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

作　　者：Jia-Si Wu Jia-Xian Li Na Shu Qi-Jia Duan Qi-Song Tong Jing-Yang Zhang Yong-Cong Huang Si-Yu Yang Zhi-Bin Zhao Jin-Zhi Du 

机构地区：[1]Institutes for Life Sciences,School of Medicine,South China University of Technology,Guangzhou 510006,China [2]School of Biomedical Sciences and Engineering,Guangzhou International Campus,South China University of Technology,Guangzhou 511442,China [3]National Engineering Research Center for Tissue Restoration and Reconstruction,Key Laboratory of Biomedical Engineering oj Guangdong Province,South China University of Technology,Guangzhou 510006,China [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

出　　处：《Nano Research》2022年第1期510-518,共9页纳米研究（英文版）

基　　金：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.

摘　　要：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.

关 键 词：poly(amidoamine)(PAMAM)dendrimer drug delivery tumor-associated macrophage macrophage repolarization cancer immunotherapy 

分 类 号：R730.51[医药卫生—肿瘤] R318[医药卫生—临床医学]