An Activatable Dual-Engine Metabolic Inhibition Switch: Sequential Blockade of Glycolysis and Mitochondrial
Xinxin Liu1, Yinhe Sikong1, Ying Sun1
1Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao 266035, China.
Abstract:
Photodynamic therapy (PDT) is an emerging treatment modality that is progressively gaining popularity in clinical practice. Its attributes of minimal adverse effects and spatiotemporal selectivity instill hope among tumor patients. However, the hypoxic microenvironment within tumors significantly compromises the efficacy of PDT. Cuproptosis has recently emerged as a novel mode of cellular death by the disturbance of the tricarboxylic acid cycle. In this investigation, we demonstrated that the mechanism underlying cuproptosis can enhance the antitumor effect of PDT by throttling cellular oxygen consumption through mitochondrial respiration. The Warburg effect exhibited by tumor cells leads to a preferential utilization of glycolysis as the primary energy source, thereby significantly reducing the reliance on mitochondrial respiration. Herein, we developed a synergistic antitumor system by constructing a photosensitizer and copper supramolecular assembly loaded with glycolysis inhibitor galloflavin (GF) and coated with polydopamine. The obtained product GF/Cu-Pc@DA exhibited pH- and protein-cascaded responsive drug release, along with switchable fluorescence and photodynamic activity, and can lead to a significant enhancement in intracellular oxygen levels to promote the generation of photodynamic reactive oxygen species (ROS), disrupt mitochondrial respiration, and inhibit glycolytic metabolism. Moreover, both in vivo and in vitro studies demonstrated the excellent synergistic antitumor effect of GF/Cu-Pc@DA with no significant side effects. This study presents novel perspectives for the development of highly effective photodynamic antitumor therapy strategies, contributing valuable guidance for further advancements in clinical PDT.
Insights
This study introduces a novel approach combining photodynamic therapy (PDT) with cuproptosis-inducing agents to overcome tumor hypoxia. This synergistic strategy enhances antitumor effects by inhibiting glycolysis and boosting oxygen levels for improved PDT efficacy.
Area of Science:
- Biomedical Engineering
- Cancer Therapy
- Cellular Biology
Background:
- Photodynamic therapy (PDT) shows promise for cancer treatment due to its selectivity and minimal side effects.
- Tumor hypoxia significantly limits PDT efficacy by reducing reactive oxygen species (ROS) generation.
- Cuproptosis, a novel cell death pathway, disrupts the tricarboxylic acid cycle and offers new therapeutic avenues.
Purpose of the Study:
- To develop a synergistic antitumor system that enhances PDT efficacy in hypoxic tumors.
- To investigate the role of cuproptosis in overcoming tumor hypoxia for improved photodynamic therapy.
- To create a smart drug delivery system for targeted cancer treatment.
Main Methods:
- Constructed a photosensitizer and copper supramolecular assembly loaded with galloflavin (GF) and coated with polydopamine (GF/Cu-Pc@DA).
- Utilized pH- and protein-cascaded responsive drug release.
- Evaluated the system's ability to enhance intracellular oxygen levels, disrupt mitochondrial respiration, and inhibit glycolysis.
Main Results:
- GF/Cu-Pc@DA exhibited switchable fluorescence and photodynamic activity.
- The system effectively increased intracellular oxygen levels, promoting ROS generation and enhancing PDT.
- Disruption of mitochondrial respiration and inhibition of glycolysis were observed, leading to a synergistic antitumor effect.
- In vitro and in vivo studies confirmed the excellent synergistic antitumor efficacy with no significant side effects.
Conclusions:
- The developed GF/Cu-Pc@DA system effectively overcomes tumor hypoxia, enhancing PDT efficacy through cuproptosis-mediated mechanisms.
- This approach offers a promising strategy for developing advanced photodynamic antitumor therapies.
- The findings provide valuable insights for future clinical applications of PDT.
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