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Evaluation of Riboflavin Transporters as Targets for Drug Delivery and Theranostics
The retention and cellular internalization of drug delivery systems and theranostics for cancer therapy can be improved by targeting molecules. Since an increased uptake of riboflavin was reported for various cancers, riboflavin and its derivatives may be promising binding moieties to trigger intern...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372557/ https://www.ncbi.nlm.nih.gov/pubmed/30787877 http://dx.doi.org/10.3389/fphar.2019.00079 |
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author | Bartmann, Lisa Schumacher, David von Stillfried, Saskia Sternkopf, Marieke Alampour-Rajabi, Setareh van Zandvoort, Marc A. M. J. Kiessling, Fabian Wu, Zhuojun |
author_facet | Bartmann, Lisa Schumacher, David von Stillfried, Saskia Sternkopf, Marieke Alampour-Rajabi, Setareh van Zandvoort, Marc A. M. J. Kiessling, Fabian Wu, Zhuojun |
author_sort | Bartmann, Lisa |
collection | PubMed |
description | The retention and cellular internalization of drug delivery systems and theranostics for cancer therapy can be improved by targeting molecules. Since an increased uptake of riboflavin was reported for various cancers, riboflavin and its derivatives may be promising binding moieties to trigger internalization via the riboflavin transporters (RFVT) 1, 2, and 3. Riboflavin is a vitamin with pivotal role in energy metabolism and indispensable for cellular growth. In previous preclinical studies on mice, we showed the target-specific accumulation of riboflavin-functionalized nanocarriers in cancer cells. Although the uptake mechanism of riboflavin has been studied for over a decade, little is known about the riboflavin transporters and their expression on cancer cells, tumor stroma, and healthy tissues. Furthermore, evidence is lacking concerning the representativeness of the preclinical findings to the situation in humans. In this study, we investigated the expression pattern of riboflavin transporters in human squamous cell carcinoma (SCC), melanoma and luminal A breast cancer samples, as well as in healthy skin, breast, aorta, and kidney tissues. Low constitutive expression levels of RFVT1–3 were found on all healthy tissues, while RFVT2 and 3 were significantly overexpressed in melanoma, RFVT1 and 3 in luminal A breast cancer and RFVT1–3 in SCC. Correspondingly, the SCC cell line A431 was highly positive for all RFVTs, thus qualifying as suitable in vitro model. In contrast, activated endothelial cells (HUVEC) only presented with a strong expression of RFVT2, and HK2 kidney cells only with a low constitutive expression of RFVT1–3. Functional in vitro studies on A431 and HK2 cells using confocal microscopy showed that riboflavin uptake is mostly ATP dependent and primarily driven by endocytosis. Furthermore, riboflavin is partially trafficked to the mitochondria. Riboflavin uptake and trafficking was significantly higher in A431 than in healthy kidney cells. Thus, this manuscript supports the hypothesis that addressing the riboflavin internalization pathway may be highly valuable for tumor targeted drug delivery. |
format | Online Article Text |
id | pubmed-6372557 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-63725572019-02-20 Evaluation of Riboflavin Transporters as Targets for Drug Delivery and Theranostics Bartmann, Lisa Schumacher, David von Stillfried, Saskia Sternkopf, Marieke Alampour-Rajabi, Setareh van Zandvoort, Marc A. M. J. Kiessling, Fabian Wu, Zhuojun Front Pharmacol Pharmacology The retention and cellular internalization of drug delivery systems and theranostics for cancer therapy can be improved by targeting molecules. Since an increased uptake of riboflavin was reported for various cancers, riboflavin and its derivatives may be promising binding moieties to trigger internalization via the riboflavin transporters (RFVT) 1, 2, and 3. Riboflavin is a vitamin with pivotal role in energy metabolism and indispensable for cellular growth. In previous preclinical studies on mice, we showed the target-specific accumulation of riboflavin-functionalized nanocarriers in cancer cells. Although the uptake mechanism of riboflavin has been studied for over a decade, little is known about the riboflavin transporters and their expression on cancer cells, tumor stroma, and healthy tissues. Furthermore, evidence is lacking concerning the representativeness of the preclinical findings to the situation in humans. In this study, we investigated the expression pattern of riboflavin transporters in human squamous cell carcinoma (SCC), melanoma and luminal A breast cancer samples, as well as in healthy skin, breast, aorta, and kidney tissues. Low constitutive expression levels of RFVT1–3 were found on all healthy tissues, while RFVT2 and 3 were significantly overexpressed in melanoma, RFVT1 and 3 in luminal A breast cancer and RFVT1–3 in SCC. Correspondingly, the SCC cell line A431 was highly positive for all RFVTs, thus qualifying as suitable in vitro model. In contrast, activated endothelial cells (HUVEC) only presented with a strong expression of RFVT2, and HK2 kidney cells only with a low constitutive expression of RFVT1–3. Functional in vitro studies on A431 and HK2 cells using confocal microscopy showed that riboflavin uptake is mostly ATP dependent and primarily driven by endocytosis. Furthermore, riboflavin is partially trafficked to the mitochondria. Riboflavin uptake and trafficking was significantly higher in A431 than in healthy kidney cells. Thus, this manuscript supports the hypothesis that addressing the riboflavin internalization pathway may be highly valuable for tumor targeted drug delivery. Frontiers Media S.A. 2019-02-06 /pmc/articles/PMC6372557/ /pubmed/30787877 http://dx.doi.org/10.3389/fphar.2019.00079 Text en Copyright © 2019 Bartmann, Schumacher, von Stillfried, Sternkopf, Alampour-Rajabi, van Zandvoort, Kiessling and Wu. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Bartmann, Lisa Schumacher, David von Stillfried, Saskia Sternkopf, Marieke Alampour-Rajabi, Setareh van Zandvoort, Marc A. M. J. Kiessling, Fabian Wu, Zhuojun Evaluation of Riboflavin Transporters as Targets for Drug Delivery and Theranostics |
title | Evaluation of Riboflavin Transporters as Targets for Drug Delivery and Theranostics |
title_full | Evaluation of Riboflavin Transporters as Targets for Drug Delivery and Theranostics |
title_fullStr | Evaluation of Riboflavin Transporters as Targets for Drug Delivery and Theranostics |
title_full_unstemmed | Evaluation of Riboflavin Transporters as Targets for Drug Delivery and Theranostics |
title_short | Evaluation of Riboflavin Transporters as Targets for Drug Delivery and Theranostics |
title_sort | evaluation of riboflavin transporters as targets for drug delivery and theranostics |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372557/ https://www.ncbi.nlm.nih.gov/pubmed/30787877 http://dx.doi.org/10.3389/fphar.2019.00079 |
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