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

Simple Summary In this study, we have developed CD44 and folate receptor-targeting multi-functional dual drug-loaded nanoparticles. This comprises hyaluronic acid (HA) and folic acid (FA) conjugated to 2-deoxy glucose (2DG) and a shell linked to a dichloroacetate (DCA) and magnesium oxide (MgO) core (2DG@DCA@MgO; DDM) to enhance the localized chemo-radiotherapy for effective breast cancer (BC) treatment. The physicochemical properties of nanoparticles including stability, selectivity, responsive release 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 for the inhibitory effects exerted by DDM. Nanoparticles exhibited sustained DDM release properties in bio-relevant media, which was responsive to acidic pH providing edibility to the control of drug release from nanoparticles. DDM-loaded and HA–FA-functionalized nanoparticles exhibited increased selectivity and uptake by BC cells. Cell-based assays indicated that the functionalized DDM significantly suppressed cancer cell growth and boosted radiotherapy (RT) efficacy via inducing cell cycle arrest, enhancing apoptosis, and modulating glycolytic and OXPHOS pathways. Accordingly, the inhibition of glycolysis/OXPHOS by DDM and RT treatment may result in cancer metabolic reprogramming via a novel PI3K/AKT/mTOR/P53NF-κB/VEGF pathway in BC cells. Therefore, the dual targeting of glycolysis/OXPHOS pathways is suggested as a promising antitumor strategy. Abstract Globally, breast cancer (BC) poses a serious public health risk. The disease exhibits a complex heterogeneous etiology and is associated with a glycolytic and oxidative phosphorylation (OXPHOS) metabolic reprogramming phenotype, which fuels 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 have developed CD44 and folate receptor-targeting multi-functional dual drug-loaded nanoparticles. This composed of hyaluronic acid (HA) and folic acid (FA) conjugated to a 2-deoxy glucose (2DG) shell linked to a layer of dichloroacetate (DCA) and a magnesium oxide (MgO) core (2DG@DCA@MgO; DDM) to enhance the localized chemo-radiotherapy for effective BC treatment. The physicochemical properties of nanoparticles including stability, selectivity, responsive release to pH, cellular uptake, and anticancer efficacy were thoroughly examined. Mechanistically, we identified multiple component signaling pathways as important regulators of BC metabolism and mediators for the inhibitory effects elicited by DDM. Nanoparticles exhibited sustained DDM release properties in a bio-relevant media, which was responsive to the acidic pH enabling eligibility to the control of drug release from nanoparticles. DDM-loaded and HA–FA-functionalized nanoparticles exhibited increased selectivity and uptake by BC cells. Cell-based assays revealed that the functionalized DDM significantly suppressed cancer cell growth and improved radiotherapy (RT) through inducing cell cycle arrest, enhancing apoptosis, and modulating glycolytic and OXPHOS pathways. By highlighting DDM mechanisms as an antitumor and radio-sensitizing reagent, our data suggest that glycolytic and OXPHOS pathway modulation occurs via the PI3K/AKT/mTOR/NF-κB/VEGFlow and P53high signaling pathway. In conclusion, the multi-functionalized DDM opposed tumor-associated metabolic reprogramming via multiple signaling pathways in BC cells as a promising targeted metabolic approach.