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In Situ Activating a Protein-Complexed Quenched Probe via Alkaline Phosphatase Response for Pyroptosis-Mediated
Jiangtao Geng1, Jie Sun1, Ling-Hong Xiong2
1State Key Laboratory of Bioinspired Interfacial Materials Science, The Key Lab of Health Chemistry and Molecular Diagnosis of Suzhou, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, China.
A novel protein-complexed probe activates cancer cell death and immune responses directly within tumors. This targeted approach suppresses tumor growth and metastasis by leveraging tumor-specific biomarkers for precise theranostics.
Area of Science:
- Biomedical Engineering
- Cancer Research
- Immunotherapy
Background:
- Precision cancer theranostics require in situ synthesis of therapeutics and immune activation within tumor cells.
- Tumor-specific biomarkers can trigger intracellular reactions for targeted therapeutic activation and immune modulation.
Purpose of the Study:
- To design a quenched probe activated by alkaline phosphatase (ALP) for in situ cancer therapy.
- To investigate the probe's ability to induce pyroptosis and immunoactivation for tumor suppression.
Main Methods:
- Developed a protein-complexed diphosphate probe (TdVPy-PP) sensitive to tumor-specific alkaline phosphatase (ALP).
- Evaluated probe responsiveness, fluorescence output, and subcellular localization (mitochondria, endoplasmic reticulum).
- Assessed pyroptosis induction, reactive oxygen species (ROS) generation, and immune cell activation (dendritic cells, T cells) in vitro and in vivo.
- Administered protein-complexed TdVPy-PP via tail vein injection for tumor targeting and visualization.
Main Results:
- TdVPy-PP showed faster ALP response and higher signal-to-noise ratio than TdVPy-P.
- The probe localized to mitochondria and endoplasmic reticulum, enhancing ROS generation and GSDME-mediated pyroptosis.
- In vivo studies demonstrated significant suppression of primary, distant, and metastatic tumor growth.
- Effective dendritic cell maturation and cytotoxic T cell activation were observed, indicating systemic immune enhancement.
Conclusions:
- Protein-assisted in situ activation of TdVPy-PP is a potent strategy for precise cancer theranostics.
- This approach combines chemodynamic/photodynamic effects with systemic immune activation for efficient tumor therapy.
- The developed probe offers a promising tool for targeted cancer treatment with excellent biocompatibility.
