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A VEGFR targeting peptide-drug conjugate (PDC) suppresses tumor angiogenesis in a TACE model for hepatocellular carcinoma therapy
Transcatheter arterial chemoembolization (TACE) has become the preferred therapy for unresectable advanced hepatocellular carcinoma (HCC). However, the embolization of tumor-feeding arteries by TACE always leads to hypoxia-related tumor angiogenesis, which limited the therapeutic effect for HCC. In...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9537177/ https://www.ncbi.nlm.nih.gov/pubmed/36202781 http://dx.doi.org/10.1038/s41420-022-01198-9 |
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author | Wang, Dongyuan Liu, Jiacheng Li, Tongqiang Wang, Yingliang Liu, Xiaoming Bai, Yaowei Wang, Chaoyang Ju, Shuguang Huang, Songjiang Yang, Chongtu Zhou, Chen Zhang, Yu Xiong, Bin |
author_facet | Wang, Dongyuan Liu, Jiacheng Li, Tongqiang Wang, Yingliang Liu, Xiaoming Bai, Yaowei Wang, Chaoyang Ju, Shuguang Huang, Songjiang Yang, Chongtu Zhou, Chen Zhang, Yu Xiong, Bin |
author_sort | Wang, Dongyuan |
collection | PubMed |
description | Transcatheter arterial chemoembolization (TACE) has become the preferred therapy for unresectable advanced hepatocellular carcinoma (HCC). However, the embolization of tumor-feeding arteries by TACE always leads to hypoxia-related tumor angiogenesis, which limited the therapeutic effect for HCC. In this paper, we used a VEGFR targeting peptide VEGF125 − 136 (QKRKRKKSRYKS) to conjugate with a lytic peptide (KLUKLUKKLUKLUK) to form a peptide-drug conjugate (PDC). We used cell affinity assay to detect the peptide binding ability to VEGFR highly expressed cell lines, and CCK8, cell apoptosis to confirm the cellular toxicity for different cell lines. Meanwhile, we created a VX2 tumor-bearing rabbit model to assess the in vivo anti-tumor effect of the peptide conjugate in combination with TAE. HE staining was used to verify the in vivo safety of the peptide conjugate. IHC was used to assess the anti-angiogenesis and cell toxicity of the peptide conjugate in tumor tissues. The peptide conjugate could not only target VEGFR in cell surface and inhibit VEGFR function, but also have potent anti-cancer effect. We luckily found the peptide conjugate showed potent cytotoxicity for liver cancer cell Huh7 (IC50 7.3 ± 0.74 μM) and endothelial cell HUVEC (IC50 10.7 ± 0.292 μM) and induced cell apoptosis of these two cell lines. We also found the peptide conjugate inhibited cell migration of HUVEC through wound healing assay. Besides, these peptides also showed better in vivo anti-tumor effect than traditional drug DOX through TACE in VX2 rabbit tumor model, and efficiently inhibit angiogenesis in tumor tissues with good safety. In conclusion, our work may provide an alternative option for clinical HCC therapy via TACE combination. |
format | Online Article Text |
id | pubmed-9537177 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-95371772022-10-08 A VEGFR targeting peptide-drug conjugate (PDC) suppresses tumor angiogenesis in a TACE model for hepatocellular carcinoma therapy Wang, Dongyuan Liu, Jiacheng Li, Tongqiang Wang, Yingliang Liu, Xiaoming Bai, Yaowei Wang, Chaoyang Ju, Shuguang Huang, Songjiang Yang, Chongtu Zhou, Chen Zhang, Yu Xiong, Bin Cell Death Discov Article Transcatheter arterial chemoembolization (TACE) has become the preferred therapy for unresectable advanced hepatocellular carcinoma (HCC). However, the embolization of tumor-feeding arteries by TACE always leads to hypoxia-related tumor angiogenesis, which limited the therapeutic effect for HCC. In this paper, we used a VEGFR targeting peptide VEGF125 − 136 (QKRKRKKSRYKS) to conjugate with a lytic peptide (KLUKLUKKLUKLUK) to form a peptide-drug conjugate (PDC). We used cell affinity assay to detect the peptide binding ability to VEGFR highly expressed cell lines, and CCK8, cell apoptosis to confirm the cellular toxicity for different cell lines. Meanwhile, we created a VX2 tumor-bearing rabbit model to assess the in vivo anti-tumor effect of the peptide conjugate in combination with TAE. HE staining was used to verify the in vivo safety of the peptide conjugate. IHC was used to assess the anti-angiogenesis and cell toxicity of the peptide conjugate in tumor tissues. The peptide conjugate could not only target VEGFR in cell surface and inhibit VEGFR function, but also have potent anti-cancer effect. We luckily found the peptide conjugate showed potent cytotoxicity for liver cancer cell Huh7 (IC50 7.3 ± 0.74 μM) and endothelial cell HUVEC (IC50 10.7 ± 0.292 μM) and induced cell apoptosis of these two cell lines. We also found the peptide conjugate inhibited cell migration of HUVEC through wound healing assay. Besides, these peptides also showed better in vivo anti-tumor effect than traditional drug DOX through TACE in VX2 rabbit tumor model, and efficiently inhibit angiogenesis in tumor tissues with good safety. In conclusion, our work may provide an alternative option for clinical HCC therapy via TACE combination. Nature Publishing Group UK 2022-10-06 /pmc/articles/PMC9537177/ /pubmed/36202781 http://dx.doi.org/10.1038/s41420-022-01198-9 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Wang, Dongyuan Liu, Jiacheng Li, Tongqiang Wang, Yingliang Liu, Xiaoming Bai, Yaowei Wang, Chaoyang Ju, Shuguang Huang, Songjiang Yang, Chongtu Zhou, Chen Zhang, Yu Xiong, Bin A VEGFR targeting peptide-drug conjugate (PDC) suppresses tumor angiogenesis in a TACE model for hepatocellular carcinoma therapy |
title | A VEGFR targeting peptide-drug conjugate (PDC) suppresses tumor angiogenesis in a TACE model for hepatocellular carcinoma therapy |
title_full | A VEGFR targeting peptide-drug conjugate (PDC) suppresses tumor angiogenesis in a TACE model for hepatocellular carcinoma therapy |
title_fullStr | A VEGFR targeting peptide-drug conjugate (PDC) suppresses tumor angiogenesis in a TACE model for hepatocellular carcinoma therapy |
title_full_unstemmed | A VEGFR targeting peptide-drug conjugate (PDC) suppresses tumor angiogenesis in a TACE model for hepatocellular carcinoma therapy |
title_short | A VEGFR targeting peptide-drug conjugate (PDC) suppresses tumor angiogenesis in a TACE model for hepatocellular carcinoma therapy |
title_sort | vegfr targeting peptide-drug conjugate (pdc) suppresses tumor angiogenesis in a tace model for hepatocellular carcinoma therapy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9537177/ https://www.ncbi.nlm.nih.gov/pubmed/36202781 http://dx.doi.org/10.1038/s41420-022-01198-9 |
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