Drug induced mitochondria dysfunction to enhance photodynamic therapy of hypoxic tumors
Yi Cen1, Xiayun Chen1, Yibin Liu1
1Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, PR China.
Abstract:
As most solid tumors are characterized by a hypoxic microenvironment, enormous efforts have been made to develop strategies to fight hypoxia. This study shows that ivermectin (IVM), an antiparasitic drug, is able to alleviate tumor hypoxia by inhibiting mitochondrial respiration. We explore this to strengthen oxygen-dependent photodynamic therapy (PDT) using chlorin e6 (Ce6) as a photosensitizer. To synergize their pharmacological behaviors, Ce6 and IVM are encapsulated into stable Pluronic F127 micelles. The micelles are uniform in size and seem well-suited for the co-delivery of Ce6 and IVM. The micelles could passively target the drugs into tumors and enhance their cellular internalization. Most importantly, through mitochondrial dysfunction, the micelles reduce the oxygen consumption (making the tumor less hypoxic). Consequently, the production of reactive oxygen species would be increase which, in turn, improves the efficacy of PDT against hypoxic tumors.
Insights
Ivermectin (IVM) alleviates tumor hypoxia by inhibiting mitochondrial respiration, enhancing oxygen-dependent photodynamic therapy (PDT). Co-delivery of IVM and chlorin e6 (Ce6) in micelles improves PDT efficacy against hypoxic tumors.
Area of Science:
- Biomedical Engineering
- Cancer Therapy
- Drug Delivery
Background:
- Solid tumors often feature a hypoxic microenvironment, hindering effective treatments like photodynamic therapy (PDT).
- Developing strategies to combat tumor hypoxia is crucial for improving cancer treatment outcomes.
- Ivermectin (IVM) demonstrates potential in modulating cellular respiration.
Purpose of the Study:
- To investigate the potential of ivermectin (IVM) in alleviating tumor hypoxia.
- To enhance oxygen-dependent photodynamic therapy (PDT) using chlorin e6 (Ce6) by combining it with IVM.
- To develop a co-delivery system for IVM and Ce6 to improve their synergistic effects in hypoxic tumors.
Main Methods:
- Encapsulation of chlorin e6 (Ce6) and ivermectin (IVM) into stable Pluronic F127 micelles for co-delivery.
- Evaluation of micelle characteristics, including size uniformity and suitability for drug co-delivery.
- Assessment of micelle-mediated tumor targeting, cellular internalization, and impact on tumor oxygen levels.
- Investigation of the mechanism involving mitochondrial dysfunction and reduced oxygen consumption.
Main Results:
- The developed Pluronic F127 micelles demonstrated uniform size and effective co-delivery of Ce6 and IVM.
- Micelles exhibited passive tumor targeting and enhanced cellular uptake.
- IVM-loaded micelles significantly reduced tumor oxygen consumption by inhibiting mitochondrial respiration, thereby alleviating hypoxia.
- The combined approach enhanced reactive oxygen species (ROS) production, leading to improved PDT efficacy in hypoxic tumors.
Conclusions:
- Co-delivery of ivermectin and chlorin e6 via Pluronic F127 micelles is a promising strategy to combat tumor hypoxia.
- This approach effectively enhances the efficacy of oxygen-dependent photodynamic therapy in solid tumors.
- The study highlights the potential of repurposing ivermectin to improve cancer treatment outcomes by targeting the tumor microenvironment.
Related Concept Videos
01:46Electron Transport Chain: Complex I and II
ROS generation is regulated and maintained at moderate levels necessary...
02:49Cancer Therapies
However, cancer treatments can pose several challenges, as therapies used to kill cancer cells are generally also toxic to normal cells. Moreover, cancer cells mutate rapidly and can develop resistance to chemical agents or radiation therapy. Besides, all types of cancer cells may not respond to the same therapy. Some cancer cells respond to one...