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Therapeutic effects of human monoclonal PSMA antibody-mediated TRIM24 siRNA delivery in PSMA-positive castration-resistant prostate cancer

Background and Aims: Prostate specific membrane antigen (PSMA) is specifically expressed on prostate epithelial cells and markedly overexpressed in almost all prostate cancers. TRIM24 is also up-regulated from localized prostate cancer to metastatic castration-resistant prostate cancer (CRPC). Becau...

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Autores principales: Shi, Sheng-Jia, Wang, Li-Juan, Han, Dong-Hui, Wu, Jie-Heng, Jiao, Dian, Zhang, Kai-Liang, Chen, Jiang-Wei, Li, Yu, Yang, Fa, Zhang, Jing-Liang, Zheng, Guo-Xu, Yang, An-Gang, Zhao, Ai-Zhi, Qin, Wei-Jun, Wen, Wei-Hong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401511/
https://www.ncbi.nlm.nih.gov/pubmed/30867828
http://dx.doi.org/10.7150/thno.29884
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author Shi, Sheng-Jia
Wang, Li-Juan
Han, Dong-Hui
Wu, Jie-Heng
Jiao, Dian
Zhang, Kai-Liang
Chen, Jiang-Wei
Li, Yu
Yang, Fa
Zhang, Jing-Liang
Zheng, Guo-Xu
Yang, An-Gang
Zhao, Ai-Zhi
Qin, Wei-Jun
Wen, Wei-Hong
author_facet Shi, Sheng-Jia
Wang, Li-Juan
Han, Dong-Hui
Wu, Jie-Heng
Jiao, Dian
Zhang, Kai-Liang
Chen, Jiang-Wei
Li, Yu
Yang, Fa
Zhang, Jing-Liang
Zheng, Guo-Xu
Yang, An-Gang
Zhao, Ai-Zhi
Qin, Wei-Jun
Wen, Wei-Hong
author_sort Shi, Sheng-Jia
collection PubMed
description Background and Aims: Prostate specific membrane antigen (PSMA) is specifically expressed on prostate epithelial cells and markedly overexpressed in almost all prostate cancers. TRIM24 is also up-regulated from localized prostate cancer to metastatic castration-resistant prostate cancer (CRPC). Because of the high relevance of TRIM24 for cancer development and the universal expression of PSMA in CPRC, we investigated the efficacy of human monoclonal PSMA antibody (PSMAb)-based platform for the targeted TRIM24 siRNA delivery and its therapeutic efficacy in CRPC in vivo and in vitro. Methods: The therapeutic complexes were constructed by conjugating PSMAb and sulfo-SMCC-protamine, and encapsulating TRIM24 siRNA. Flow cytometry, immunofluorescence, and fluorescence imaging were performed to detect the receptor-binding, internalization, and targeted delivery of PSMAb-sulfo-SMCC-protamine (PSP)-FAM-siRNA complex (PSPS) in vitro and in vivo. CCK-8, plate-colony formation, apoptosis, cell cycle, and Transwell assays were performed to evaluate the therapeutic potential of the PSP-TRIM24 siRNA complex in vitro, whereas the in vivo therapeutic efficacy was monitored by small animal imaging, radiography, and micro CT. Results: We confirmed that PSP could efficiently protect siRNA from enzymatic digestion, enable targeted delivery of siRNA, and internalize and release siRNA into PSMA-positive (PSMA+) prostate cancer cells in vitro and in vivo. Silencing TRIM24 expression by the PSP-TRIM24 siRNA complex could dramatically suppress proliferation, colony-formation, and invasion of PSMA+ CRPC cells in vitro, and inhibit tumor growth of PSMA+ CRPC xenografts and bone loss in PSMA+ CRPC bone metastasis model without obvious toxicity at therapeutic doses in vivo. Conclusion: PSMAb mediated TRIM24 siRNA delivery platform could significantly inhibit cell proliferation, colony-formation, and invasion in PSMA+ CRPC in vitro and suppressed tumor growth and bone loss in PSMA+ CRPC xenograft and bone metastasis model.
