Novel dual responsive embelin functionalised ZnO nanomaterials amplify DNA damage and induce apoptosis via pERK1/2/p53 pathway in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor prognosis and chemoresistance. Nano-bioconjugates, due to their enhanced surface-to-volume ratio, offer significant potential in cancer therapy. In this study, we synthesized ZnO nanoparticles (NPs) using solution combustion method and exhibited a particle size range of 20-70 nm as confirmed by TEM analysis. These NPs were conjugated with embelin, a natural benzoquinone compound. Successful conjugation was confirmed using FTIR spectroscopy. Structural and morphological characteristics of the conjugates were confirmed using XRD, SEM, TEM, FTIR, and EDS color mapping. Embelin conjugated ZnO NPs (Emb-ZnO NPs) were evaluated against PDAC cell lines (PANC-1 and MIA PaCa-2). The nanoconjugates showed significant cytotoxicity compared to individual Embelin and ZnO NPs, with IC values of 7.05 ± 0.96 μg/ml (PANC-1) and 8.66 ± 1.46 μg/ml (MIA PaCa-2). Emb-ZnO NPs exhibited tumoricidal effects in clonogenic and migration assays. Fluorescent staining revealed disrupted cellular architecture and significant apoptosis. Immunoblot analysis exhibits deregulation of key pathways, including amplified expression of γ-H2AX (88.48 %), indicative of DNA damage. Concurrently, elevated levels of pChk2 (68.07 %), p53 (89.34 %), and caspase-3 (26.67 %) promote Cell cycle halting and programmed cell death triggered by genomic instability. Conversely, reduced pERK1/2 (53.77 %) expression suggested inhibition of the MAPK pathway by Emb-ZnO NPs. Additionally, the formulation inhibited neovascularization in the CAM model, indicating anti-angiogenic potential. Molecular dynamics simulations of p53 and pERK1/2 aligned with in vitro results. In conclusion, Emb-ZnO NPs is a promising therapeutic candidate for PDAC and other cancers.