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A Dual-Key Gated Nuclear-DNA-Targeted Photogenerator for Amplified Photodynamic Immunotherapy of Breast Cancer
Ting Wang1, Yingcui Bu2, Xuan Zhao1
1School of Chemistry and Chemical Engineering, School of Materials Science and Engineering, Key Laboratory of Chemistry for Inorganic/Organic Hybrid Functionalized Materials of Anhui Province, Anhui University, Hefei, P.R. China.
Abstract:
Developing therapeutic agents that are capable of directly damaging nuclear DNA is critical for curing metastatic breast cancer. Herein, an enzyme-mediated nuclear DNA-targeted photogenerator (P-NO3) was constructed through dual-key gating for amplified photodynamic immunotherapy (PDIT) against breast cancer, which has rarely been reported. Specifically, bilateral pyridinone units were included in the design to interact with overactivated cyclin-dependent kinases 4 and 6 (CDK4/6) within breast cancer cells, which can circumvent the limitation of an impermeable nuclear envelope (the first key). Once inside the nucleus, the equipped dual-positive pyridine groups can further competitively bind with DNA, promoting P-NO3 to precisely anchor and illuminate nuclear DNA (the second key). Upon cascade activation, P-NO3 utilized photogenerated highly toxic hydroxyl radical (·OH) in situ to damage the nucleus even under hypoxia, causing the up-regulated expression of related genes (DDI2, KDM4D, RGCC). Concomitantly, damage-associated high-mobility group box 1 (HMGB1) and calreticulin (CRT) were released, triggering a systemic immune response to further suppress distant tumors, realizing efficient PDIT for breast cancer. This study provides new insight into designing nuclear-DNA-targeted phototherapeutic agents for complete ablation of metastatic tumors.
Insights
Researchers developed a novel photogenerator (P-NO3) that targets cancer cell nuclei. This agent amplifies photodynamic immunotherapy (PDIT) to effectively treat metastatic breast cancer by damaging nuclear DNA and stimulating an immune response.
Area of Science:
- Biomedical Engineering
- Cancer Research
- Photodynamic Therapy
Background:
- Directly damaging nuclear DNA is crucial for treating metastatic breast cancer.
- Current therapies face challenges in nuclear penetration and efficacy under hypoxic conditions.
Purpose of the Study:
- To construct an enzyme-mediated nuclear DNA-targeted photogenerator (P-NO3) for amplified photodynamic immunotherapy (PDIT).
- To overcome the nuclear envelope barrier and precisely target nuclear DNA for enhanced therapeutic effects.
Main Methods:
- Designed P-NO3 with dual-key gating, incorporating pyridinone units to interact with cyclin-dependent kinases 4 and 6 (CDK4/6).
- Utilized dual-positive pyridine groups for competitive DNA binding within the nucleus.
- Activated P-NO3 to generate hydroxyl radicals (·OH) for nuclear DNA damage and subsequent immune response induction.
Main Results:
- P-NO3 successfully penetrated the nuclear envelope and targeted nuclear DNA, even under hypoxia.
- Photogeneration of ·OH induced nuclear damage, upregulating genes like DDI2, KDM4D, and RGCC.
- Released damage-associated molecular patterns (HMGB1, CRT) triggered a systemic immune response, suppressing distant tumors.
Conclusions:
- The developed P-NO3 agent enables efficient, enzyme-mediated, nuclear DNA-targeted PDIT for metastatic breast cancer.
- This approach offers a novel strategy for designing phototherapeutic agents for complete tumor ablation.
- The dual-key gating mechanism provides a new insight into overcoming nuclear impermeability for targeted therapies.
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