Development of Stimuli-Responsive Nanoparticles for Targeted Delivery of Encorafenib in BRAF-Mutant Cancer Therapy

Abstract

Background: Cancers that are driven by mutations in the BRAF gene, such as those in melanoma and colorectal cancer, tend to grow very quickly and are resistant to traditional chemotherapy. Encorafenib, a newer generation BRAF inhibitor, is more effective, but also more likely to be toxic at non-target sites and to fail to accumulate in tumors. Nanotechnology based delivery strategies have been emerging as a potential tool for the precise and efficient delivery of drugs. Objective: The objective of this research was to formulate and test stimuli-responsive nanoparticles for targeted delivery of Encorafenib, which could release the drug in response to tumor specific microenvironmental conditions like acidic pH and redox state. Methods: Polymeric nanoparticles loaded with encorafenib were prepared by nanoprecipitation method in which nanoparticles were formed using the pH/redox-sensitive polymer. The characteristics of the nanoparticles such as particle size, particle size index, drug loading and morphology were determined. The in-vitro-related studies were performed at both physiological and tumor-mimicking conditions. The MTT assay was used to evaluate cytotoxicity on BRAF-mutant cancer cell lines and cellular uptake was analyzed using confocal microscopy. Results:The optimized nanoparticles had a mean diameter of ~ 160 nm with high EE (more than 80%). The drug release was significantly increased at pH 5.5, showing stimuli responsiveness, as well as in the presence of glutathione. In vitro, the inhibition of the growth of cancer cells was found to be greater than with the free drug, Encorafenib. Cells were also observed by confocal imaging to verify efficient cellular uptake of the fluorescently labeled nanoparticles. Conclusion:The delivery of Encorafenib with stimuli-responsive nanoparticles has the potential to be a very attractive strategy for targeted delivery and reduce systemic toxicity. This nanoplatform could be a future approach to the treatment of BRAF-mutant malignancies.