Self-assembled organic nanoparticles of benzimidazole analogue exhibit enhanced uptake in 3D tumor spheroids and oxidative stress induced cytotoxicity in breast cancer

Abstract

Organic nanoparticles (ONPs) possess great research interests for their promising effects in the enhancement of bioactivity including anticancer activity with less toxicity. The present study describes the preparation, characterization and biological evaluation of aqueous phase ONPs of potent 1,2-disubstituted benzimidazole derivative (BZ6) for anticancer activity. BZ6-ONPs were characterized through UV-absorption and fluorescence spectroscopic analysis for their photo-physical properties. DLS, TEM and SEM studies were carried out for morphological and structural analysis. Cytotoxicity determination on a panel of four different cancer cell lines (MCF-7, MiaPaca-2, HT-29 and HCT-116) revealed that the BZ6-ONPs show highest activity in human breast cancer MCF-7 cells. Surprisingly, the BZ6-ONPs were found to be non-toxic towards normal breast epithelial fR2 cells. Additionally, the FITC-ONPs showed enhanced uptake in 3D tumor spheroids of MCF-7 cells compared to the free FITC. BZ6-ONPs strongly halted cell proliferation and induced apoptosis, possibly through oxidative stress-mediated reactive oxygen species (ROS) generation and loss of mitochondrial membrane potential (MMP) in MCF-7 cells. Moreover, molecular mechanism-based studies revealed that BZ6-ONPs downregulated AKT/NF-κB/vimentin/survivin-mediated oncogenic signaling pathway promoting cell proliferation and malignancy. In a nutshell, BZ6-ONPs are therapeutically efficacious, which needs further development as a treatment option in human mammary gland carcinomas.

Keywords: 3D spheroid uptake; Apoptosis; Benzimidazole; Breast cancer; Organic nanoparticles; Reactive oxygen species (ROS).