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A polyamidoamine (PAMAM) derivative dendrimer with high loading capacity of TLR7/8 agonist for improved cancer immunotherapy

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Abstract

Tumor associated macrophages (TAMs) tend to exhibit tumor-promoting M2 phenotype and contribute to the development of immunosuppressive microenvironment of solid tumors. Reprograming TAMs from M2 into tumoricidal M1 phenotype is robust for stimulating tumor immunosuppressive microenvironment (TIME). In this study, we developed a poly(amidoamine) (PAMAM) derivative dendrimer (denoted as fourth generation-N,N-diethylaminoethyl (G4-DEEA)) for efficient loading of Toll-like receptor 7 and 8 (TLR7/8) agonist (R848) to remodel the TIME for potent cancer immunotherapy. G4-DEEA exhibited a high loading capacity of R848 up to 35.9 wt% by taking advantage of its dendritic structure. The resulting formulation (designated as G4-DEEA@R848) effectively polarized M2 macrophages into M1 phenotype in vitro, and improved the maturation and activation of antigen-presenting cells. In the 4T1 orthotopic breast cancer model, G4-DEEA@R848 showed a stronger tumor inhibitory effect than free drug. The mechanistic studies suggested that G4-DEEA@R848 could significantly stimulate the TIME by repolarizing TAMs into M1 phenotype, reducing the presence of immunosuppressive myeloid cells and increasing the infiltration of tumor cytotoxic T cells. This study provides a simple but effective dendrimer-based strategy to improve the formulation of R848 for improved cancer immunotherapy.

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Acknowledgements

This work was supported by National Key R&D Program of China (No. 2017YFA0205600), Guangdong Natural Science Funds for Distinguished Young Scholar (No. 2017A030306018), National Natural Science Foundation of China (Nos. 51922043 and 31771091), Guangdong Provincial Programs (Nos. 2017ZT07S054 and 2017GC010304), the Science and Technology Program of Guangzhou (No. 201902020018), and Fundamental Research Funds for Central Universities.

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  1. Jia-Si Wu and Jia-Xian Li contributed equally to this work.

Authors and Affiliations

  1. Institutes for Life Sciences, School of Medicine, South China University of Technology, Guangzhou, 510006, China

    Jia-Si Wu, Jia-Xian Li, Qi-Jia Duan, Si-Yu Yang, Zhi-Bin Zhao & Jin-Zhi Du

  2. School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, 511442, China

    Jia-Si Wu, Na Shu, Qi-Song Tong, Jing-Yang Zhang & Yong-Cong Huang

  3. National Engineering Research Center for Tissue Restoration and Reconstruction, Key Laboratory of Biomedical Engineering of Guangdong Province, South China University of Technology, Guangzhou, 510006, China

    Jia-Si Wu, Jia-Xian Li & Jin-Zhi Du

  4. Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, Innovation Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, China

    Jin-Zhi Du

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  1. Jia-Si Wu
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Correspondence to Zhi-Bin Zhao or Jin-Zhi Du.

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A polyamidoamine (PAMAM) derivative dendrimer with high loading capacity of TLR7/8 agonist for improved cancer immunotherapy

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Wu, JS., Li, JX., Shu, N. et al. A polyamidoamine (PAMAM) derivative dendrimer with high loading capacity of TLR7/8 agonist for improved cancer immunotherapy. Nano Res. 15, 510–518 (2022). https://doi.org/10.1007/s12274-021-3510-0

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