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Antihypertension Nanoblockers Increase Intratumoral Perfusion of Sequential Cytotoxic Nanoparticles to Enhance Chemotherapy Efficacy against Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC), one of the worst prognosis types of tumors, is characterized by dense extracellular matrix, which compresses tumor vessels and forms a physical barrier to inhibit therapeutic drug penetration and efficacy. Herein, losartan, an antihypertension agent, is appli...

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Autores principales: Bian, Suchen, Dong, Haijiang, Zhao, Long, Li, Zequn, Chen, Jian, Zhu, Xingxin, Qiu, Nasha, Jia, Xing, Song, Wenfeng, Li, Zekuan, Zheng, Shusen, Wang, Hangxiang, Song, Penghong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9561769/
https://www.ncbi.nlm.nih.gov/pubmed/36026578
http://dx.doi.org/10.1002/advs.202201931
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author Bian, Suchen
Dong, Haijiang
Zhao, Long
Li, Zequn
Chen, Jian
Zhu, Xingxin
Qiu, Nasha
Jia, Xing
Song, Wenfeng
Li, Zekuan
Zheng, Shusen
Wang, Hangxiang
Song, Penghong
author_facet Bian, Suchen
Dong, Haijiang
Zhao, Long
Li, Zequn
Chen, Jian
Zhu, Xingxin
Qiu, Nasha
Jia, Xing
Song, Wenfeng
Li, Zekuan
Zheng, Shusen
Wang, Hangxiang
Song, Penghong
author_sort Bian, Suchen
collection PubMed
description Pancreatic ductal adenocarcinoma (PDAC), one of the worst prognosis types of tumors, is characterized by dense extracellular matrix, which compresses tumor vessels and forms a physical barrier to inhibit therapeutic drug penetration and efficacy. Herein, losartan, an antihypertension agent, is applied as a tumor stroma modulator and developed into a nanosystem. A series of lipophilic losartan prodrugs are constructed by esterification of the hydroxyl group on losartan to fatty acids. Based on the self‐assembly ability and hydrodynamic diameter, the losartan‐linoleic acid conjugate is selected for further investigation. To improve the stability in vivo, nanoassemblies are refined with PEGylation to form losartan nanoblocker (Los NB), and administered via intravenous injection for experiments. On murine models of pancreatic cancer, Los NB shows a greater ability to remodel the tumor microenvironment than free losartan, including stromal depletion, vessel perfusion increase, and hypoxia relief. Furthermore, Los NB pretreatment remarkably enhances the accumulation and penetration of 7‐ethyl‐10‐hydroxycamptothecin (SN38)‐loaded nanodrugs (SN38 NPs) in tumor tissues. Expectedly, overall therapeutic efficacy of SN38 NPs is significantly enhanced after Los NB pretreatment. Since losartan is one of the most commonly used antihypertension agents, this study may provide a potential for clinical transformation in stroma‐rich PDAC treatment.
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spelling pubmed-95617692022-10-16 Antihypertension Nanoblockers Increase Intratumoral Perfusion of Sequential Cytotoxic Nanoparticles to Enhance Chemotherapy Efficacy against Pancreatic Cancer Bian, Suchen Dong, Haijiang Zhao, Long Li, Zequn Chen, Jian Zhu, Xingxin Qiu, Nasha Jia, Xing Song, Wenfeng Li, Zekuan Zheng, Shusen Wang, Hangxiang Song, Penghong Adv Sci (Weinh) Research Articles Pancreatic ductal adenocarcinoma (PDAC), one of the worst prognosis types of tumors, is characterized by dense extracellular matrix, which compresses tumor vessels and forms a physical barrier to inhibit therapeutic drug penetration and efficacy. Herein, losartan, an antihypertension agent, is applied as a tumor stroma modulator and developed into a nanosystem. A series of lipophilic losartan prodrugs are constructed by esterification of the hydroxyl group on losartan to fatty acids. Based on the self‐assembly ability and hydrodynamic diameter, the losartan‐linoleic acid conjugate is selected for further investigation. To improve the stability in vivo, nanoassemblies are refined with PEGylation to form losartan nanoblocker (Los NB), and administered via intravenous injection for experiments. On murine models of pancreatic cancer, Los NB shows a greater ability to remodel the tumor microenvironment than free losartan, including stromal depletion, vessel perfusion increase, and hypoxia relief. Furthermore, Los NB pretreatment remarkably enhances the accumulation and penetration of 7‐ethyl‐10‐hydroxycamptothecin (SN38)‐loaded nanodrugs (SN38 NPs) in tumor tissues. Expectedly, overall therapeutic efficacy of SN38 NPs is significantly enhanced after Los NB pretreatment. Since losartan is one of the most commonly used antihypertension agents, this study may provide a potential for clinical transformation in stroma‐rich PDAC treatment. John Wiley and Sons Inc. 2022-08-26 /pmc/articles/PMC9561769/ /pubmed/36026578 http://dx.doi.org/10.1002/advs.202201931 Text en © 2022 The Authors. Advanced Science published by Wiley‐VCH GmbH https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Bian, Suchen
Dong, Haijiang
Zhao, Long
Li, Zequn
Chen, Jian
Zhu, Xingxin
Qiu, Nasha
Jia, Xing
Song, Wenfeng
Li, Zekuan
Zheng, Shusen
Wang, Hangxiang
Song, Penghong
Antihypertension Nanoblockers Increase Intratumoral Perfusion of Sequential Cytotoxic Nanoparticles to Enhance Chemotherapy Efficacy against Pancreatic Cancer
title Antihypertension Nanoblockers Increase Intratumoral Perfusion of Sequential Cytotoxic Nanoparticles to Enhance Chemotherapy Efficacy against Pancreatic Cancer
title_full Antihypertension Nanoblockers Increase Intratumoral Perfusion of Sequential Cytotoxic Nanoparticles to Enhance Chemotherapy Efficacy against Pancreatic Cancer
title_fullStr Antihypertension Nanoblockers Increase Intratumoral Perfusion of Sequential Cytotoxic Nanoparticles to Enhance Chemotherapy Efficacy against Pancreatic Cancer
title_full_unstemmed Antihypertension Nanoblockers Increase Intratumoral Perfusion of Sequential Cytotoxic Nanoparticles to Enhance Chemotherapy Efficacy against Pancreatic Cancer
title_short Antihypertension Nanoblockers Increase Intratumoral Perfusion of Sequential Cytotoxic Nanoparticles to Enhance Chemotherapy Efficacy against Pancreatic Cancer
title_sort antihypertension nanoblockers increase intratumoral perfusion of sequential cytotoxic nanoparticles to enhance chemotherapy efficacy against pancreatic cancer
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9561769/
https://www.ncbi.nlm.nih.gov/pubmed/36026578
http://dx.doi.org/10.1002/advs.202201931
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