MUC1 aptamer-conjugated niclosamide-loaded PLGA-PEG nanoparticles attenuate HIF-1 stabilization upon hypoxia in MCF7 breast cancer cells

Abstract

Hypoxia is related to aggressive phenotype and poor prognosis in breast cancer. HIF-1, a transcription factor (TF), plays an essential role in the adaptation of tumor cells to hypoxia. It is stabilized in hypoxic conditions and activates other TFs and signaling pathways that are associated with the proliferation, survival, and progression of cancer cells in hypoxia. As a result, targeting hypoxia by destabilizing HIF-1 is a promising approach to inhibit cell adaptation to hypoxia. Niclosamide (NIC) has been identified as a HIF-1 inhibitor and it is envisioned that the anti-cancer efficacy of NIC can be improved through targeted drug delivery systems (DDSs) as a therapeutic strategy. Here, MUC1 aptamer (Ap)-targeted PLGA/PEGylated nanoparticles (Ap-PLGA-NPs) were developed for targeted delivery of NIC (Ap-NIC-PLGA-NPs) to MUC1 positive breast cancer cell line in hypoxia environment. The obtained findings showed that targeted inhibition of HIF-1 using fabricated targeted-NIC-loaded NPs increased the rate of apoptosis in breast cancer cells in hypoxic conditions which was further confirmed by geno-/cytotoxicity assays and flow cytometry analysis. Downregulation of HIF-1α, HIF-1β, Eno1, and GluT1 in treated breast cancer cells under hypoxic conditions also indicated a potential role for Ap-NIC-PLGA-NPs in tumor cell adaptation to hypoxia.