/PK prediction Small and wide-angle X-ray diffraction Fluorescence spectroscopy Human serum albumin (HSA) ADMET PK prediction Science & Technology |
topic |
Camptothecin Drug distribution Drug-membrane interaction Biophysical profiling Biomimetic models Partition coefficient ADMET/PK prediction Small and wide-angle X-ray diffraction Fluorescence spectroscopy Human serum albumin (HSA) ADMET PK prediction Science & Technology |
description |
Camptothecin (CPT) is a potent anticancer drug, and its putative oral administration is envisioned although difficult due to physiological barriers that must be overcome. A comprehensive biophysical analysis of CPT interaction with biointerface models can be used to predict some pharmacokinetic issues after oral administration of this or other drugs. To that end, different models were used to mimic the phospholipid composition of normal, cancer, and blood–brain barrier endothelial cell membranes. The logD values obtained indicate that the drug is well distributed across membranes. CPT-membrane interaction studies also confirm the drug’s location at the membrane cooperative and interfacial regions. The drug can also permeate membranes at more ordered phases by altering phospholipid packing. The similar logD values obtained in membrane models mimicking cancer or normal cells imply that CPT has limited selectivity to its target. Furthermore, CPT binds strongly to serum albumin, leaving only 8.05% of free drug available to be distributed to the tissues. The strong interaction with plasma proteins, allied to the large distribution (VD<sub>SS</sub> = 5.75 ± 0.932 L·Kg<sup>−1</sup>) and tendency to bioaccumulate in off-target tissues, were predicted to be pharmacokinetic issues of CPT, implying the need to develop drug delivery systems to improve its biodistribution. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-06-12 2021-06-12T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/1822/74221 |
url |
http://hdl.handle.net/1822/74221 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Almeida, A.; Fernandes, E.; Sarmento, B.; Lúcio, M. A Biophysical Insight of Camptothecin Biodistribution: Towards a Molecular Understanding of Its Pharmacokinetic Issues. Pharmaceutics 2021, 13, 869. https://doi.org/10.3390/pharmaceutics13060869 1999-4923 10.3390/pharmaceutics13060869 https://www.mdpi.com/1999-4923/13/6/869 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Multidisciplinary Digital Publishing Institute (MDPI) |
publisher.none.fl_str_mv |
Multidisciplinary Digital Publishing Institute (MDPI) |
dc.source.none.fl_str_mv |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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