Potential of overpowering Drugs Resistance in MC F-7/Adr cells by regulation of apoptotic pathways using sorafenib incorporating chitosan conjugated folic acid nanoparticles: An Experimental Study

Abstract

Abstract Introduction: To overcome drug resistance and induce apoptosis in MCF-7/Adr human breast cancer cells which has a multidrug resistance, this study aims to develop a novel formulation of chitosan-sorafenib-conjugated FA nanoparticles (CsNPs-Sor-FA) for the efficient treatment of breast cancer. Methods The prepared formula was analyzed by using the FTIR, XRD, HRTEM, and UV-VIS spectrometers. A drug release experiment was performed in vitro, and the loading capacity and entrapment efficiency were estimated. The MTT assay was used to test for cytotoxicity. The nanoformula (CsNPs-Sor-FA) was tested as an anticancer treatment against MCF-7/adr cells by flow cytometry assay, cell cycle analysis, DNA fragmentation assay, real-time quantitative PCR (qRT-PCR), and western blot. Results We found that the CsNPs-Sor-FA formation had an average particle size of about 60 nm, an entrapment efficiency of 79 ± 2.9%, and a loading capacity 13.6 ± 1.2%. Around 90% of sorafenib was released from CsNPs-Sor after 120 hours, whereas CsNPs-Sor-FA nanoparticles exhibited an 88% sustained release pattern. The tested formulation of CsNPs-Sor-FA was not lethal to healthy lung cells. In addition, the morphological changes and DNA fragmentation results indicate that treatment with CsNPs-Sor-FA resulted in higher apoptosis data. Inhibition of cell cycle progression and inhibition of Nrf2 were also higher with CsNPs-Sor-FA treatment. Upregulation of apoptosis markers p53, caspase 9, caspase 8 and caspase 3, cytochrome c and TNFR was also observed; in contrast, expression of the anti-apoptotic marker Bcl-2 was reduced in the CsNPs-Sor-FA treated group compared to their individual treatments. Therefore, the nanoformula (CsNPs-Sor-FA) can be very useful for treating breast cancer. Conclusion Therefore, the present study has developed a nanoformula that shows promising antitumor activity against breast cancer cells and can improve survival rate of breast cancer patients.