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Chemodynamic therapy (CDT) is an emerging cancer treatment strategy that leverages the unique tumor microenvironment to generate toxic reactive oxygen species (ROS) in situ. Unlike conventional chemotherapy, which often has systemic toxicity, CDT aims to induce localized cell death through chemical reactions that occur preferentially within tumors.
How Chemodynamic Therapy Works
1.Tumor Microenvironment Exploitation:
Tumors often exhibit a higher concentration of hydrogen peroxide (H₂O₂), an acidic environment, and elevated levels of certain metal ions (e.g., Fe²⁺). CDT exploits these characteristics to trigger chemical reactions selectively within the tumor.
2.Fenton and Fenton-like Reactions:
At the heart of CDT is the Fenton reaction, where transition metal ions (typically iron) catalyze the decomposition of H₂O₂ to generate hydroxyl radicals (•OH). These radicals are highly reactive and induce oxidative damage to cellular components like lipids, proteins, and DNA. The basic Fenton reaction:
Fe²⁺ + H₂O₂ → Fe³⁺ + •OH + OH⁻
3.Minimizing Systemic Toxicity:
Because the reaction heavily depends on the tumor’s specific conditions (e.g., acidic pH and high H₂O₂ levels), CDT can achieve a localized therapeutic effect with reduced harm to healthy tissues.
4.Nanomaterials as Catalysts:
Often, CDT is facilitated by nanoparticle catalysts (e.g., iron oxide, copper-based, or other metal-based nanoparticles) that can be engineered to accumulate in tumor tissues. These nanomaterials not only provide a catalytic surface but can also be modified for improved tumor targeting and controlled release.
Chemodynamic therapy provides a promising approach for cancer treatment by using the tumor’s inherent properties—like high H₂O₂ and acidic pH—to catalyze ROS generation via Fenton reactions. By targeting pathways related to oxidative stress, iron metabolism, redox balance, and cell survival signaling, CDT aims to selectively induce cancer cell death while reducing collateral damage to normal tissues.
Target Pathways in Chemodynamic Therapy
Oxidative Stress Pathways:ROS Generation, Mitochondrial Dysfunction, MMP, DNA Damage
Iron Homeostasis and Metabolism: Fenton Reaction Catalysis: The availability of Fe²⁺ is crucial for the Fenton reaction, making the iron uptake pathways a critical target.
MAPK/ERK Pathway, PI3K/Akt Pathway: increased ROS can inhibit pro-survival pathways like PI3K/Akt, tipping the balance towards cell death.
Glutathione (GSH) Depletion:
Nrf2 Pathway Inhibition: Inhibiting Nrf2 can make cancer cells more susceptible to ROS.
Acidic Tumor Microenvironment: Many nanomaterials used in CDT are designed to be activated in acidic conditions, ensuring that the Fenton reaction proceeds efficiently within the tumor milieu.
Autophagic: Increased ROS levels can also affect autophagy—a cellular “self-eating” process