Layered Double Hydroxide Nanoparticles Loaded with Resveratrol Inhibit Glycolysis and Show Efficacy in the Treatment of Breast Cancer

Chenchen Geng,1,2 Liuyang Yan,1,2 Yunhao Li,1,3 Houcong Li,1,3 Yuxin Ji,1,4 Yuhan Xiao,1,4 Zhifa Wang,1,2 Xiaoqi Chen,1 Changjie Chen,1,4,5 Qingling Yang,1,4,5 Baoding Tang,1,2,6 Wenrui Wang1,2,6 1Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu Medical University, Bengbu, Anhui, People’s Republic of China; 2School of Life Sciences, Bengbu Medical University, Bengbu, Anhui, People’s Republic of China; 3School of Basic Courses, Bengbu Medical University, Bengbu, Anhui, People’s Republic of China; 4Clinical Testing and Diagnose Experimental Center, Bengbu Medical University, Bengbu, Anhui, People’s Republic of China; 5Department of Biochemistry and Molecular Biology, Bengbu Medical University, Bengbu, Anhui, People’s Republic of China; 6Anhui Engineering Research Center for Neural Regeneration Technology and Medical New Materials, Bengbu Medical University, Bengbu, Anhui, People’s Republic of ChinaCorrespondence: Wenrui Wang; Baoding Tang, Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui, 233030, People’s Republic of China, Email [email protected]; [email protected]: Breast cancer is one of the most common cancers among women. Tumor cell proliferation is highly dependent on aerobic glycolysis, so regulating aerobic glycolysis in breast cancer cells is a promising therapeutic strategy. Resveratrol (Res), as a potential new anti-breast cancer drug, has been shown to regulate the glycolysis of cancer cells and inhibit the metastasis and recurrence of breast cancer. The nano drug delivery system can regulate the aerobic glycolysis metabolism by targeting the signaling factors and reaction products of the tumor aerobic glycolysis process to enhance the anti-tumor effect.Methods: A new albumin-modified layered double hydroxide resveratrol dosage form (BSA@LDHs-Res) was synthesized by hydrothermal co-precipitation. Characterization was carried out to determine the successful synthesis of the nanocarrier system. The bioactivity, glycolytic activity and biocompatibility were examined by in vitro cellular assays; in vivo experiments were performed to further evaluate the anti-tumor effects of the BSA@LDHs-Res dosage form for breast cancer.Results: In this study, we obtained for the first time a bovine serum albumin-modified BSA@LDHs-Res loaded dosage form, which was able to enter breast cancer cells SKBR3 and MDA-MB-231 via endocytosis and successfully escaped from lysosomal capture. BSA@LDHs-Res inhibited the proliferation, migration, and invasion of two types of breast cancer cells, induced apoptosis, and promoted the reduction of mitochondrial membrane potential and ROS. BSA@LDHs-Res inhibited the expression and viability of the key enzymes of glycolysis, hexokinase 2 (HK2), pyruvate kinase (PK), and lactate dehydrogenase, resulting in decreased glucose consumption, decreased lactate accumulation, and decreased intracellular ATP levels. BSA@LDHs-Res was examined in the mouse model with good anti-tumor effects.Conclusion: BSA@LDHs-Res is an efficient nanoreagent for the treatment of breast cancer. The albumin-modified resveratrol layered double hydroxide delivery system developed in this study will provide some theoretical references for further research and clinical application of tumor aerobic glycolysis.Keywords: layered double hydroxides, glycolysis, resveratrol, BSA