taribavirin and Breast-Neoplasms

Current estimates indicate that hepatocarcinoma is the leading cause of death globally. There is interest in utilizing nanomedicine for cancer therapy to overcome side effects of chemo-interventions. Ribavirin, an antiviral nucleoside inhibitor, accumulates inside red blood cells, causing anemia. Its analog, viramidine, can concentrate within hepatocytes and spare red blood cells, thus limiting anemia. Hepatocarcinoma cells have a large number of asialoglycoprotein receptors on their membranes that can bind galactosyl-terminating solid lipid nanoparticles (Gal-SLN) and internalize them. Here, viramidine, 5-fluorouracil, and paclitaxel-loaded Gal-SLN were characterized inside cells. Cytotoxicities of free-drug, nano-void, and drug-loaded Gal-SLN were evaluated using HepG2 cells; over 3 days, cell viability was measured. To test the mechanistic pathway, we investigated in vitro apoptosis using flow cytometry and in ovo angiogenesis using the CAM assay. Results showed that 1 and 2 μM of the viramidine-encapsulated Gal-SLN had the highest cytotoxic effect, achieving 80% cell death with a steady increase over 3 days, with induction of apoptosis and reduction of necrosis and angiogenesis, compared to free-drugs. Gal-SLN application on breast cancer MCF-7 cells confirmed its specificity against liver cancer HepG2 cells. We conclude that viramidine-encapsulated Gal-SLN has anticancer and anti-angiogenic activities against hepatocarcinoma.

Topics: Angiogenesis Inhibitors; Apoptosis; Breast Neoplasms; Carcinoma, Hepatocellular; Galactose; Hep G2 Cells; Humans; Liver Neoplasms; MCF-7 Cells; Nanoparticles; Neovascularization, Pathologic; Ribavirin

Breast cancer is the second most common cause of mortality in women in the United States. Targeted delivery of antitumor breast cancer drugs as a drug-delivery strategy may allow direct delivery into the tumor. Currently, chemotherapy is one of the principle strategies for cancer treatment, but it can have toxic side effects. Nanotechnology attempts to resolve these challenges by loading drugs in nanoparticles, such as solid lipid nanoparticles (SLN). In response to the breast cancer drug 5-fluorouracil (5-FU), p38MAPK signaling has been investigated since the 1990s. Ribavirin, a nucleotide derivative, inhibits p38MAPK in infected hepatocytes. A ribavirin prodrug, taribavirin (TBV), was recently synthesized to concentrate in the liver and have minimal concentration in red blood cells.. In this study, TBV and 5-FU-pegylated SLNs were prepared and characterized. The in vitro cytotoxicity was evaluated against MCF-7 breast cancer cells. Using molecular docking experiments, 5-FU and TBV were docked on p38MAPK protein.. The TBV nanoformulation had the highest cytotoxic effects, achieving IC. The effect of TBV nanoparticles on MCF-7 cells may be due to its inhibitory effect against p38MAPK protein, where it fits inside the active pocket site of the p38 protein molecular surface, with a minimum binding affinity of -5.5 kcal/mol (rmsd of 1.07), and it formed strong hydrogen bonds with amino acids ASP'168, ILE'166, HIS'148, and ILE'147. Further studies are warranted to investigate the mechanistic details of the proposed approach.

Topics: Antineoplastic Agents; Biological Availability; Breast Neoplasms; Drug Carriers; Drug Compounding; Drug Screening Assays, Antitumor; Fluorouracil; Humans; Inhibitory Concentration 50; Lipids; MCF-7 Cells; Mitogen-Activated Protein Kinase 14; Molecular Docking Simulation; Nanoparticles; Polyethylene Glycols; Ribavirin