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

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.

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“…The suppression of the expression of kinases involved in growth-factor-associated growth and survival of cells likely contributed to the reduction In the survival of tumor cells and the activation of apoptosis [ 23 ]. Liu et al (2021) [ 133 ] observed similar changes in the phosphorylation of p38, JNK, and Erk1/2 in U251 cells (human glioma). After the application of GSH (an antioxidant), they recorded a decrease in the activation of these kinases, and therefore, the authors point to the involvement of ROS in the activation of MAPK signaling pathways.…”

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“…Our previous work also indicated that Se NPs could induce cancer cell apoptosis by inhibiting EGFR-mediated PI3K/AKT and Ras/Raf/MEK/ERK pathways after loading with oridonin ( 53 ). What is more, it is reported that Se NPs could trigger MAPK activation and the caspase-3 signal pathway, eventually inducing apoptosis of tumor cells ( 54 , 55 ). These results suggest that Se NPs could serve as strong apoptosis-induction agents, which therefore shows the potential of Se NPs as novel antitumor agents by inducing cancer cell apoptosis.…”

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“…Similarly, Song et al synthesized "smart" nanosystems based on Se NPs modified with HER-2 antibody for effective delivery into the brain tumor [299]. Wenjian has developed inorganic hybrids made of Ag and Se NPs (Ag@Se NPs) for the GBM therapy [300]. Ag@Se NPs were conjugated with RGD peptides (Ag@Se-RGD NPs) for GBM targeting.…”

“…Ag@Se NPs were conjugated with RGD peptides (Ag@Se-RGD NPs) for GBM targeting. The results showed that Ag@Se-RGD NPs possessed high in vitro stability and induced a significant intracellular uptake by human glioma cells U251 with the following cell apoptosis due to ROS effect [300].…”