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spelling pubmed-64015112019-03-13 Therapeutic effects of human monoclonal PSMA antibody-mediated TRIM24 siRNA delivery in PSMA-positive castration-resistant prostate cancer Shi, Sheng-Jia Wang, Li-Juan Han, Dong-Hui Wu, Jie-Heng Jiao, Dian Zhang, Kai-Liang Chen, Jiang-Wei Li, Yu Yang, Fa Zhang, Jing-Liang Zheng, Guo-Xu Yang, An-Gang Zhao, Ai-Zhi Qin, Wei-Jun Wen, Wei-Hong Theranostics Research Paper Background and Aims: Prostate specific membrane antigen (PSMA) is specifically expressed on prostate epithelial cells and markedly overexpressed in almost all prostate cancers. TRIM24 is also up-regulated from localized prostate cancer to metastatic castration-resistant prostate cancer (CRPC). Because of the high relevance of TRIM24 for cancer development and the universal expression of PSMA in CPRC, we investigated the efficacy of human monoclonal PSMA antibody (PSMAb)-based platform for the targeted TRIM24 siRNA delivery and its therapeutic efficacy in CRPC in vivo and in vitro. Methods: The therapeutic complexes were constructed by conjugating PSMAb and sulfo-SMCC-protamine, and encapsulating TRIM24 siRNA. Flow cytometry, immunofluorescence, and fluorescence imaging were performed to detect the receptor-binding, internalization, and targeted delivery of PSMAb-sulfo-SMCC-protamine (PSP)-FAM-siRNA complex (PSPS) in vitro and in vivo. CCK-8, plate-colony formation, apoptosis, cell cycle, and Transwell assays were performed to evaluate the therapeutic potential of the PSP-TRIM24 siRNA complex in vitro, whereas the in vivo therapeutic efficacy was monitored by small animal imaging, radiography, and micro CT. Results: We confirmed that PSP could efficiently protect siRNA from enzymatic digestion, enable targeted delivery of siRNA, and internalize and release siRNA into PSMA-positive (PSMA+) prostate cancer cells in vitro and in vivo. Silencing TRIM24 expression by the PSP-TRIM24 siRNA complex could dramatically suppress proliferation, colony-formation, and invasion of PSMA+ CRPC cells in vitro, and inhibit tumor growth of PSMA+ CRPC xenografts and bone loss in PSMA+ CRPC bone metastasis model without obvious toxicity at therapeutic doses in vivo. Conclusion: PSMAb mediated TRIM24 siRNA delivery platform could significantly inhibit cell proliferation, colony-formation, and invasion in PSMA+ CRPC in vitro and suppressed tumor growth and bone loss in PSMA+ CRPC xenograft and bone metastasis model. Ivyspring International Publisher 2019-02-07 /pmc/articles/PMC6401511/ /pubmed/30867828 http://dx.doi.org/10.7150/thno.29884 Text en © Ivyspring International Publisher This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Shi, Sheng-Jia
Wang, Li-Juan
Han, Dong-Hui
Wu, Jie-Heng
Jiao, Dian
Zhang, Kai-Liang
Chen, Jiang-Wei
Li, Yu
Yang, Fa
Zhang, Jing-Liang
Zheng, Guo-Xu
Yang, An-Gang
Zhao, Ai-Zhi
Qin, Wei-Jun
Wen, Wei-Hong
Therapeutic effects of human monoclonal PSMA antibody-mediated TRIM24 siRNA delivery in PSMA-positive castration-resistant prostate cancer
title Therapeutic effects of human monoclonal PSMA antibody-mediated TRIM24 siRNA delivery in PSMA-positive castration-resistant prostate cancer
title_full Therapeutic effects of human monoclonal PSMA antibody-mediated TRIM24 siRNA delivery in PSMA-positive castration-resistant prostate cancer
title_fullStr Therapeutic effects of human monoclonal PSMA antibody-mediated TRIM24 siRNA delivery in PSMA-positive castration-resistant prostate cancer
title_full_unstemmed Therapeutic effects of human monoclonal PSMA antibody-mediated TRIM24 siRNA delivery in PSMA-positive castration-resistant prostate cancer
title_short Therapeutic effects of human monoclonal PSMA antibody-mediated TRIM24 siRNA delivery in PSMA-positive castration-resistant prostate cancer
title_sort therapeutic effects of human monoclonal psma antibody-mediated trim24 sirna delivery in psma-positive castration-resistant prostate cancer
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401511/
https://www.ncbi.nlm.nih.gov/pubmed/30867828
http://dx.doi.org/10.7150/thno.29884
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