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Theranostics 2019; 9(5):1247-1263. doi:10.7150/thno.29884 This issue Cite

Research Paper

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

Sheng-Jia Shi^1#, Li-Juan Wang^2#, Dong-Hui Han^1#, Jie-Heng Wu^3#, Dian Jiao⁴, Kai-Liang Zhang⁵, Jiang-Wei Chen⁶, Yu Li¹, Fa Yang¹, Jing-Liang Zhang¹, Guo-Xu Zheng⁷, An-Gang Yang³, Ai-Zhi Zhao^8✉, Wei-Jun Qin^1✉, Wei-Hong Wen^3✉

1. Department of Urology, Xijing Hospital, Fourth Military Medical University, 710032 Xi'an, P.R. China
2. Department of Dermatology, First Affiliated Hospital of Xi'an Jiaotong University, 710061 Xi'an, P.R. China
3. State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, 710032 Xi'an, P.R. China
4. Department of Urology, Tangdu Hospital, Fourth Military Medical University, 710038 Xi'an, P.R. China
5. Department of Orthopedics, Tangdu Hospital, Fourth Military Medical University, 710038 Xi'an, P.R. China
6. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 710032 Xi'an, P.R. China.
7. Department of Physiology and Pathophysiology, Fourth Military Medical University, 710032 Xi'an, P.R. China
8. OriMAbs Ltd. Science center, Room 544. 3624 Market Street, PA 19104, USA
^# These authors contributed equally to this work.

✉ Corresponding authors: Weihong Wen, Department of Immunology, Fourth Military Medical University, 169 Changle West Road, Xi'an, China 710032. Tel.: +86 29 84774532; Fax: +86 29 83253816; Email: wenweihedu.cn; Weijun Qin, Department of Urology, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an, China 710032. Tel.: +86 29 84775321; Email: qinweijedu.cn; Aizhi Zhao, OriMAbs Ltd. Science center, Room 544. 3624 Market Street, PA 19104, USA. Tel: 215-966-6286; Email: zhaoaizhicom. More

Abstract

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.

Keywords: CRPC, PSMA, TRIM24, RNA interference

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