Dual Targeting of Endoplasmic Reticulum by Redox-Deubiquitination Regulation for Cancer Therapy

被引：17

作者：

Cai, Biao ^{[1
]}

Hou, Mengfei ^{[2
]}

Zhang, Shijun ^{[3
]}

Xin, Zhixiang ^{[1
]}

Huang, Jiwei ^{[1
]}

Yang, Jingxing ^{[2
]}

Wang, Yueming ^{[1
]}

Cai, Xingyun ^{[1
]}

Xie, Shaowei ^{[3
]}

Zhang, Chunfu ^{[2
]}

Huang, Yiran ^{[1
]}

机构：

[1] Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Dept Urol, 160 Pujian Rd, Shanghai 200127, Peoples R China

[2] Shanghai Jiao Tong Univ, Sch Biomed Engn, Shanghai 200030, Peoples R China

[3] Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Dept Ultrasound, 160 Pujian Rd, Shanghai 200127, Peoples R China

来源：

INTERNATIONAL JOURNAL OF NANOMEDICINE | 2021年 / 16卷

基金：

中国国家自然科学基金;

关键词：

endoplasmic reticulum stress; unfolded protein response; nanocatalytic medicine; reactive oxygen species; deubiquitinase inhibitor; apoptosis; OXIDE NANOPARTICLES; ER STRESS; NEUROPILIN-1; APOPTOSIS; CELLS;

D O I：

10.2147/IJN.S321612

中图分类号：

TB3 [工程材料学];

学科分类号：

0805 ; 080502 ;

摘要：

Background: Recently, nanocatalyst-induced endoplasmic reticulum (ER) stress for cancer therapy has been attracting considerable attention. However, cancer cells are often able to overcome ER stress-induced death by activating the unfolded protein response (UPR), making nanocatalytic monotherapy a poor defense against cancer progression. Purpose: In this study, to improve the nanocatalytic treatment efficacy, a phase change material (PCM) was used to encapsulate the upstream ER stress initiator, iron oxide nanoparticles (Fe3O4 NPs), and the downstream UPR modulator, PR-619. Subsequently, the tumor-homing peptide tLyP-1 was coupled to it to form tLyP-1/PR-619/Fe3O4@PCM (tPF@PCM) theranostic platform. Materials and Methods: tPF@PCM was synthesized using nanoprecipitation and resolidification methods followed by the EDC/NHS cross-linking method. The targeting capacity of tPF@PCM was evaluated in vitro and in vivo using flow cytometry and magnetic resonance imaging, respectively. The therapeutic efficacy of tPF@PCM was investigated in a renal cell carcinoma mouse model. Moreover, we explored the synergistic anti-tumor mechanism by examining the intracellular reactive oxygen species (ROS), aggregated proteins, ER stress response levels, and type of cell death. Results: tPF@PCM had excellent tumor-targeting properties and exhibited satisfactory photothermal-enhanced tumor inhibition efficacy both in vitro and in vivo. Specifically, the phase transition temperature (45 degrees C) maintained using 808 nm laser irradiation significantly increased the release and catalytic activity of the peroxidase mimic Fe3O4 NPs. This strongly catalyzed the generation of hydroxyl radicals (center dot OH) via the Fenton reaction in the acidic tumor microenvironment. The redox imbalance subsequently resulted in an increase in the level of damaged proteins in the ER and initiated ER stress. Moreover, the pan-deubiquitinase inhibitor PR-619 blocked the "adaptive" UPR-mediated degradation of these damaged proteins, exacerbating the ER burden. Consequently, irremediable ER stress activated the "terminal" UPR, leading to apoptosis in cancer cells. Conclusion: This ER stress-exacerbating strategy effectively suppresses tumorigenesis, offering novel directions for advances in the treatment of conventional therapy-resistant cancers.

引用

页码：5193 / 5209

页数：17