Combined inhibition of EZH2 and CD73 molecules by folic acid-conjugated SPION-TMC nanocarriers loaded with siRNA molecules prevents TNBC progression and restores anti-tumor responses

Abstract

BackgroundAbnormal function or overexpression of CD73 and EZH2 within the tumor microenvironment and tumor cells enhances tumor growth and progression, and in many cases, causes drug resistance. Hence, it seems that silencing the expression of CD73 and EZH2 molecules in breast cancer reduces cancer development and enhances anti-tumor immune responses. Methodswe used siRNA-loaded superparamagnetic iron oxide (SPIONs) nanoparticles (NPs) coated with trimethyl chitosan (TMC) and functionalized with folic acid for co-delivery of EZH2/CD73 siRNAs to 4 T1 murine cancer cells both in vitro and in vivo. ResultsCombination therapy markedly inhibited cancer cells' proliferation, migration, and viability and induced apoptosis in vitro. Moreover, in vivo administration of this combination therapy promoted tumor regression and induced anti-tumor immune responses. DiscussionThe findings indicated the CD73/EZH2 factors inhibition by SPION-TMC-FA NPs as a promising therapeutic strategy in breast cancer treatment.