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Preclinical safety and hepatotoxicity evaluation of biomineralized copper sulfide nanoagents

Albumin-biomineralized copper sulfide nanoparticles (Cu(2−x)S NPs) have attracted much attention as an emerging phototheranostic agent due to their advantages of facile preparation method and high biocompatibility. However, comprehensive preclinical safety evaluation is the only way to meet its furt...

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Autores principales: Xia, Ya-Nan, Zu, He, Guo, Haoxiang, Jiang, Tianyan, Yang, Siqi, Yu, Huan, Zhang, Shaodian, Ding, Heng, Li, Xiaoyu, Wang, Yangyun, Wang, Yong, Zhang, Leshuai W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9004045/
https://www.ncbi.nlm.nih.gov/pubmed/35414075
http://dx.doi.org/10.1186/s12951-022-01399-5
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author Xia, Ya-Nan
Zu, He
Guo, Haoxiang
Jiang, Tianyan
Yang, Siqi
Yu, Huan
Zhang, Shaodian
Ding, Heng
Li, Xiaoyu
Wang, Yangyun
Wang, Yong
Zhang, Leshuai W.
author_facet Xia, Ya-Nan
Zu, He
Guo, Haoxiang
Jiang, Tianyan
Yang, Siqi
Yu, Huan
Zhang, Shaodian
Ding, Heng
Li, Xiaoyu
Wang, Yangyun
Wang, Yong
Zhang, Leshuai W.
author_sort Xia, Ya-Nan
collection PubMed
description Albumin-biomineralized copper sulfide nanoparticles (Cu(2−x)S NPs) have attracted much attention as an emerging phototheranostic agent due to their advantages of facile preparation method and high biocompatibility. However, comprehensive preclinical safety evaluation is the only way to meet its further clinical translation. We herein evaluate detailedly the safety and hepatotoxicity of bovine serum albumin-biomineralized Cu(2−x)S (BSA@Cu(2−x)S) NPs with two different sizes in rats. Large-sized (LNPs, 17.8 nm) and small-sized (SNPs, 2.8 nm) BSA@Cu(2−x)S NPs with great near-infrared absorption and photothermal conversion efficiency are firstly obtained. Seven days after a single-dose intravenous administration, SNPs distributed throughout the body are cleared primarily through the feces, while a large amount of LNPs remained in the liver. A 14-day subacute toxicity study with a 28-day recovery period are conducted, showing long-term hepatotoxicity without recovery for LNPs but reversible toxicity for SNPs. Cellular uptake studies indicate that LNPs prefer to reside in Kupffer cells, leading to prolonged and delayed hepatotoxicity even after the cessation of NPs administration, while SNPs have much less Kupffer cell uptake. RNA-sequencing analysis for gene expression indicates that the inflammatory pathway, lipid metabolism pathway, drug metabolism-cytochrome P450 pathway, cholesterol/bile acid metabolism pathway, and copper ion transport/metabolism pathway are compromised in the liver by two sizes of BSA@Cu(2−x)S NPs, while only SNPs show a complete recovery of altered gene expression after NPs discontinuation. This study demonstrates that the translational feasibility of small-sized BSA@Cu(2−x)S NPs as excellent nanoagents with manageable hepatotoxicity. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12951-022-01399-5.
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spelling pubmed-90040452022-04-13 Preclinical safety and hepatotoxicity evaluation of biomineralized copper sulfide nanoagents Xia, Ya-Nan Zu, He Guo, Haoxiang Jiang, Tianyan Yang, Siqi Yu, Huan Zhang, Shaodian Ding, Heng Li, Xiaoyu Wang, Yangyun Wang, Yong Zhang, Leshuai W. J Nanobiotechnology Research Albumin-biomineralized copper sulfide nanoparticles (Cu(2−x)S NPs) have attracted much attention as an emerging phototheranostic agent due to their advantages of facile preparation method and high biocompatibility. However, comprehensive preclinical safety evaluation is the only way to meet its further clinical translation. We herein evaluate detailedly the safety and hepatotoxicity of bovine serum albumin-biomineralized Cu(2−x)S (BSA@Cu(2−x)S) NPs with two different sizes in rats. Large-sized (LNPs, 17.8 nm) and small-sized (SNPs, 2.8 nm) BSA@Cu(2−x)S NPs with great near-infrared absorption and photothermal conversion efficiency are firstly obtained. Seven days after a single-dose intravenous administration, SNPs distributed throughout the body are cleared primarily through the feces, while a large amount of LNPs remained in the liver. A 14-day subacute toxicity study with a 28-day recovery period are conducted, showing long-term hepatotoxicity without recovery for LNPs but reversible toxicity for SNPs. Cellular uptake studies indicate that LNPs prefer to reside in Kupffer cells, leading to prolonged and delayed hepatotoxicity even after the cessation of NPs administration, while SNPs have much less Kupffer cell uptake. RNA-sequencing analysis for gene expression indicates that the inflammatory pathway, lipid metabolism pathway, drug metabolism-cytochrome P450 pathway, cholesterol/bile acid metabolism pathway, and copper ion transport/metabolism pathway are compromised in the liver by two sizes of BSA@Cu(2−x)S NPs, while only SNPs show a complete recovery of altered gene expression after NPs discontinuation. This study demonstrates that the translational feasibility of small-sized BSA@Cu(2−x)S NPs as excellent nanoagents with manageable hepatotoxicity. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12951-022-01399-5. BioMed Central 2022-04-12 /pmc/articles/PMC9004045/ /pubmed/35414075 http://dx.doi.org/10.1186/s12951-022-01399-5 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Xia, Ya-Nan
Zu, He
Guo, Haoxiang
Jiang, Tianyan
Yang, Siqi
Yu, Huan
Zhang, Shaodian
Ding, Heng
Li, Xiaoyu
Wang, Yangyun
Wang, Yong
Zhang, Leshuai W.
Preclinical safety and hepatotoxicity evaluation of biomineralized copper sulfide nanoagents
title Preclinical safety and hepatotoxicity evaluation of biomineralized copper sulfide nanoagents
title_full Preclinical safety and hepatotoxicity evaluation of biomineralized copper sulfide nanoagents
title_fullStr Preclinical safety and hepatotoxicity evaluation of biomineralized copper sulfide nanoagents
title_full_unstemmed Preclinical safety and hepatotoxicity evaluation of biomineralized copper sulfide nanoagents
title_short Preclinical safety and hepatotoxicity evaluation of biomineralized copper sulfide nanoagents
title_sort preclinical safety and hepatotoxicity evaluation of biomineralized copper sulfide nanoagents
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9004045/
https://www.ncbi.nlm.nih.gov/pubmed/35414075
http://dx.doi.org/10.1186/s12951-022-01399-5
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