Dual Hyaluronic Acid and Folic Acid Targeting pH-Sensitive Multifunctional 2DG@DCA@MgO-Nano-Core-Shell-Radiosensitizer for Breast Cancer Therapy

Abstract Background: Globally, breast cancer (BC) poses a serious public health risk. The disease exhibits a complex heterogeneous etiology and is associated with glycolysis and oxidative phosphorylation (OXPHOS) metabolic reprograming pathways which fuel proliferation and progression. Due to the late manifestation of symptoms, rigorous treatment regimens are required following diagnosis. Existing treatments are limited by a lack of specificity, systemic toxicity, temporary remission, and radio-resistance in BC. In this study, we developed CD44 and folate receptor-targeting multi-functional dual drug-loaded nanoparticles (DDM). These contained a hyaluronic acid (HA) and folic acid (FA) conjugated to a dichloroacetate (DCA) shell linked to a 2-deoxy glucose (2DG) and magnesium oxide (MgO) core to enhance localized chemo-radiotherapy for effective BC treatment.Methods: The physicochemical properties of nanoparticles, including stability, selectivity, release in response to pH, cellular uptake, and anticancer efficacy were comprehensively examined. Mechanistically, we identified multiple component signal pathways as important regulators of BC metabolism and mediators of inhibitory effects toward DDM.Results: Nanoparticles exhibited sustained DDM release properties in bio-relevant media, which was responsive to acidic pH providing flexibility to the control of drug release from nanoparticles. DDM-loaded and HA-FA-functionalized nanoparticles exhibited increased selectivity and uptake by BC cells. Cells study indicated that functionalized DDM significantly suppressed cancer cell growth and radiotherapy (RT) improvement via cell cycle arrest, apoptosis enhancement, and modulation of glycolysis and OXPHOS pathways.Conclusions: By highlighting DDM mechanisms as an antitumor and radio-sensitizing reagent, our analysis also revealed glycolysis and OXPHOS modulation via PI3K/AKT/mTOR/NF-κB/VEGFlow and P53high signal pathways. In conclusion, we indicated that multi-functionalized DDM depletion-mediated metabolic reprogramming via multiple signal pathways in BC cells is a promising targeted metabolic therapy.