Theranostics 2021; 11(8):3580-3594. doi:10.7150/thno.55441

Research Paper

Calcium phosphate engineered photosynthetic microalgae to combat hypoxic-tumor by in-situ modulating hypoxia and cascade radio-phototherapy

Danni Zhong1,2, Wanlin Li2, Shiyuan Hua2, Yuchen Qi2, Tingting Xie2, Yue Qiao2, Min Zhou1,2,3✉

1. Department of Surgery, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, China.
2. Institute of Translational Medicine, Zhejiang University, Hangzhou 310009, China.
3. State Key Laboratory of Modern Optical Instrumentations, Zhejiang University, Hangzhou, 310058, China.

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Zhong D, Li W, Hua S, Qi Y, Xie T, Qiao Y, Zhou M. Calcium phosphate engineered photosynthetic microalgae to combat hypoxic-tumor by in-situ modulating hypoxia and cascade radio-phototherapy. Theranostics 2021; 11(8):3580-3594. doi:10.7150/thno.55441. Available from

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Rationale: Hypoxia is one of the crucial restrictions in cancer radiotherapy (RT), which leads to the hypoxia-associated radioresistance of tumor cells and may result in the sharp decline in therapeutic efficacy.

Methods: Herein, living photosynthetic microalgae (Chlorella vulgaris, C. vulgaris), were used as oxygenators, for in situ oxygen generation to relieve tumor hypoxia. We engineered the surface of C. vulgaris (CV) cells with calcium phosphate (CaP) shell by biomineralization, to form a biomimetic system (CV@CaP) for efficient tumor delivery and in-situ active photosynthetic oxygenation reaction in tumor.

Results: After intravenous injection into tumor-bearing mice, CV@CaP could remarkably alleviate tumor hypoxia by continuous oxygen generation, thereby achieving enhanced radiotherapeutic effect. Furthermore, a cascade phototherapy could be fulfilled by the chlorophyll released from photosynthetic microalgae combined thermal effects under 650 nm laser irradiation. The feasibility of CV@CaP-mediated combinational treatment was finally validated in an orthotropic breast cancer mouse model, revealing its prominent anti-tumor and anti-metastasis efficacy in hypoxic-tumor management. More importantly, the engineered photosynthetic microalgae exhibited excellent fluorescence and photoacoustic imaging properties, allowing the self-monitoring of tumor therapy and tumor microenvironment.

Conclusions: Our studies of this photosynthetic microsystem open up a new dimension for solving the radioresistance issue of hypoxic tumors.

Keywords: Chlorella vulgaris, chlorophyll, photosynthetic microalgae, tumor hypoxia, radiotherapy, phototherapy