Synergistic Silencing of Skp2 by siRNA Self-Assembled Nanoparticles as a Therapeutic Strategy for Advanced Prostate Cancer

Hong Liang; Fangming Zhang; Yannv Hong; Yue Wu; Huanzhang Xie; Chen Zhang; Zonghua Wang; Zhonglei Lu; Huanghao Yang

doi:10.1002/smll.202106046

Synergistic Silencing of Skp2 by siRNA Self-Assembled Nanoparticles as a Therapeutic Strategy for Advanced Prostate Cancer

Small. 2022 Apr;18(14):e2106046. doi: 10.1002/smll.202106046. Epub 2022 Feb 19.

Authors

Hong Liang^{1

2}, Fangming Zhang¹, Yannv Hong¹, Yue Wu¹, Huanzhang Xie², Chen Zhang², Zonghua Wang², Zhonglei Lu¹, Huanghao Yang³

Affiliations

¹ College of Biological Science and Engineering, Fuzhou University, Fuzhou, 350108, P. R. China.
² Fujian Key Laboratory of Functional Marine Sensing Materials, Fuzhou Institute of Oceanography, Minjiang University, Fuzhou, 350108, P. R. China.
³ MOE Key Laboratory for Analytical Science of Food Safety and Biology, Fujian Provincial Key Laboratory of Analysis and Detection Technology for Food Safety, State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou, 350108, P. R. China.

PMID: 35182014
DOI: 10.1002/smll.202106046

Abstract

Advanced prostate cancer, harboring multiple mutations of tumor suppressor genes, is refractory to conventional therapies. Knockout of the Skp2 gene blocks pRb/p53 doubly deficient prostate cancer in mice, which inspired the authors to develop an approach for delivering siRNA that would efficiently silence Skp2 (siSkp2) in vivo. Here, a facile strategy is reported to directly assemble siSkp2 with the natural compound quercetin (Que) into supramolecular nanoparticles (NPs). This carrier-free siSkp2 delivery system could effectively protect siSkp2 from degradation in serum and enhance its cellular internalization. Furthermore, the siSkp2/Que NPs exhibit synergistic effects in Skp2 silencing, because they can degrade the mRNA and protein of Skp2 simultaneously. Indeed, siSkp2/Que NPs remarkably diminish the Skp2 abundance and further inhibit the proliferation and migration of TMU cells (RB1/TP53/KRAS triple mutations) in vitro. The in vivo results further show that i.v. administration of siSkp2/Que NPs efficiently accumulates in tumor sites and strongly inhibits the growth of TMU tumors in nude mice. Importantly, the siSkp2/Que NPs do not induce any abnormality in the treated mice, which suggests satisfactory biocompatibility. Collectively, this study describes a tractable siRNA self-assembled strategy for Skp2 silencing, which might be a promising nanodrug to cure multitherapy-resistant advanced prostate cancer.

Keywords: Skp2; advanced prostate cancer; nanodrugs; self-assembly; siRNA delivery.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Humans
Male
Mice
Mice, Knockout
Mice, Nude
Nanoparticles*
Prostatic Neoplasms* / drug therapy
Prostatic Neoplasms* / genetics
RNA, Small Interfering / genetics

Substances

RNA, Small Interfering