Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783400152584683520 |
---|---|
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. |
format | Online Article Text |
id | pubmed-6401511 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT shishengjia therapeuticeffectsofhumanmonoclonalpsmaantibodymediatedtrim24sirnadeliveryinpsmapositivecastrationresistantprostatecancer AT wanglijuan therapeuticeffectsofhumanmonoclonalpsmaantibodymediatedtrim24sirnadeliveryinpsmapositivecastrationresistantprostatecancer AT handonghui therapeuticeffectsofhumanmonoclonalpsmaantibodymediatedtrim24sirnadeliveryinpsmapositivecastrationresistantprostatecancer AT wujieheng therapeuticeffectsofhumanmonoclonalpsmaantibodymediatedtrim24sirnadeliveryinpsmapositivecastrationresistantprostatecancer AT jiaodian therapeuticeffectsofhumanmonoclonalpsmaantibodymediatedtrim24sirnadeliveryinpsmapositivecastrationresistantprostatecancer AT zhangkailiang therapeuticeffectsofhumanmonoclonalpsmaantibodymediatedtrim24sirnadeliveryinpsmapositivecastrationresistantprostatecancer AT chenjiangwei therapeuticeffectsofhumanmonoclonalpsmaantibodymediatedtrim24sirnadeliveryinpsmapositivecastrationresistantprostatecancer AT liyu therapeuticeffectsofhumanmonoclonalpsmaantibodymediatedtrim24sirnadeliveryinpsmapositivecastrationresistantprostatecancer AT yangfa therapeuticeffectsofhumanmonoclonalpsmaantibodymediatedtrim24sirnadeliveryinpsmapositivecastrationresistantprostatecancer AT zhangjingliang therapeuticeffectsofhumanmonoclonalpsmaantibodymediatedtrim24sirnadeliveryinpsmapositivecastrationresistantprostatecancer AT zhengguoxu therapeuticeffectsofhumanmonoclonalpsmaantibodymediatedtrim24sirnadeliveryinpsmapositivecastrationresistantprostatecancer AT yangangang therapeuticeffectsofhumanmonoclonalpsmaantibodymediatedtrim24sirnadeliveryinpsmapositivecastrationresistantprostatecancer AT zhaoaizhi therapeuticeffectsofhumanmonoclonalpsmaantibodymediatedtrim24sirnadeliveryinpsmapositivecastrationresistantprostatecancer AT qinweijun therapeuticeffectsofhumanmonoclonalpsmaantibodymediatedtrim24sirnadeliveryinpsmapositivecastrationresistantprostatecancer AT wenweihong therapeuticeffectsofhumanmonoclonalpsmaantibodymediatedtrim24sirnadeliveryinpsmapositivecastrationresistantprostatecancer |