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

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.

<p>Co-Delivery of Curcumin and Paclitaxel by “Core-Shell” Targeting Amphiphilic Copolymer to Reverse Resistance in the Treatment of Ovarian Cancer</p>

“…(PEI-SA)HA/PC inhibited the cell invasiveness of SKOV3 and SKOV3-TR30 significantly. The cell apoptosis and metastasis were inhibited in a dose-dependent manner, which was consistent with the reported views 22,23. Therefore, (PEI-SA) HA/PC is effective not only for the treatment of SKOV3 cells but also for the resistant cell line SKOV3-TR30.…”

Efficacy-shaping nanomedicine by loading Calcium Peroxide into Tumor Microenvironment-responsive Nanoparticles for the Antitumor Therapy of Prostate Cancer

“…FCM based on Annexin-V-FITC/PI staining was adopted to evaluate the cell apoptosis induced by CaO 2 @HMSNs-PAA. Apoptotic cells were considered to be those situated in the lower right quadrants 67 . As shown in Figure 6 , under the condition of pH 7.4, the gourps of CaO 2 @HMSNs-PAA and CaO 2 @HMSNs exhibited significantly higher apoptosis rates of 20.42% and 17.22% than that of only 7.52% in the CaO 2 group ( p < 0.01).…”

Recent Advances in Nanomedicine for the Diagnosis and Treatment of Prostate Cancer Bone Metastasis

“…Shi et al developed a TRIM24 delivery system using the human antibody that binds to PSMA. Using known bioconjugation chemistry, the PSMA antibody was first covalently tethered to protamine sulfate, and the modified antibody (PSP) was then able to efficiently encapsulate the TRIM24 siRNA (PSP-TRIM24) [ 223 ]. Cell assays revealed that the PSP-TRIM24 complexes were internalized by PSMA-positive cell lines (C4-2, LNCaP, PC3-PSMA+) but did not bind to or deliver TRIM 24 to PSMA-negative cell lines (DU-145, PC3).…”