GSH and H2 O2 Co-Activatable Mitochondria-Targeted Photodynamic Therapy under Normoxia and Hypoxia
Jian Sun1, Ke Du1, Jiajie Diao2
1Department of Polymer Science & Engineering, School of Chemistry and Chemical Engineering, Nanjing University, Jiangsu, Nanjing, 210023, P. R. China.
Abstract:
Currently, photosensitizers (PSs) that are microenvironment responsive and hypoxia active are scarcely available and urgently desired for antitumor photodynamic therapy (PDT). Presented herein is the design of a redox stimuli activatable metal-free photosensitizer (aPS), also functioning as a pre-photosensitizer as it is converted to a PS by the mutual presence of glutathione (GSH) and hydrogen peroxide (H2 O2 ) with high specificity on a basis of domino reactions on the benzothiadiazole ring. Superior to traditional PSs, the activated aPS contributed to efficient generation of reactive oxygen species including singlet oxygen and superoxide ion through both type 1 and type 2 pathways, alleviating the aerobic requirement for PDT. Equipped with a triphenylphosphine ligand for mitochondria targeting, mito aPS showed excellent phototoxicity to tumor cells with low light fluence under both normoxic and hypoxic conditions, after activation by intracellular GSH and H2 O2 . The mito aPS was also compatible to near infrared PDT with two photon excitation (800 nm) for extensive bioapplications.
Insights
This study introduces a novel metal-free photosensitizer activated by glutathione and hydrogen peroxide for enhanced antitumor photodynamic therapy (PDT). The activated photosensitizer effectively targets mitochondria and generates reactive oxygen species, showing potent phototoxicity under both normoxic and hypoxic conditions.
Area of Science:
- Biomedical Engineering
- Photochemistry
- Oncology
Background:
- Antitumor photodynamic therapy (PDT) requires photosensitizers (PSs) that are responsive to the tumor microenvironment and active under hypoxia.
- Current PSs often have limitations in specificity and efficacy under low-oxygen conditions prevalent in tumors.
Purpose of the Study:
- To design and synthesize a redox-stimuli activatable, metal-free photosensitizer (aPS) for enhanced antitumor PDT.
- To investigate the activation mechanism and reactive oxygen species (ROS) generation of the aPS.
- To evaluate the efficacy of mitochondria-targeted aPS (mito aPS) in tumor cells under various oxygen conditions.
Main Methods:
- Synthesis of a metal-free photosensitizer (aPS) based on benzothiadiazole.
- Activation mechanism study involving glutathione (GSH) and hydrogen peroxide (H2O2) via domino reactions.
- Evaluation of ROS generation (singlet oxygen, superoxide ion) through Type 1 and Type 2 pathways.
- Mitochondrial targeting using a triphenylphosphine ligand.
- In vitro phototoxicity assays on tumor cells under normoxic and hypoxic conditions.
- Near-infrared two-photon excitation (800 nm) compatibility assessment.
Main Results:
- The aPS was specifically activated by the combined presence of GSH and H2O2, converting to a potent PS.
- Activated aPS efficiently generated singlet oxygen and superoxide ions via both Type 1 and Type 2 pathways, reducing aerobic dependence.
- Mitochondria-targeted mito aPS demonstrated significant phototoxicity against tumor cells at low light fluences, irrespective of oxygen levels.
- Mito aPS showed compatibility with near-infrared two-photon excitation for potential deep-tissue applications.
Conclusions:
- A novel redox-activatable, metal-free photosensitizer (aPS) was developed for highly specific activation within the tumor microenvironment.
- The mito aPS exhibits potent antitumor activity under both normoxic and hypoxic conditions by efficient ROS generation and mitochondrial targeting.
- This photosensitizer holds promise for advanced photodynamic therapy applications, particularly in challenging hypoxic tumor environments.
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