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Aptamer–drug conjugate: targeted delivery of doxorubicin in a HER3 aptamer-functionalized liposomal delivery system reduces cardiotoxicity

INTRODUCTION: The toxic side effects of doxorubicin (DOX) have limited its use in chemotherapy. Neither liposomal DOX nor pegylated liposomal DOX are able to completely resolve this issue. This is a proof-of-concept study testing aptamer-drug conjugate (ApDC) targeted delivery systems for chemothera...

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Autores principales: Dou, Xiao-qian, Wang, Hua, Zhang, Jing, Wang, Fang, Xu, Gui-li, Xu, Cheng-cheng, Xu, Huan-hua, Xiang, Shen-si, Fu, Jie, Song, Hai-feng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5804143/
https://www.ncbi.nlm.nih.gov/pubmed/29440899
http://dx.doi.org/10.2147/IJN.S149887
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author Dou, Xiao-qian
Wang, Hua
Zhang, Jing
Wang, Fang
Xu, Gui-li
Xu, Cheng-cheng
Xu, Huan-hua
Xiang, Shen-si
Fu, Jie
Song, Hai-feng
author_facet Dou, Xiao-qian
Wang, Hua
Zhang, Jing
Wang, Fang
Xu, Gui-li
Xu, Cheng-cheng
Xu, Huan-hua
Xiang, Shen-si
Fu, Jie
Song, Hai-feng
author_sort Dou, Xiao-qian
collection PubMed
description INTRODUCTION: The toxic side effects of doxorubicin (DOX) have limited its use in chemotherapy. Neither liposomal DOX nor pegylated liposomal DOX are able to completely resolve this issue. This is a proof-of-concept study testing aptamer-drug conjugate (ApDC) targeted delivery systems for chemotherapeutic drugs. METHODS: Aptamer library targeting human epidermal growth factor receptor 3 (HER3) was screened and affinity was determined by enzyme-linked immunosorbent assay. Specificity was tested in MCF-7(HER3-high), BT474(HER3-high), and 293T(HER3-negative) cells using flow cytometry and confocal microscopy. We further developed a HER3 aptamer-functionalized liposome encapsulating DOX and the efficiency of this ApDC was detected by cellular uptake analysis and cell viability assay. In MCF-7 tumor-bearing mice, tumor targeting evaluation, efficacy, toxicity and preliminary pharmocokinetic study was performed. RESULTS: The candidate #13 aptamer had highest affinity (Kd =98±9.7 nM) and specificity. ApDC effectively reduces the half maximal inhibitory concentration of DOX compared with lipsome-DOX and free DOX. In vivo imaging and preliminary distribution studies showed that actively targeted nanoparticles, such as Apt-Lip-DOX molecules, could facilitate the delivery of DOX into tumors in MCF-7–bearing mice. This targeted chemotherapy caused greater tumor suppression than other groups and alleviated side effects such as weight loss, low survival rate, and organ (heart and liver) injury demonstrated by H&E staining. CONCLUSION: The results indicate that targeted chemotherapy using the aptamer–drug conjugate format could provide better tolerability and efficacy compared with non-targeted delivery in relatively low-dose toxic drugs.
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spelling pubmed-58041432018-02-13 Aptamer–drug conjugate: targeted delivery of doxorubicin in a HER3 aptamer-functionalized liposomal delivery system reduces cardiotoxicity Dou, Xiao-qian Wang, Hua Zhang, Jing Wang, Fang Xu, Gui-li Xu, Cheng-cheng Xu, Huan-hua Xiang, Shen-si Fu, Jie Song, Hai-feng Int J Nanomedicine Original Research INTRODUCTION: The toxic side effects of doxorubicin (DOX) have limited its use in chemotherapy. Neither liposomal DOX nor pegylated liposomal DOX are able to completely resolve this issue. This is a proof-of-concept study testing aptamer-drug conjugate (ApDC) targeted delivery systems for chemotherapeutic drugs. METHODS: Aptamer library targeting human epidermal growth factor receptor 3 (HER3) was screened and affinity was determined by enzyme-linked immunosorbent assay. Specificity was tested in MCF-7(HER3-high), BT474(HER3-high), and 293T(HER3-negative) cells using flow cytometry and confocal microscopy. We further developed a HER3 aptamer-functionalized liposome encapsulating DOX and the efficiency of this ApDC was detected by cellular uptake analysis and cell viability assay. In MCF-7 tumor-bearing mice, tumor targeting evaluation, efficacy, toxicity and preliminary pharmocokinetic study was performed. RESULTS: The candidate #13 aptamer had highest affinity (Kd =98±9.7 nM) and specificity. ApDC effectively reduces the half maximal inhibitory concentration of DOX compared with lipsome-DOX and free DOX. In vivo imaging and preliminary distribution studies showed that actively targeted nanoparticles, such as Apt-Lip-DOX molecules, could facilitate the delivery of DOX into tumors in MCF-7–bearing mice. This targeted chemotherapy caused greater tumor suppression than other groups and alleviated side effects such as weight loss, low survival rate, and organ (heart and liver) injury demonstrated by H&E staining. CONCLUSION: The results indicate that targeted chemotherapy using the aptamer–drug conjugate format could provide better tolerability and efficacy compared with non-targeted delivery in relatively low-dose toxic drugs. Dove Medical Press 2018-02-05 /pmc/articles/PMC5804143/ /pubmed/29440899 http://dx.doi.org/10.2147/IJN.S149887 Text en © 2018 Dou et al. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.
spellingShingle Original Research
Dou, Xiao-qian
Wang, Hua
Zhang, Jing
Wang, Fang
Xu, Gui-li
Xu, Cheng-cheng
Xu, Huan-hua
Xiang, Shen-si
Fu, Jie
Song, Hai-feng
Aptamer–drug conjugate: targeted delivery of doxorubicin in a HER3 aptamer-functionalized liposomal delivery system reduces cardiotoxicity
title Aptamer–drug conjugate: targeted delivery of doxorubicin in a HER3 aptamer-functionalized liposomal delivery system reduces cardiotoxicity
title_full Aptamer–drug conjugate: targeted delivery of doxorubicin in a HER3 aptamer-functionalized liposomal delivery system reduces cardiotoxicity
title_fullStr Aptamer–drug conjugate: targeted delivery of doxorubicin in a HER3 aptamer-functionalized liposomal delivery system reduces cardiotoxicity
title_full_unstemmed Aptamer–drug conjugate: targeted delivery of doxorubicin in a HER3 aptamer-functionalized liposomal delivery system reduces cardiotoxicity
title_short Aptamer–drug conjugate: targeted delivery of doxorubicin in a HER3 aptamer-functionalized liposomal delivery system reduces cardiotoxicity
title_sort aptamer–drug conjugate: targeted delivery of doxorubicin in a her3 aptamer-functionalized liposomal delivery system reduces cardiotoxicity
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5804143/
https://www.ncbi.nlm.nih.gov/pubmed/29440899
http://dx.doi.org/10.2147/IJN.S149887
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