A potent formula against Triple-negative Breast Cancer - Sorafenib-Carbon Nanotubes- Folic Acid: Targeting, Apoptosis triggering, and bioavailability enhancing

Abstract

Abstract Triple-negative breast cancer (TNBC) has short survival rates, a high recurrence rate, aggressive clinical behavior, a high risk of metastasis and it is difficult to be targeted by ordinary medicines. This study aimed to (i) prepare a novel formula of sorafenib, carbon nanotubes, and folic acid to be tested as a drug delivery system targeting TNBC with higher safety and efficacy compared with free sorafenib and to (ii) evaluate the formula stability, in vitro pharmacodynamic, and in vivo pharmacokinetic properties. The formula preparation was done by the synthesis of polyethylene glycol bis amine linker, carbon nanotube pegylation, folic acid attachment, and sorafenib loading. The prepared formula has been characterized using XRD, FTIR, 1HNMR, UV, HR-TEM, FESEM, Zeta sizer and Zeta potential. In vitro studies included drug release determination, MTT assay, flow cytometry to determine the apoptotic stage with percent, cell cycle analysis, and apoptotic marker assays for caspase-3, 8, 9, cytochrome c, and BCL-2. The in vivo study was performed to determine bioavailability and half-life in rats. The in vitro MTT anti-proliferative assay revealed that the formula was 3-fold more cytotoxic towards TNBC cells than free sorafenib, and the flow cytometry showed a significant increase in apoptosis and necrosis. The formula has a greater inhibitory effect on BCL-2 and a lessening effect on cytochrome c and caspases 3, 8, and 9 than free sorafenib. Moreover, in vivo experiments proved that our novel formula was superior to free sorafenib by increasing bioavailability by eight times and prolonging the half-life by three times. These results confirmed the successful preparation of the desired formula with better pharmacodynamic and pharmacokinetic properties. These promising results may show a novel therapeutic strategy for TNBC patients.