Evaluation of carcinogenic ability of N-nitroso-N-methylurea, 7, 12-dimethylbenz anthracene and gold nanoparticles on in silico, in vitro and in vivo breast cancer models

Abstract

Breast cancer incidence rate in Pakistan is the highest in Asia. Resistance to the endocrine and chemotherapeutics drugs is the limitation of the current available treatments. There is an immense need to introduce targeted drugs to overcome resistance. Nanotechnology due to its targeted delivery, efficacy, controlled drug release to tumor cells and reduced toxicity have gained much importance to treat breast cancer in the advance stages. The aim of this study was to investigate the cytotoxic effect of Aloe vera and Gymnema sylvestre leaf extract derived gold nanoparticles conjugated with 4-Hydroxytamoxifen, Hypoxia inducible factor-1 Alpha inhibitor and H-[1, 2, and 4] oxadiazolo [4, 3,-a] quinoxalin-1 on breast cancer cells both in silico and in vitro. Furthermore, animal model of ER+ breast cancer was developed to check these formulations cytotoxicity and optimized dosage for clinical use. For the rat model of breast cancer, carcinogens such as NMU and DMBA were used in silico and among these two, the most appropriate was selected for in vivo model development. The in silico and in vitro interactions of 4-OHT, HIF-1A inhibitor or ODQ conjugated with AuNPs derived from the two biological sources with Estrogen receptor, HIF-1A and Guanylyl cyclase receptor protein revealed stronger hydrogen bonding with higher binding energy score by PatchDock docking and FireDock refinement. These chemically induced breast cancer rat models will be used for in vivo testing of our drug conjugated gold nanoparticles for pre-clinical studies. In future, we can perform analysis on combinatorial drug conjugation on AuNPs to block multiple pathways.