Targeting BMI-1 with PLGA\u2013PEG nanoparticle-containing PTC209 modulates the behavior of human glioblastoma stem cells and cancer cells

Elham Poonaki,Mehdi Shafiee Ardestani,Gholamhossein Tondro,Sepideh Ghasemi,Fatemeh Ariakia,Mohammad Jalili-Nik,Fariborz Samini,Sajad Sahab-Negah,Ali Gorji

doi:10.1186/s12645-021-00078-8

Abstract

Despite advances in glioblastoma (GBM) treatments, current approaches have failed to improve the overall survival of patients. The oncogene BMI-1, a core member of the polycomb group proteins, is a potential novel therapeutic target for GBM. To enhance the efficacy and reduce the toxicity, PTC209, a BMI-1 inhibitor, was loaded into a PLGA–PEG nanoparticle conjugated with CD133 antibody (Nano-PTC209) and its effect on the behavior of human GBM stem-like cells (GSCs) and the human glioblastoma cell line (U87MG) was assessed. Nano-PTC209 has a diameter of ~ 75 nm with efficient drug loading and controlled release. The IC50 values of Nano-PTC209 for GSCs and U87MG cells were considerably lower than PTC209. Nano-PTC209 significantly decreased the viability of both GSCs and U87MG cells in a dose-dependent manner and caused a significant enhancement of apoptosis and p53 levels as well as inhibition of AKT and JNK signaling pathways. Furthermore, Nano-PTC209 significantly inhibited the migration ability, decreased the activity of metalloproteinase-2 and -9, and increased the generation of reactive oxygen species in both GSCs and U87MG cells. Our data indicate that PLGA–PEG nanoparticle conjugated with CD133 antibody could be an ideal nanocarrier to deliver PTC209 and effectively target BMI-1 for potential approaches in the treatment of GBM.

Highlights

Glioblastoma multiforme (GBM), the most common malignant brain tumor, is a highly aggressive cancer with extremely poor clinical outcomes (Hanif et al 2017)
The present study aimed to investigate the effect of PTC209 loaded into a PLGA–PEG nanoparticle conjugated with CD133 antibody (Nano-PTC209) on the survival, proliferation, migration, and invasive properties of human GBM stem-like cells (GSCs) and the human glioblastoma cell line (U87MG)
The peak at 666.47 cm−1 is related to bromide, which exists in the structure of PTC209 (Fig. 2c)

Summary

Introduction

Glioblastoma multiforme (GBM), the most common malignant brain tumor, is a highly aggressive cancer with extremely poor clinical outcomes (Hanif et al 2017). The mean value of BMI-1 expression is markedly upregulated in GBM and inhibits the activation of the tumor-suppressor signaling pathway (Yoshimoto et al 2011). The expression of BMI-1 has considerably upregulated in glioblastoma stem-like cells (GSCs) and acts as a key regulator of their self-renewal and differentiation (Hong et al 2015). The selective inhibition of post-transcriptional regulation of BMI-1 significantly impairs GSCs proliferation and differentiation in vitro and reduces GBM growth in vivo (Kong et al 2018). The expression of the CD133, a glycoprotein antigen, in GBM correlates with tumor progression and patient survival (Lim et al 2014). BMI-1 is expressed in human GBM tumors and highly enriched in CD133-positive cells (Abdouh et al 2009; Venugopal et al 2012). Silencing BMI-1 led to the elimination of the tumor-forming capacity of CD133+ GBM cells (Baxter et al 2014)

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Discussion

Conclusion