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Enrichment-triggered Prodrug Activation Demonstrated through Mitochondria-targeted Delivery of Doxorubicin and Carbon Monoxide

Controlled activation is a critical component in prodrug development. Herein we report a concentration-sensitive platform approach for bioorthogonal prodrug activation by taking advantage of reaction kinetics. Using two “click and release” systems, we demonstrate enrichment and prodrug activation sp...

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Autores principales: Zheng, Yueqin, Ji, Xingyue, Yu, Bingchen, Ji, Kaili, Gallo, David, Csizmadia, Eva, Zhu, Mengyuan, Choudhury, Manjusha Roy, De La Cruz, Ladie Kimberly C., Chittavong, Vayou, Pan, Zhixiang, Yuan, Zhengnan, Otterbein, Leo E., Wang, Binghe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235738/
https://www.ncbi.nlm.nih.gov/pubmed/29760413
http://dx.doi.org/10.1038/s41557-018-0055-2
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author Zheng, Yueqin
Ji, Xingyue
Yu, Bingchen
Ji, Kaili
Gallo, David
Csizmadia, Eva
Zhu, Mengyuan
Choudhury, Manjusha Roy
De La Cruz, Ladie Kimberly C.
Chittavong, Vayou
Pan, Zhixiang
Yuan, Zhengnan
Otterbein, Leo E.
Wang, Binghe
author_facet Zheng, Yueqin
Ji, Xingyue
Yu, Bingchen
Ji, Kaili
Gallo, David
Csizmadia, Eva
Zhu, Mengyuan
Choudhury, Manjusha Roy
De La Cruz, Ladie Kimberly C.
Chittavong, Vayou
Pan, Zhixiang
Yuan, Zhengnan
Otterbein, Leo E.
Wang, Binghe
author_sort Zheng, Yueqin
collection PubMed
description Controlled activation is a critical component in prodrug development. Herein we report a concentration-sensitive platform approach for bioorthogonal prodrug activation by taking advantage of reaction kinetics. Using two “click and release” systems, we demonstrate enrichment and prodrug activation specifically in mitochondria to demonstrate the principle of this approach. In both cases, the payload (doxorubicin or carbon monoxide) was released inside the mitochondrial matrix upon the enrichment-initiated click reaction. Furthermore, mitochondria-targeted delivery yielded substantial augmentation of functional biological and therapeutic effects in vitro and in vivo, as compared to controls that did not result in enrichment. This method is thus a platform for targeted drug delivery amenable to conjugation with a variety of molecules and not limited to cell-surface delivery. Taken together, these two click and release pairs clearly demonstrate the concept of enrichment-triggered drug release and critical feasibility of treating clinically relevant diseases such as acute liver injury and cancer.
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spelling pubmed-62357382018-11-15 Enrichment-triggered Prodrug Activation Demonstrated through Mitochondria-targeted Delivery of Doxorubicin and Carbon Monoxide Zheng, Yueqin Ji, Xingyue Yu, Bingchen Ji, Kaili Gallo, David Csizmadia, Eva Zhu, Mengyuan Choudhury, Manjusha Roy De La Cruz, Ladie Kimberly C. Chittavong, Vayou Pan, Zhixiang Yuan, Zhengnan Otterbein, Leo E. Wang, Binghe Nat Chem Article Controlled activation is a critical component in prodrug development. Herein we report a concentration-sensitive platform approach for bioorthogonal prodrug activation by taking advantage of reaction kinetics. Using two “click and release” systems, we demonstrate enrichment and prodrug activation specifically in mitochondria to demonstrate the principle of this approach. In both cases, the payload (doxorubicin or carbon monoxide) was released inside the mitochondrial matrix upon the enrichment-initiated click reaction. Furthermore, mitochondria-targeted delivery yielded substantial augmentation of functional biological and therapeutic effects in vitro and in vivo, as compared to controls that did not result in enrichment. This method is thus a platform for targeted drug delivery amenable to conjugation with a variety of molecules and not limited to cell-surface delivery. Taken together, these two click and release pairs clearly demonstrate the concept of enrichment-triggered drug release and critical feasibility of treating clinically relevant diseases such as acute liver injury and cancer. 2018-05-14 2018-07 /pmc/articles/PMC6235738/ /pubmed/29760413 http://dx.doi.org/10.1038/s41557-018-0055-2 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Zheng, Yueqin
Ji, Xingyue
Yu, Bingchen
Ji, Kaili
Gallo, David
Csizmadia, Eva
Zhu, Mengyuan
Choudhury, Manjusha Roy
De La Cruz, Ladie Kimberly C.
Chittavong, Vayou
Pan, Zhixiang
Yuan, Zhengnan
Otterbein, Leo E.
Wang, Binghe
Enrichment-triggered Prodrug Activation Demonstrated through Mitochondria-targeted Delivery of Doxorubicin and Carbon Monoxide
title Enrichment-triggered Prodrug Activation Demonstrated through Mitochondria-targeted Delivery of Doxorubicin and Carbon Monoxide
title_full Enrichment-triggered Prodrug Activation Demonstrated through Mitochondria-targeted Delivery of Doxorubicin and Carbon Monoxide
title_fullStr Enrichment-triggered Prodrug Activation Demonstrated through Mitochondria-targeted Delivery of Doxorubicin and Carbon Monoxide
title_full_unstemmed Enrichment-triggered Prodrug Activation Demonstrated through Mitochondria-targeted Delivery of Doxorubicin and Carbon Monoxide
title_short Enrichment-triggered Prodrug Activation Demonstrated through Mitochondria-targeted Delivery of Doxorubicin and Carbon Monoxide
title_sort enrichment-triggered prodrug activation demonstrated through mitochondria-targeted delivery of doxorubicin and carbon monoxide
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235738/
https://www.ncbi.nlm.nih.gov/pubmed/29760413
http://dx.doi.org/10.1038/s41557-018-0055-2
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