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Theranostics 2020; 10(4):1619-1632. doi:10.7150/thno.40489 This issue Cite

Research Paper

SREBP1 siRNA enhance the docetaxel effect based on a bone-cancer dual-targeting biomimetic nanosystem against bone metastatic castration-resistant prostate cancer

Jiyuan Chen¹, Zhenjie Wu², Weihong Ding³, Chengwu Xiao², Yu Zhang¹, Shen Gao², Yuan Gao^1,2✉, Weimin Cai^1✉

1. Department of Clinical Pharmacy and Drug Administration, School of Pharmacy, Fudan University, Shanghai 201203, China
2. Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
3. Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, China

✉ Corresponding authors: Yuan Gao: yuan_gaoedu.cn (Y. Gao), Weimin Cai: weimincaiedu.cn (W. Cai)

Abstract

Until recently, there have been limited options for patients with bone metastatic castration-resistant prostate cancer (BmCRPC) following the failure of or development of resistance to docetaxel (DTX), which is one of the frontline treatments. Sterol regulatory element-binding protein 1 (SREBP1) is reported to regulate abnormal lipid metabolism and to promote the progression and metastasis of prostate cancer (PCa). The siRNA interferes SREBP1 may provide an efficient treatment when combined with DTX.

Methods: In this study, lipoic acid (LA) and cross-linked peptide-lipoic acid micelles were cross-linked (LC) for DTX and siSREBP1 delivery (LC/D/siR). Then, cell membrane of PCa cells (Pm) and bone marrow mesenchymal stem cells (Bm) were fused for cloaking LC/D/siR (PB@LC/D/siR). Finally, the synthesized PB@LC/D/siR was evaluated in vitro and in vivo.

Results: PB@LC/D/siR is internalized in PCa cells by a mechanism of lysosome escape. Tumor targeting and bone homing studies are evaluated using bone metastatic CRPC (BmCRPC) models, both in vitro and in vivo. Moreover, the enhanced anti-proliferation, anti-migration and anti-invasion capacities of DTX- and siSREBP1- loaded PB@LC (PB@LC/D/siR) were observed in vitro. Furthermore, PB@LC/D/siR was able to suppress the growth of the tumor effectively with deep tumor penetration, high safety and good protection of the bone at the tumor site. Additionally, the mRNA levels and protein levels of SREBP1 and SCD1 were able to be significantly downregulated by PB@LC/D/siR.

Conclusion: This study presented a bone-cancer dual-targeting biomimetic nanodelivery system for bone metastatic CRPC.

Keywords: bone metastatic prostate cancer, fused cell membrane, bone marrow mesenchymal stem cells, docetaxel, SREBP1 siRNA

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