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Synthesis and In Vitro Assessment of pH-Sensitive Human Serum Albumin Conjugates of Pirarubicin

In a previous study, we reported on the development of a synthetic polymer conjugate of pirarubicin (THP) that was formed via an acid-labile hydrazone bond between the polymer and the THP. However, the synthetic polymer itself was non-biodegradable, which could lead to unexpected adverse effects. Hu...

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Autores principales: Tsukigawa, Kenji, Imoto, Shuhei, Yamasaki, Keishi, Nishi, Koji, Tsutsumi, Toshihiko, Yokoyama, Shoko, Ishima, Yu, Otagiri, Masaki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823624/
https://www.ncbi.nlm.nih.gov/pubmed/33396604
http://dx.doi.org/10.3390/ph14010022
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author Tsukigawa, Kenji
Imoto, Shuhei
Yamasaki, Keishi
Nishi, Koji
Tsutsumi, Toshihiko
Yokoyama, Shoko
Ishima, Yu
Otagiri, Masaki
author_facet Tsukigawa, Kenji
Imoto, Shuhei
Yamasaki, Keishi
Nishi, Koji
Tsutsumi, Toshihiko
Yokoyama, Shoko
Ishima, Yu
Otagiri, Masaki
author_sort Tsukigawa, Kenji
collection PubMed
description In a previous study, we reported on the development of a synthetic polymer conjugate of pirarubicin (THP) that was formed via an acid-labile hydrazone bond between the polymer and the THP. However, the synthetic polymer itself was non-biodegradable, which could lead to unexpected adverse effects. Human serum albumin (HSA), which has a high biocompatibility and good biodegradability, is also a potent carrier for delivering antitumor drugs. The objective of this study was to develop pH-sensitive HSA conjugates of THP (HSA-THP), and investigate the release of THP and the cytotoxicity under acidic conditions in vitro for further clinical development. HSA-THP was synthesized by conjugating maleimide hydrazone derivatives of THP with poly-thiolated HSA using 2-iminothiolane, via a thiol-maleimide coupling reaction. We synthesized two types of HSA-THP that contained different amounts of THP (HSA-THP2 and HSA-THP4). Free THP was released from both of the HSA conjugates more rapidly at an acidic pH, and the rates of release for HSA-THP2 and HSA-THP4 were similar. Moreover, both HSA-THPs exhibited a higher cytotoxicity at acidic pH than at neutral pH, which is consistent with the effective liberation of free THP under acidic conditions. These findings suggest that these types of HSA-THPs are promising candidates for further development.
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spelling pubmed-78236242021-01-24 Synthesis and In Vitro Assessment of pH-Sensitive Human Serum Albumin Conjugates of Pirarubicin Tsukigawa, Kenji Imoto, Shuhei Yamasaki, Keishi Nishi, Koji Tsutsumi, Toshihiko Yokoyama, Shoko Ishima, Yu Otagiri, Masaki Pharmaceuticals (Basel) Article In a previous study, we reported on the development of a synthetic polymer conjugate of pirarubicin (THP) that was formed via an acid-labile hydrazone bond between the polymer and the THP. However, the synthetic polymer itself was non-biodegradable, which could lead to unexpected adverse effects. Human serum albumin (HSA), which has a high biocompatibility and good biodegradability, is also a potent carrier for delivering antitumor drugs. The objective of this study was to develop pH-sensitive HSA conjugates of THP (HSA-THP), and investigate the release of THP and the cytotoxicity under acidic conditions in vitro for further clinical development. HSA-THP was synthesized by conjugating maleimide hydrazone derivatives of THP with poly-thiolated HSA using 2-iminothiolane, via a thiol-maleimide coupling reaction. We synthesized two types of HSA-THP that contained different amounts of THP (HSA-THP2 and HSA-THP4). Free THP was released from both of the HSA conjugates more rapidly at an acidic pH, and the rates of release for HSA-THP2 and HSA-THP4 were similar. Moreover, both HSA-THPs exhibited a higher cytotoxicity at acidic pH than at neutral pH, which is consistent with the effective liberation of free THP under acidic conditions. These findings suggest that these types of HSA-THPs are promising candidates for further development. MDPI 2020-12-30 /pmc/articles/PMC7823624/ /pubmed/33396604 http://dx.doi.org/10.3390/ph14010022 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tsukigawa, Kenji
Imoto, Shuhei
Yamasaki, Keishi
Nishi, Koji
Tsutsumi, Toshihiko
Yokoyama, Shoko
Ishima, Yu
Otagiri, Masaki
Synthesis and In Vitro Assessment of pH-Sensitive Human Serum Albumin Conjugates of Pirarubicin
title Synthesis and In Vitro Assessment of pH-Sensitive Human Serum Albumin Conjugates of Pirarubicin
title_full Synthesis and In Vitro Assessment of pH-Sensitive Human Serum Albumin Conjugates of Pirarubicin
title_fullStr Synthesis and In Vitro Assessment of pH-Sensitive Human Serum Albumin Conjugates of Pirarubicin
title_full_unstemmed Synthesis and In Vitro Assessment of pH-Sensitive Human Serum Albumin Conjugates of Pirarubicin
title_short Synthesis and In Vitro Assessment of pH-Sensitive Human Serum Albumin Conjugates of Pirarubicin
title_sort synthesis and in vitro assessment of ph-sensitive human serum albumin conjugates of pirarubicin
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823624/
https://www.ncbi.nlm.nih.gov/pubmed/33396604
http://dx.doi.org/10.3390/ph14010022
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