Selective antitumor effect of novel protease-mediated photodynamic agent
Yongdoo Choi1, Ralph Weissleder, Ching-Hsuan Tung
1Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Abstract:
A new approach to selective photodynamic therapy (PDT) was developed by designing chlorin e6 (Ce6)-containing macromolecules, which are sensitive to tumor-associated proteases. The agents are nontoxic in their native state but become fluorescent and produce singlet oxygen on protease conversion. Coupled with optimized delivery systems, we show that (a) the agents efficiently accumulate in tumors due to the enhanced permeability and retention effect, (b) the agents are locally activated by proteases, (c) local drug concentrations can be measured by quantitative fluorescence tomography, and (d) light-treated tumors show reduced growth. A single low dose of PDT (0.125 mg Ce6 equivalent/kg) was sufficient to suppress tumor growth by >50%. Activatable singlet oxygen generation agents provide increased efficacy with reduced toxicity, and it could become a powerful PDT.
Insights
New photodynamic therapy (PDT) agents activate selectively using tumor proteases. This approach enhances tumor targeting and reduces toxicity, significantly suppressing tumor growth with a low dose.
Area of Science:
- Biomedical Engineering
- Photodynamic Therapy
- Drug Delivery Systems
Background:
- Photodynamic therapy (PDT) faces challenges in selectivity and toxicity.
- Developing activatable agents can improve therapeutic outcomes.
- Tumor microenvironments offer potential targets for selective drug activation.
Purpose of the Study:
- To develop protease-sensitive chlorin e6 (Ce6)-containing macromolecules for selective PDT.
- To evaluate the tumor accumulation, activation, and therapeutic efficacy of these novel agents.
- To demonstrate reduced toxicity and enhanced efficacy compared to conventional PDT.
Main Methods:
- Design and synthesis of Ce6-containing macromolecules sensitive to tumor-associated proteases.
- Evaluation of enhanced permeability and retention (EPR) effect for tumor accumulation.
- Assessment of protease-triggered fluorescence and singlet oxygen generation.
- Quantitative fluorescence tomography for monitoring local drug concentrations.
- In vivo studies to assess tumor growth inhibition after PDT.
Main Results:
- The developed agents efficiently accumulated in tumors via the EPR effect.
- Protease activation led to localized fluorescence and singlet oxygen production.
- Quantitative fluorescence tomography enabled real-time monitoring of drug concentration.
- A single low dose of PDT (0.125 mg Ce6/kg) suppressed tumor growth by over 50%.
Conclusions:
- Activatable singlet oxygen generation agents offer enhanced efficacy and reduced toxicity in PDT.
- Protease-sensitive macromolecules represent a promising strategy for targeted cancer therapy.
- This approach holds potential for a powerful and safer PDT modality.
