Multifunctional tumor-targeted PLGA nanoparticles delivering Pt(IV)/siBIRC5 for US/MRI imaging and overcoming ovarian cancer resistance

Yanhua Zhang; Yang Dong; Hao Fu; Hui Huang; Zhihua Wu; Meng Zhao; Xupeng Yang; Qianqian Guo; Yourong Duan; Ying Sun

doi:10.1016/j.biomaterials.2020.120478

Multifunctional tumor-targeted PLGA nanoparticles delivering Pt(IV)/siBIRC5 for US/MRI imaging and overcoming ovarian cancer resistance

Biomaterials. 2021 Feb:269:120478. doi: 10.1016/j.biomaterials.2020.120478. Epub 2020 Nov 12.

Authors

Yanhua Zhang¹, Yang Dong¹, Hao Fu¹, Hui Huang¹, Zhihua Wu¹, Meng Zhao¹, Xupeng Yang¹, Qianqian Guo¹, Yourong Duan², Ying Sun³

Affiliations

¹ State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, China.
² State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, China. Electronic address: yrduan@shsci.org.
³ State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, China. Electronic address: ysun@shsci.org.

PMID: 33213862
DOI: 10.1016/j.biomaterials.2020.120478

Abstract

Cisplatin (Pt(II)) resistance is an important factor in the high mortality rates of ovarian cancer. Herein, we synthesized multifunctional tumor-targeted poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs-cRGD) for monitoring therapeutic effects by dual-mode imaging and overcoming cisplatin resistance. Uniformly sized NPs-cRGD demonstrated controlled and sustained release of drugs and genes, excellent gene loading and gene protection capacity, good storage stability and no serum-induced aggregation in vitro. NPs-cRGD demonstrated clear, targeting and prolonged ultrasound imaging and magnetic resonance imaging (MRI) in vivo. The targeting of NPs-cRGD combined with ultrasound facilitated nanoparticle penetrattion into cells; entry was time-dependent. NPs-cRGD escaped from lysosomes, thereby preventing siBIRC5 degradation, which enabled siBIRC5 to efficiently inhibit the antiapoptosis effects of BIRC5 in SKO3-DDP to overcome the antiapoptosis properties of resistant cells. Furthermore, Pt(IV) in NPs-cRGD exhausted glutathione (GSH), thereby increasing drug accumulation to effectively increase Pt(II) levels. The subsequent combination of Pt(II) with DNA prevented the expressions of genes and upregulated the expression of p53 to induce the mitochondria apoptosis pathway. The reduced GSH activity and the generation of Pt(II) further promoted high levels of reactive oxygen species (ROS) to induce cell apoptosis. Therefore, NPs-cRGD with ultrasound promoted the apoptosis of resistant ovarian cancer cells by multiple mechanisms, including increased cellular drug accumulation, reversed antiapoptotic effects by siBIRC5, and enhanced ROS levels. In a tumor-bearing nude mice model, NPs-cRGD with US demonstrated excellent tumor-targeting, high efficiency tumor inhibition and low systemic toxicity. Therefore, NPs-cRGD provides a means to monitor treatment processes and can be combined with ultrasound treatment to overcome ovarian cancer resistance in vitro and in vivo.

Keywords: MRI; Ovarian cancer resistance; Prodrug Pt(IV); US imaging; siBIRC5.

Publication types

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

MeSH terms

Animals
Cell Line, Tumor
Female
Humans
Magnetic Resonance Imaging
Mice
Mice, Nude
Multifunctional Nanoparticles*
Nanoparticles*
Ovarian Neoplasms* / diagnostic imaging
Ovarian Neoplasms* / drug therapy