Key Takeaways & Executive Findings
- •• • TTAn demonstrated a 2800-fold higher cellular uptake than clinical photosensitizer Ce6 in Eca-109 cells, indicating exceptional tumor accumulation potential for enhanced PDT efficacy. • • Under white light irradiation, TTAn achieved an IC50 of 21 nM, which is 50-fold lower than Ce6, signifying potent photocytotoxicity at nanomolar concentrations. • • TTAn exhibited balanced generation of singlet oxygen and superoxide anion, enabling effective ROS-mediated cell death while maintaining biosafety in vivo. • • TTAn enabled fluorescence imaging of tumors in mice under both one- and two-photon excitation, detectable by smartphones and DSLR cameras, eliminating the need for sophisticated imaging systems.
Abstract
Fluorescence image-guided photodynamic therapy (PDT) enables real-time monitoring of photosensitizer biodistribution and metabolism for optimized treatment timing. However, its application remains limited by reliance on high-end imaging systems. To address this, we designed three novel small-molecule photosensitizers (TTNb, TTAn, TTPh) based on a 2-vinylbenzoic acid scaffold, functionalized at the 5-position with nitro, amino, or hydrogen groups. Replacing the nitro group with amino or hydrogen switched aggregation behavior from aggregation-induced emission (AIE) to aggregation-caused quenching (ACQ), accompanied by a red-to-green fluorescence shift and subcellular relocation from liposomes to lysosomes. These findings establish design principles for ratiometric nitroreductase probes and enable systematic comparison between AIE and ACQ photosensitizers. Among these, TTAn exhibited superior cellular uptake (2800 times higher than Ce6 in Eca-109 cells), specific lysosomal targeting, balanced reactive oxygen species (singlet oxygen/superoxide anion) generation, and intense fluorescence. Under white light irradiation, TTAn achieved an IC50 of 21 nM, surpassing Ce6 by 50-fold. Notably, TTAn produced strong fluorescence in mice tumors under both one- and two-photon excitation, detectable using conventional imaging tools (smartphones, DSLR cameras) or even visible to the naked eye, confirming outstanding tumor specificity. Leveraging these advantages, TTAn enabled successful image-guided two-photon PDT in Eca-109 tumor-bearing mice with a single treatment, demonstrating potent therapeutic efficacy and biosafety. This work provides a strategic blueprint for developing small-molecule theranostic agents that operate without complex fluorescence imaging systems.
1. Introduction
Photodynamic therapy (PDT) relies on light-activated photosensitizers to generate reactive oxygen species (ROS) that destroy tumor cells. However, conventional photosensitizers are often activated by ultraviolet-visible light, which suffers from limited tissue penetration, restricting their use to superficial lesions. Two-photon excitation offers a solution by shifting the excitation wavelength into the near-infrared region, enhancing depth penetration while maintaining sufficient energy for ROS production. Yet, the clinical translation of two-photon PDT is hindered by the requirement for high-end imaging systems to guide treatment, limiting its accessibility in resource-constrained settings.
This study addresses this bottleneck by developing small-molecule photosensitizers with intense fluorescence that can be visualized using simple, low-cost devices such as DSLR cameras or even the naked eye. By engineering the aggregation behavior and subcellular localization, the lead compound TTAn achieves superior cellular uptake, specific lysosomal targeting, and balanced ROS generation, resulting in an exceptional IC50 of 21 nM. This work not only provides a strategic blueprint for image-guided PDT without complex instrumentation but also establishes design principles for ratiometric nitroreductase probes, bridging the gap between fundamental photochemistry and practical cancer therapy.
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Qiuyu Yang, Xiaohong Pan, Yaqi Wang, Hongyu Wang, Liangzhi Cai, Xiaoying Shang, Wenzhen Liu, Jincan Chen, Zhuo Chen (2026). A Highly Fluorescent Tumor-Targeting Photosensitizer for DSLR Camera Image-Guided Two-Photon Photodynamic Therapy. SCIENCE CHINA Materials. https://doi.org/10.1007/s40843-025-4098-8
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Frequently Asked Questions
What is the mechanism behind the aggregation-induced emission (AIE) to aggregation-caused quenching (ACQ) switch observed in the photosensitizers?
The switch is attributed to the substitution at the 5-position of the 2-vinylbenzoic acid scaffold. Replacing the nitro group (TTNb) with amino (TTAn) or hydrogen (TTPh) alters the molecular packing and intramolecular motions, leading to a transition from AIE to ACQ. This is accompanied by a red-to-green fluorescence shift and relocation from liposomes to lysosomes, as detailed in the study.
How does TTAn achieve such high cellular uptake compared to Ce6, and what are the implications for clinical translation?
TTAn exhibits 2800 times higher cellular uptake than Ce6 in Eca-109 cells, likely due to its small-molecule structure and specific lysosomal targeting. This high uptake enhances the local concentration of the photosensitizer, improving PDT efficacy at lower doses and potentially reducing systemic toxicity, making it a promising candidate for clinical use.
What are the advantages of using two-photon excitation over single-photon excitation for PDT, and how does TTAn perform under two-photon conditions?
Two-photon excitation shifts the effective excitation wavelength into the infrared region, improving tissue penetration and spatial resolution, thereby minimizing damage to healthy tissue. TTAn produced strong fluorescence in mice tumors under two-photon excitation, confirming its suitability for image-guided two-photon PDT, as demonstrated in the study.
How does the balanced generation of singlet oxygen and superoxide anion contribute to the therapeutic efficacy of TTAn?
Balanced ROS generation ensures that both Type II (singlet oxygen) and Type I (superoxide anion) mechanisms are activated, which can overcome hypoxia-related resistance and enhance the overall photodynamic effect. This balance is critical for achieving potent antitumor activity, as evidenced by the low IC50 of 21 nM.
What is the significance of using conventional imaging tools like DSLR cameras for image-guided PDT?
The use of DSLR cameras and smartphones for fluorescence imaging eliminates the need for expensive, specialized imaging systems, making image-guided PDT more accessible and cost-effective. This could facilitate broader adoption in clinical settings, particularly in resource-limited environments, without compromising the precision of treatment guidance.
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