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Hypoxia-activated NIR photosensitizer anchoring in the mitochondria for photodynamic therapy
Feng Xu1, Haidong Li1, Qichao Yao1
1State Key Laboratory of Fine Chemicals , Dalian University of Technology , 2 Linggong Road , Dalian 116024 , P. R. China .
Abstract:
Photodynamic therapy is considered as a promising treatment for cancer, but still faces several challenges. The hypoxic environment in solid tumors, imprecise tumor recognition and the lack of selectivity between normal and cancer cells extremely hinder the applications of photodynamic therapy in clinics. Moreover, the "always on" property of photosensitizers also increases the toxicity to normal tissues when exposed to light irradiation. In this study, a hypoxia-activated NIR photosensitizer ICy-N was synthesized and successfully applied for in vivo cancer treatment. ICy-N is in the inactivated state with low fluorescence whereas its NIR emission (λ em = 716 nm) was induced via reduction caused by nitroreductase at the tumor site. In addition, the reduced product ICy-OH was specially located in the mitochondria and demonstrated a high singlet oxygen production under 660 nm light irradiation, which efficiently induced cell apoptosis (IC50 = 0.63 μM). The in vivo studies carried out in Balb/c mice indicated that ICy-N was suitable for precise tumor hypoxia imaging and can work as an efficient photosensitizer for restraining tumor growth through the PDT process.
Insights
A novel hypoxia-activated near-infrared photosensitizer, ICy-N, enables precise tumor imaging and effective photodynamic therapy (PDT) by selectively targeting hypoxic tumor environments and minimizing damage to healthy tissues.
Area of Science:
- Biomedical Engineering
- Photochemistry
- Oncology
Background:
- Photodynamic therapy (PDT) faces challenges in cancer treatment due to tumor hypoxia, poor tumor recognition, and lack of selectivity.
- The inherent activity of photosensitizers can lead to toxicity in normal tissues upon light exposure.
Purpose of the Study:
- To synthesize and evaluate a hypoxia-activated near-infrared (NIR) photosensitizer for improved cancer treatment.
- To develop a photosensitizer with enhanced tumor targeting and reduced off-target toxicity.
Main Methods:
- Synthesis of a hypoxia-activated NIR photosensitizer, ICy-N.
- Evaluation of ICy-N's fluorescence properties and activation mechanism via nitroreductase.
- Assessment of mitochondrial localization and singlet oxygen production of the reduced form (ICy-OH).
- In vivo studies in Balb/c mice for tumor imaging and therapeutic efficacy.
Main Results:
- ICy-N exhibits low fluorescence in its inactive state and NIR emission upon reduction by nitroreductase at the tumor site.
- The reduced product, ICy-OH, localizes in mitochondria and generates high singlet oxygen levels under 660 nm irradiation, inducing efficient apoptosis (IC50 = 0.63 μM).
- In vivo studies demonstrated ICy-N's suitability for precise tumor hypoxia imaging and effective tumor growth inhibition via PDT.
Conclusions:
- Hypoxia-activated ICy-N offers a promising strategy for targeted cancer photodynamic therapy.
- The developed photosensitizer enhances tumor selectivity and imaging capabilities, overcoming key limitations of traditional PDT.
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