Tumor-Targeted Nano-Assemblies for Energy-Blocking Cocktail Therapy in Cancer

Abstract

Starvation therapy aims to "starve" tumor cells by cutting off their nutritional supply. However, due to the complex and varied energy metabolism of tumors, targeting a single nutrient supply often fails to yield significant therapeutic benefits. This study proposes a tumor energy cocktail therapy that combines metformin, an oxidative phosphorylation inhibitor, with 2-deoxy-D-glucose (2-DG), a glycolysis inhibitor, to target tumor cells. To minimize the dosage of both drugs, we developed a drug delivery strategy using nanosized metformin (MA-dots) to target tumors and carry 2-DG, facilitating efficient delivery of both drugs to the tumor site. Upon reaching the acidic tumor environment, the composite disintegrates, releasing 2-DG to inhibit glycolysis by targeting hexokinase 2 (HK2), the key enzyme in glycolysis, while MA-dots inhibit mitochondrial OXPHOS. This dual action significantly reduces ATP production in tumor cells, leading to apoptosis. In human lung tumor cells, the half-maximal inhibitory concentration (IC50) of 2-DG@MA-dots was significantly lower than that of either metformin or 2-DG alone, showing a nearly 100-fold and 30-fold reduction in IC50 values to 11.78 µg mL-1, from 1159 µg mL-1 and 351.20 µg mL-1, respectively. In studies with A549 tumor-bearing mice, the combination of low-dose 2-DG and metformin did not impede tumor growth, whereas 2-DG@MA-dots markedly decreased tumor volume, with the mean final tumor volume in the combination treatment group being approximately 89 times greater than that in the 2-DG@MA-dot group.

Note:
Funding Information: This work was supported by National Natural Science Foundation of China (51873085), Natural Science Foundation of Liaoning Province-Outstanding Youth Foundation (2022-YQ-14), Liaoning Revitalization Talents Program (XLYC2007056), China Scholarship Council (CSC Scholarship No. 202006800009), and the Shenyang Science and Technology Project (RC230707).

Declaration of Interests: All authors have given approval to the final version of the manuscript and declare no conflict of interest.

Ethical Approval Statement: The animal experiments were conducted following the guidelines and approved by the Animal Ethics Committee of China Medical University (CMUXN2023014).

Keywords: Metformin, 2-deoxy-D-glucose, energy-blocking, cocktail therapy, nano-assemblies