RGD Peptide-Conjugated Selenium Nanocomposite Inhibits Human Glioma Growth by Triggering Mitochondrial Dysfunction and ROS-Dependent MAPKs Activation

Wenjian Liu,Jie Cui,Beibei Sun,Mengkao Li,Jing Su,Shizhong Zhang,Xiao Chen,Jinlei Wang,Cundong Fan,Qiang Shi,Guojun Wang

doi:10.3389/fbioe.2021.781608

Abstract

Chemotherapy is still one of the most common ways to treat human glioblastoma in clinic. However, severe side effects limited its clinic application. Design of cancer-targeted drugs with high efficiency and low side effect is urgently needed. Herein, silver nanoparticles (Ag NPs) and nano-selenium (Se NPs) conjugated with RGD peptides (Ag@Se@RGD NPs) to target integrin high-expressed glioma were designed. The results found that Ag@Se@RGD NPs displayed stable particle size and morphology in physiological condition, and induced significant integrin-targeted intracellular uptake. Ag@Se@RGD NPs in vitro dose-dependently inhibited U251 human glioma cells growth by induction of cells apoptosis through triggering the loss of mitochondrial membrane potential, overproduction of reactive oxygen species (ROS), and MAPKs activation. However, ROS inhibition dramatically attenuated Ag@Se@RGD NPs-induced MAPKs activation, indicating the significant role of ROS as an early apoptotic event. Importantly, Ag@Se@RGD NPs administration in vivov effectively inhibited U251 tumor xenografts growth by induction of apoptosis through regulation MAPKs activation. Taken together, our findings validated the rational design that Ag-Se NPs conjugated with RGD peptides was a promising strategy to combat human glioma by induction of apoptosis through triggering mitochondrial dysfunction and ROS-dependent MAPKs activation.

Highlights

Glioma is still considered as the most common primary malignant brain tumors, accounting for about 80% of malignant brain tumors (Gittleman et al, 2020)
The formation and modification of the Se shell resulted in the color of the yellow-green Ag NPs colloidal solution changing to yellow-brown, and the modification of Cs-RGD did not cause a significant change in color (Figure 1G)
The results showed that the composite nano-system Ag@Se@RGD NPs was successfully assembled

Summary

INTRODUCTION

Glioma is still considered as the most common primary malignant brain tumors, accounting for about 80% of malignant brain tumors (Gittleman et al, 2020). The toxicity of 0–60 μg/ml Ag@Se. NPs and Ag@Se@RGD NPs to Glioma cells was examined by standard MTT analysis (Sun et al, 2020). U251 cells were cultured in 96-well plates at a density of 5 × 103 cells/well for 24 h, and coumarin-6-labeled Ag@Se NPs and Ag@Se@RGD NPs were added and incubated for 2 h. U251 cells were treated with 5, 10, or 20 μg/ ml Ag@Se@RGD NPs for 24 h, and the operation was performed according to the instructions of the apoptosis detection kit and the mitochondrial membrane potential detection kit. In order to determine the side effects of Ag@Se@RGD NPs treatment on vital organs, 0–80 mg/kg of Ag@Se@RGD NPs was continuously administered through the tail vein, and the survival rate and body weight changes of the mice were recorded every day. Signifificant differences between the treatment and control groups are indicated at *p < 0.05, **p < 0.01

RESULTS AND DISCUSSION

CONCLUSION

ETHICS STATEMENT