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In situ sprayed bioresponsive immunotherapeutic gel for post-surgical cancer treatment

Nature Nanotechnology volume 14, pages 89–97 (2019)Cite this article

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Abstract

Cancer recurrence after surgical resection remains a significant cause of treatment failure. Here, we have developed an in situ formed immunotherapeutic bioresponsive gel that controls both local tumour recurrence after surgery and development of distant tumours. Briefly, calcium carbonate nanoparticles pre-loaded with the anti-CD47 antibody are encapsulated in the fibrin gel and scavenge H+ in the surgical wound, allowing polarization of tumour-associated macrophages to the M1-like phenotype. The released anti-CD47 antibody blocks the ‘don’t eat me’ signal in cancer cells, thereby increasing phagocytosis of cancer cells by macrophages. Macrophages can promote effective antigen presentation and initiate T cell mediated immune responses that control tumour growth. Our findings indicate that the immunotherapeutic fibrin gel ‘awakens’ the host innate and adaptive immune systems to inhibit both local tumour recurrence post surgery and potential metastatic spread.

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Fig. 1: Schematic and characterization of the in situ formed immunotherapeutic fibrin gel.
Fig. 2: Incorporation of CaCO3@fibrin for relieving immunosuppressive TME.
Fig. 3: CD47 blockade for increasing phagocytosis in vitro and exerting antitumour immune responses in vivo.
Fig. 4: aCD47@CaCO3@fibrin for reducing recurrence of B16F10 tumours after surgery.
Fig. 5: aCD47@CaCO3@fibrin for triggering antitumour immune response.
Fig. 6: Local treatment of aCD47@CaCO3@fibrin for systemic antitumour immune response.

Data availability

The data that support the plots within this paper and other findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by grants from start-up packages from UNC/NC state and UCLA, the Jonsson Comprehensive Cancer Center at UCLA, the Alfred P. Sloan Foundation (Sloan Research Fellowship), the National Key R&D Program of China (2017YFA0205600), the Program for Guangdong Introducing Innovative and Enterpreneurial Teams (2017ZT07S054) and the National Natural Science Foundation of China (51728301). The authors thank L. Huang at UNC at Chapel Hill for providing the B16F10-Luc-GFP.

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Authors and Affiliations

  1. Department of Bioengineering, University of California, Los Angeles, CA, USA

    Qian Chen, Xudong Zhang, Guojun Chen, Quanyin Hu, Di Wen, Guang Yang & Zhen Gu

  2. California NanoSystems Institute, University of California, Los Angeles, CA, USA

    Qian Chen, Xudong Zhang, Guojun Chen, Quanyin Hu, Di Wen, Guang Yang & Zhen Gu

  3. Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC, USA

    Qian Chen, Chao Wang, Quanyin Hu, Jinqiang Wang, Yuqi Zhang, Yifei Lu & Zhen Gu

  4. National Engineering Research Center for Tissue Restoration and Reconstruction, and School of Biomedical Science and Engineering, South China University of Technology, Guangzhou, Guangdong, China

    Hongjun Li & Jun Wang

  5. Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, China

    Yifei Lu & Chen Jiang

  6. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA

    Gianpietro Dotti

  7. Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA

    Zhen Gu

  8. Center for Minimally Invasive Therapeutics, University of California, Los Angeles, CA, USA

    Zhen Gu

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  1. Qian Chen
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Contributions

Q.C., G.D. and Z.G. conceived and designed the experiments. Q.C., C.W., X.Z., G.C., Q.H., Ji.W., D.W., Y.Z., H.L., Y.L., G.Y. and X.Z. performed the experiments and analysed data. Q.C., G.C., C.J., Ju.W., G.D. and Z.G. co-wrote the paper. All authors discussed the results and implications and edited the manuscript at all stages.

Corresponding author

Correspondence to Zhen Gu.

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Competing interests

Z.G. and Q.C. have applied for patents related to this study. Z.G. is a scientific co-founder of ZenCapsule Inc.

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Chen, Q., Wang, C., Zhang, X. et al. In situ sprayed bioresponsive immunotherapeutic gel for post-surgical cancer treatment. Nature Nanotech 14, 89–97 (2019). https://doi.org/10.1038/s41565-018-0319-4

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