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Updated: May 15, 2025
Computed Tomography-guided Time-domain Diffuse Fluorescence Tomography in Small Animals for Localization of Cancer Biomarkers
Published on: July 17, 2012
Tumor-specific cathepsin B-triggered fluorescence imaging and prodrug activation
Luyang Wang1, Houchi Yang1, Wanyun Huang1
1Department of Pharmaceutical Engineering, College of Food and Bioengineering, Sichuan Engineering Research Center for Molecular Targeted Diagnostic & Therapeutic Drugs, Xihua University, Chengdu 610039, PR China.
Abstract:
Bioorthogonal activation chemistries have great potential in the development of novel drug treatments due to their versatility, tunability, and the ability to generate therapies with improved spatial targeting. The upregulation of Cathepsin B is highly correlated with the development of cancers, however, few fluorescent probes or prodrugs-based on Cathepsin B activity have demonstrated high tumor selectivity, since Cathepsin B is expressed in a variety of normal tissues. In this study, we report a strain-promoted azide-alkyne cycloaddition-activation strategy whereby a para-azido safety-catch linker is triggered by the tumor locating Biotin-TCO (trans-cyclooctene) conjugate, with subsequent tumor-specific Cathepsin B-triggered activation, generating a fluorescent reporter/cytotoxic drug, with high tumor selectivity. Our results suggest that this dual AND-Gate strategy of orthogonal Biotin AND Cathepsin B action would be advantageous for tumor-specific fluorescence labelling, fluorescence-guided surgery and targeted treatment.
Insights
This study introduces a dual-action bioorthogonal strategy for cancer therapy. It uses Biotin-TCO and Cathepsin B to selectively activate drugs or fluorescent reporters in tumors, improving targeting.
Area of Science:
- Biochemistry
- Chemical Biology
- Oncology
Background:
- Bioorthogonal chemistry offers versatile tools for drug development with enhanced spatial targeting.
- Cathepsin B upregulation correlates with cancer, but existing probes lack tumor selectivity due to expression in normal tissues.
Purpose of the Study:
- To develop a novel dual AND-gate strategy for highly tumor-selective activation of therapeutic agents or fluorescent reporters.
- To leverage bioorthogonal chemistry and tumor-specific enzyme activity for improved cancer treatment and diagnostics.
Main Methods:
- Utilized a strain-promoted azide-alkyne cycloaddition (SPAAC) reaction with a para-azido safety-catch linker.
- Employed a tumor-locating Biotin-trans-cyclooctene (TCO) conjugate to trigger the initial linker activation.
- Incorporated subsequent tumor-specific Cathepsin B-triggered cleavage for final payload release.
Main Results:
- Demonstrated successful dual AND-gate activation requiring both Biotin-TCO and Cathepsin B.
- Generated a fluorescent reporter and/or cytotoxic drug with high tumor selectivity.
- Showcased the potential for precise spatial control in drug delivery and diagnostics.
Conclusions:
- The developed dual AND-gate strategy achieves high tumor selectivity by requiring orthogonal Biotin and Cathepsin B activation.
- This approach is advantageous for tumor-specific fluorescence labeling, fluorescence-guided surgery, and targeted cancer therapy.
