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Cathepsin B-Overexpressed Tumor Cell Activatable Albumin-Binding Doxorubicin Prodrug for Cancer-Targeted Therapy

Prodrugs are bioreversible medications that should undergo an enzymatic or chemical transformation in the tumor microenvironment to release active drugs, which improve cancer selectivity to reduce toxicities of anticancer drugs. However, such approaches have been challenged by poor therapeutic effic...

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Autores principales: Cho, Hanhee, Shim, Man Kyu, Yang, Suah, Song, Sukyung, Moon, Yujeong, Kim, Jinseong, Byun, Youngro, Ahn, Cheol-Hee, Kim, Kwangmeyung
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8780658/
https://www.ncbi.nlm.nih.gov/pubmed/35056979
http://dx.doi.org/10.3390/pharmaceutics14010083
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author Cho, Hanhee
Shim, Man Kyu
Yang, Suah
Song, Sukyung
Moon, Yujeong
Kim, Jinseong
Byun, Youngro
Ahn, Cheol-Hee
Kim, Kwangmeyung
author_facet Cho, Hanhee
Shim, Man Kyu
Yang, Suah
Song, Sukyung
Moon, Yujeong
Kim, Jinseong
Byun, Youngro
Ahn, Cheol-Hee
Kim, Kwangmeyung
author_sort Cho, Hanhee
collection PubMed
description Prodrugs are bioreversible medications that should undergo an enzymatic or chemical transformation in the tumor microenvironment to release active drugs, which improve cancer selectivity to reduce toxicities of anticancer drugs. However, such approaches have been challenged by poor therapeutic efficacy attributed to a short half-life and low tumor targeting. Herein, we propose cathepsin B-overexpressed tumor cell activatable albumin-binding doxorubicin prodrug, Al-ProD, that consists of a albumin-binding maleimide group, cathepsin B-cleavable peptide (FRRG), and doxorubicin. The Al-ProD binds to in situ albumin, and albumin-bound Al-ProD indicates high tumor accumulation with prolonged half-life, and selctively releases doxorubicin in cathepsin B-overexpressed tumor cells, inducing a potent antitumor efficacy. Concurrently, toxicity of Al-ProD toward normal tissues with innately low cathepsin B expression is significantly reduced by maintaining an inactive state, thereby increasing the safety of chemotherapy. This study offers a promising approach for effective and safe chemotherapy, which may open new avenues for drug design and translational medicine.
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spelling pubmed-87806582022-01-22 Cathepsin B-Overexpressed Tumor Cell Activatable Albumin-Binding Doxorubicin Prodrug for Cancer-Targeted Therapy Cho, Hanhee Shim, Man Kyu Yang, Suah Song, Sukyung Moon, Yujeong Kim, Jinseong Byun, Youngro Ahn, Cheol-Hee Kim, Kwangmeyung Pharmaceutics Article Prodrugs are bioreversible medications that should undergo an enzymatic or chemical transformation in the tumor microenvironment to release active drugs, which improve cancer selectivity to reduce toxicities of anticancer drugs. However, such approaches have been challenged by poor therapeutic efficacy attributed to a short half-life and low tumor targeting. Herein, we propose cathepsin B-overexpressed tumor cell activatable albumin-binding doxorubicin prodrug, Al-ProD, that consists of a albumin-binding maleimide group, cathepsin B-cleavable peptide (FRRG), and doxorubicin. The Al-ProD binds to in situ albumin, and albumin-bound Al-ProD indicates high tumor accumulation with prolonged half-life, and selctively releases doxorubicin in cathepsin B-overexpressed tumor cells, inducing a potent antitumor efficacy. Concurrently, toxicity of Al-ProD toward normal tissues with innately low cathepsin B expression is significantly reduced by maintaining an inactive state, thereby increasing the safety of chemotherapy. This study offers a promising approach for effective and safe chemotherapy, which may open new avenues for drug design and translational medicine. MDPI 2021-12-29 /pmc/articles/PMC8780658/ /pubmed/35056979 http://dx.doi.org/10.3390/pharmaceutics14010083 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Cho, Hanhee
Shim, Man Kyu
Yang, Suah
Song, Sukyung
Moon, Yujeong
Kim, Jinseong
Byun, Youngro
Ahn, Cheol-Hee
Kim, Kwangmeyung
Cathepsin B-Overexpressed Tumor Cell Activatable Albumin-Binding Doxorubicin Prodrug for Cancer-Targeted Therapy
title Cathepsin B-Overexpressed Tumor Cell Activatable Albumin-Binding Doxorubicin Prodrug for Cancer-Targeted Therapy
title_full Cathepsin B-Overexpressed Tumor Cell Activatable Albumin-Binding Doxorubicin Prodrug for Cancer-Targeted Therapy
title_fullStr Cathepsin B-Overexpressed Tumor Cell Activatable Albumin-Binding Doxorubicin Prodrug for Cancer-Targeted Therapy
title_full_unstemmed Cathepsin B-Overexpressed Tumor Cell Activatable Albumin-Binding Doxorubicin Prodrug for Cancer-Targeted Therapy
title_short Cathepsin B-Overexpressed Tumor Cell Activatable Albumin-Binding Doxorubicin Prodrug for Cancer-Targeted Therapy
title_sort cathepsin b-overexpressed tumor cell activatable albumin-binding doxorubicin prodrug for cancer-targeted therapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8780658/
https://www.ncbi.nlm.nih.gov/pubmed/35056979
http://dx.doi.org/10.3390/pharmaceutics14010083
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