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

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.

Application of a Dual-Probe Coloading Nanodetection System in the Process Monitoring and Efficacy Assessment of Photodynamic Therapy: An In Vitro Study

“…60,61 Besides, DCApromoting oxidative phosphorylation can reduce the promoting effect of anaerobic glycolysis on VEGF mRNA expression, thereby reducing the risk of angiogenesis. 62,63 In this work, the H 2 O 2 and VEGF changes during DCA treatment were consistent with the research results. Moreover, at low DCA incubation concentrations (2 mg/mL), the generated ROS level was lower than the tolerance threshold of tumor cells, resulting in fewer dead cells.…”

“…The related mechanism studies have shown that DCA activates the mitochondrial enzyme pyruvate dehydrogenase (PDH), a gate-keeping mitochondrial enzyme, by inhibiting the pyruvate dehydrogenase kinase (PDK) activity, thus gradually shifting the tumor metabolic pattern from glycolysis to mitochondrial oxidative phosphorylation, which promotes a massive increase of ROS including H 2 O 2 to lead to cytotoxicity. ,, In hypoxia, DCA enhances cytotoxicity by further inhibiting glycolysis and amplifying oxidative phosphorylation to promote ROS expansion. , Besides, DCA-promoting oxidative phosphorylation can reduce the promoting effect of anaerobic glycolysis on VEGF mRNA expression, thereby reducing the risk of angiogenesis. , In this work, the H 2 O 2 and VEGF changes during DCA treatment were consistent with the research results. Moreover, at low DCA incubation concentrations (2 mg/mL), the generated ROS level was lower than the tolerance threshold of tumor cells, resulting in fewer dead cells.…”

Pomegranate Peel Extract Sensitizes Hepatocellular Carcinoma Cells to Ionizing Radiation, Induces Apoptosis and Inhibits MAPK, JAK/STAT3, β-Catenin/NOTCH, and SOCS3 Signaling

“…The findings of this study showed that PPE treatment of HepG2 cells considerably slowed the proliferation of malignant cells, and that PPE therapy combined with ɣ-irradiation had a synergistic impact. The PPE administration period relative to RT was significant in determining effects, according to radio-modifying implications of PPE in liver cancer cells; reinforcement is often stronger after exposure for 24 hours prior to R. The 6 Gy-R was chosen for additional research since Askar et al 53 found that most of the stimulated damage response systems operate efficiently for a few hours after RT.…”

Advances in Nanodelivery Systems Based on Metabolism Reprogramming Strategies for Enhanced Tumor Therapy

“…More interestingly, the combination of DCA and 2DG could act as a dual inhibitor of aerobic glycolysis. Given this, a dual-targeted pH-sensitive multifunctional nanoplatform 2DG@DCA@MgO was developed . It is important to note that the MgO core also enhanced the potency of 2DG and DCA.…”