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Aptamers with Self-Loading Drug Payload and pH-Controlled Drug Release for Targeted Chemotherapy

Doxorubicin (DOX) is a common anti-tumor drug that binds to DNA or RNA via non-covalent intercalation between G-C sequences. As a therapeutic agent, DOX has been used to form aptamer–drug conjugates for targeted cancer therapy in vitro and in vivo. To improve the therapeutic potential of aptamer–DOX...

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Autores principales: Zeng, Zihua, Qi, Jianjun, Wan, Quanyuan, Zu, Youli
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8398837/
https://www.ncbi.nlm.nih.gov/pubmed/34452182
http://dx.doi.org/10.3390/pharmaceutics13081221
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author Zeng, Zihua
Qi, Jianjun
Wan, Quanyuan
Zu, Youli
author_facet Zeng, Zihua
Qi, Jianjun
Wan, Quanyuan
Zu, Youli
author_sort Zeng, Zihua
collection PubMed
description Doxorubicin (DOX) is a common anti-tumor drug that binds to DNA or RNA via non-covalent intercalation between G-C sequences. As a therapeutic agent, DOX has been used to form aptamer–drug conjugates for targeted cancer therapy in vitro and in vivo. To improve the therapeutic potential of aptamer–DOX conjugates, we synthesized trifurcated Newkome-type monomer (TNM) structures with three DOX molecules bound through pH-sensitive hydrazone bonds to formulate TNM-DOX. The aptamer–TNM–DOX conjugate (Apt–TNM-DOX) was produced through a simple self-loading process. Chemical validation revealed that Apt–TNM-DOX stably carried high drug payloads of 15 DOX molecules per aptamer sequence. Functional characterization showed that DOX payload release from Apt–TNM-DOX was pH-dependent and occurred at pH 5.0, which reflects the microenvironment of tumor cell lysosomes. Further, Apt–TNM-DOX specifically targeted lymphoma cells without affecting off-target control cells. Aptamer-mediated cell binding resulted in the uptake of Apt–TNM-DOX into targeted cells and the release of DOX payload within cell lysosomes to inhibit growth of targeted lymphoma cells. The Apt–TNM-DOX provides a simple, non-toxic approach to develop aptamer-based targeted therapeutics and may reduce the non-specific side effects associated with traditional chemotherapy.
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spelling pubmed-83988372021-08-29 Aptamers with Self-Loading Drug Payload and pH-Controlled Drug Release for Targeted Chemotherapy Zeng, Zihua Qi, Jianjun Wan, Quanyuan Zu, Youli Pharmaceutics Article Doxorubicin (DOX) is a common anti-tumor drug that binds to DNA or RNA via non-covalent intercalation between G-C sequences. As a therapeutic agent, DOX has been used to form aptamer–drug conjugates for targeted cancer therapy in vitro and in vivo. To improve the therapeutic potential of aptamer–DOX conjugates, we synthesized trifurcated Newkome-type monomer (TNM) structures with three DOX molecules bound through pH-sensitive hydrazone bonds to formulate TNM-DOX. The aptamer–TNM–DOX conjugate (Apt–TNM-DOX) was produced through a simple self-loading process. Chemical validation revealed that Apt–TNM-DOX stably carried high drug payloads of 15 DOX molecules per aptamer sequence. Functional characterization showed that DOX payload release from Apt–TNM-DOX was pH-dependent and occurred at pH 5.0, which reflects the microenvironment of tumor cell lysosomes. Further, Apt–TNM-DOX specifically targeted lymphoma cells without affecting off-target control cells. Aptamer-mediated cell binding resulted in the uptake of Apt–TNM-DOX into targeted cells and the release of DOX payload within cell lysosomes to inhibit growth of targeted lymphoma cells. The Apt–TNM-DOX provides a simple, non-toxic approach to develop aptamer-based targeted therapeutics and may reduce the non-specific side effects associated with traditional chemotherapy. MDPI 2021-08-07 /pmc/articles/PMC8398837/ /pubmed/34452182 http://dx.doi.org/10.3390/pharmaceutics13081221 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
Zeng, Zihua
Qi, Jianjun
Wan, Quanyuan
Zu, Youli
Aptamers with Self-Loading Drug Payload and pH-Controlled Drug Release for Targeted Chemotherapy
title Aptamers with Self-Loading Drug Payload and pH-Controlled Drug Release for Targeted Chemotherapy
title_full Aptamers with Self-Loading Drug Payload and pH-Controlled Drug Release for Targeted Chemotherapy
title_fullStr Aptamers with Self-Loading Drug Payload and pH-Controlled Drug Release for Targeted Chemotherapy
title_full_unstemmed Aptamers with Self-Loading Drug Payload and pH-Controlled Drug Release for Targeted Chemotherapy
title_short Aptamers with Self-Loading Drug Payload and pH-Controlled Drug Release for Targeted Chemotherapy
title_sort aptamers with self-loading drug payload and ph-controlled drug release for targeted chemotherapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8398837/
https://www.ncbi.nlm.nih.gov/pubmed/34452182
http://dx.doi.org/10.3390/pharmaceutics13081221
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