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Updated: Jun 6, 2025
Near Infrared Photoimmunotherapy for Mouse Models of Pleural Dissemination
Published on: February 9, 2021
Bypassing Ca2+ Influx for Antimetastasis Photodynamic Therapy via Robust Nucleus-Targeted Near-Infrared Cyanines
Xianghan Zhang1,2, Huaicong Zhang1,2, Qunyan Dong1
1Engineering Research Center of Molecular and Neuro Imaging (Ministry of Education), School of Life Science and Technology, Xidian University, Xi'an, Shaanxi 710126, China.
Abstract:
Hypoxia-induced tumor metastasis severely hinders the efficacy of photodynamic therapy (PDT) in cancer treatment. Current strategies predominantly offer palliative suppression of the HIF-1α pathway, emphasizing the urgent need for innovative PDT approaches to prevent metastasis from the outset. Our study revealed that typical PDT triggers an increase in cytoplasmic Ca2+ levels, activating HIF-1α, and that reducing Ca2+ levels can, in turn, mitigate metastasis. Considering cytoplasm's role in Ca2+ storage and regulation, we propose that PDT-induced metastasis can be addressed at its source by precise intracellular localization of photosensitizers (PSs). We developed near-infrared (NIR) cyanine PSs with inherent nucleus targeting capabilities. These PSs effectively inhibit cytoplasmic Ca2+ elevation and reduce HIF-1α activity upon irradiation, achieving remarkable antimetastatic effects in 4T1 tumors. Consequently, our findings highlight the pivotal role of Ca2+ in PDT-induced metastasis and provide a robust approach for circumventing metastasis from the outset using new nucleus-targeting organic PSs.
Insights
Photodynamic therapy (PDT) can increase cancer metastasis by raising calcium levels and activating HIF-1α. New nucleus-targeting photosensitizers prevent this by blocking calcium increases, offering a novel anti-metastasis strategy.
Area of Science:
- Biomedical Engineering
- Cancer Research
- Photodynamic Therapy
Background:
- Hypoxia-induced tumor metastasis is a major challenge in cancer treatment, limiting photodynamic therapy (PDT) efficacy.
- Current strategies for managing metastasis often provide only palliative suppression of the Hypoxia-Inducible Factor 1-alpha (HIF-1α) pathway.
- There is a critical need for innovative PDT approaches that prevent metastasis from the onset.
Purpose of the Study:
- To investigate the role of cytoplasmic calcium (Ca2+) in PDT-induced metastasis.
- To develop novel photosensitizers (PSs) for targeted intracellular localization to mitigate metastasis.
- To evaluate the antimetastatic efficacy of nucleus-targeting near-infrared (NIR) cyanine PSs.
Main Methods:
- Investigated the effect of standard PDT on cytoplasmic Ca2+ levels and HIF-1α activation.
- Designed and synthesized NIR cyanine PSs with inherent nucleus-targeting capabilities.
- Assessed the inhibition of cytoplasmic Ca2+ elevation and HIF-1α activity upon irradiation in 4T1 tumor models.
Main Results:
- Standard PDT was found to increase cytoplasmic Ca2+ levels, subsequently activating HIF-1α and promoting metastasis.
- The developed nucleus-targeting PSs effectively inhibited PDT-induced cytoplasmic Ca2+ elevation upon irradiation.
- Irradiation with nucleus-targeting PSs led to reduced HIF-1α activity and demonstrated significant antimetastatic effects in 4T1 tumors.
Conclusions:
- Cytoplasmic Ca2+ plays a critical role in mediating metastasis induced by photodynamic therapy.
- Precise intracellular localization of photosensitizers, specifically to the nucleus, can prevent metastasis at its source.
- Nucleus-targeting organic PSs represent a promising strategy for overcoming PDT-induced metastasis and improving cancer treatment outcomes.
