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Tandem-Activatable PROTAC Prodrug for Tumor Biomarker-Driven Near-Infrared Opto-Proteolysis
Xiaoyan Lu1, Xiaoning Wang1, Hanwen Liao1
1State Key Laboratory of Analytical Chemistry for Life Sciences, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Chemistry and Biomedicine Innovation Center (ChemBIC), ChemBioMed Interdisciplinary Research Center at Nanjing University, Nanjing University, Nanjing, 210023, China.
Abstract:
Tumor-specific protein degradation is crucial for successful cancer treatment by proteolysis-targeting chimera (PROTAC), which however still remains challenging. Here, we report a tandem-activatable PROTAC prodrug (TAP) strategy for precise on-tumor proteolysis in vivo. TAP is constructed by caging PROTAC with a tumor-homing cyclopeptide through a tandem-locking linker, which comprises a singlet-oxygen (1O2) cleavable moiety, a near-infrared (NIR) photosensitizer (PS) and a Cathepsin B (CatB)-cleavable dipeptide substrate. The proteolytic activity of TAP is initially turned off but can be sequentially switched on by tumor biomarker enzyme CatB and NIR light. Such a tandem-lock design ensures that PROTAC exclusively degrade oncoprotein target in tumor. The results revealed that TAP carried out a tumor-selective degradation of bromodomain-containing protein 4 (BRD4) under the cooperative action by CatB and NIR light, which further synergized with photodynamic therapy (PDT) by the PS to suppress tumor growth. This work thus presents the first tandem-activatable approach for spatiotemporally controlled proteolysis to minimize the off-tumor toxicity of PROTAC.
Insights
This study introduces a tandem-activatable PROTAC prodrug (TAP) strategy for precise on-tumor protein degradation. This approach uses tumor enzyme and light activation to minimize off-tumor toxicity in cancer treatment.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Targeted protein degradation is key for cancer therapy using proteolysis-targeting chimeras (PROTACs).
- Achieving tumor-specific PROTAC activity remains a significant challenge, leading to potential off-tumor toxicity.
Purpose of the Study:
- To develop a novel tandem-activatable PROTAC prodrug (TAP) strategy for precise on-tumor proteolysis.
- To enhance cancer treatment efficacy by minimizing off-tumor side effects of PROTACs.
Main Methods:
- Constructed TAP by linking PROTAC to a tumor-homing cyclopeptide via a tandem-locking linker.
- The linker incorporated a singlet-oxygen cleavable moiety, a near-infrared photosensitizer, and a Cathepsin B-cleavable substrate.
- Activated TAP sequentially using Cathepsin B and near-infrared light for on-demand proteolysis.
Main Results:
- Demonstrated tumor-selective degradation of bromodomain-containing protein 4 (BRD4) by TAP.
- Achieved synergistic tumor suppression through combined PROTAC activity and photodynamic therapy.
- Validated the tandem-lock design for controlled proteolysis exclusively within the tumor microenvironment.
Conclusions:
- The tandem-activatable PROTAC prodrug (TAP) strategy enables spatiotemporally controlled proteolysis.
- This approach effectively minimizes off-tumor toxicity, offering a safer and more precise cancer therapeutic strategy.
- Presents the first tandem-activatable system for targeted protein degradation in vivo.
