Benzimidazole-Based Organic-Inorganic Gold Nanohybrids Suppress Invasiveness of Cancer Cells by Modulating EMT Signaling Cascade.

Over the past few years, nanotechnology-based approaches have emerged to override drug resistance owing to their superiority over other formulations because of their diverse therapeutic advantages such as target-specific drug delivery, enhanced bioavailability, biodegradability, and minimal off-target effects. Hybrid nanomaterials as a formulation of anticancer drugs with gold nanoparticles (AuNPs) have adequately proven efficacious in controlled release as well as disintegration into ultrasmall nanoparticles dragging the drug to penetrate deep into tumor tissues and consequently getting cleared from the body. In this study, to achieve better antitumor responses, we engineered self-assembled organic nanoparticles of potent anticancer compound BZ6 (BZ6-ONPs), BZ6-gold nanoparticle conjugates (BZ6-AuNPs), and organic-inorganic nanohybrids involving amalgamation of AuNPs with BZ6-ONPs (AuNPs@BZ6-ONPs) and comparatively analyzed their physicochemical as well as biological activities. The epithelial-mesenchymal transition (EMT) is a critical biological event that facilitates metastatic spread of cancer cells and contributes to chemoresistance. AuNPs@BZ6-ONPs consistently suppressed EMT characteristics including invasion, cell scattering, and migration abilities of aggressive breast cancer (MDA-MB-231) and pancreatic adenocarcinoma (PANC-1) cells much more efficiently than BZ6-ONPs and BZ6-AuNPs. Western blotting and immunocytochemistry analysis unveiled that the nanohybrids downregulated expression of the key mesenchymal markers NF-κß p65, Twist-1, vimentin, and MMP-2, meanwhile augmenting epithelial marker E-cadherin and tumor suppressor Par-4. The in vivo syngenic mouse tumor model demonstrated remarkable reduction of tumor growth (84.3%) and metastatic lung nodules (66.1%) following 14 days of treatment without any adverse effects. Finally, the facile and ecofriendly method of synthesis of AuNPs@BZ6-ONPs demonstrating promising antitumor/antimetastatic efficacies suggests its therapeutic implication for the treatment of advanced cancers.

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

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.