Copper Chlorophyllin as an Antioxidant and Photosensitizer: Mitigating Ifosfamide Toxicity and Enhancing Photodynamic Therapy

ABSTRACT Copper chlorophyllin (Cu‐Chl) is known for its antioxidant and anticancer properties, particularly as a photosensitizer in photodynamic therapy (PDT). This study aimed to explore the protective effects of Cu‐Chl against ifosfamide (IFO)‐induced toxicity. Moreover, it aimed to assess the anticancer activity of Cu‐Chl as a photosensitizing agent in PDT when used alone or when combined with IFO against Ehrlich solid tumors in mice. To achieve our objectives, we conducted two experiments. The first assessed the potential protective effects of orally administered Cu‐Chl in a rat model of IFO‐induced toxicity. The liver and kidney tissues underwent biochemical, oxidative stress, inflammatory markers, and histological analyses. The second experiment evaluated the combined effects of IFO and Cu‐Chl as part of PDT on Ehrlich solid tumors in mice. The Ehrlich tumor, liver, and kidney tissues underwent histological and biochemical analyses. The results of the present study demonstrated that Cu‐Chl administration significantly mitigated IFO‐induced liver and kidney damage, as evidenced by improved liver enzyme profiles, reduced levels of oxidative stress and inflammatory markers, and improved histological outcomes. Higher doses of Cu‐Chl (100 mg/kg) demonstrated significant protective effects. In the second experiment, Cu‐Chl in PDT exerts an antitumorigenic effect by reducing tumor cell viability and promoting necrosis; however, its effect appears weaker than that of IFO. Our histological analysis revealed extensive necrotic regions in tumor tissues treated with Cu‐Chl, highlighting its antitumorigenic effect, which was weaker than IFO. Our findings suggest that Cu‐Chl, as part of PDT, exerts a dose‐dependent apoptotic‐modulating effect, as evidenced by reduced caspase‐3 and restored Bcl‐2 levels when combined with IFO. Combinations of higher Cu‐Chl ratios relative to IFO minimized systemic toxicity while maintaining antitumor efficacy. The 3IFO+2Cu‐Chl group, in which the rats were treated with IFO for 3 days, followed by 30 min of red light exposure per day for 2 days after the oral administration of Cu‐Chl (50 mg/kg), demonstrated an optimal balance between antitumor effects and organ protection. Cu‐Chl protects against IFO‐induced toxicity and is an effective photosensitizer in PDT. This combination offers a promising approach for enhancing cancer treatment efficacy while minimizing adverse effects on vital organs.