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Nanoparticles (NPs)-mediated Siglec15 silencing and macrophage repolarization for enhanced cancer immunotherapy

Acta Pharmaceutica Sinica B 2023年第12期13卷 5048-5059页

作者： Xiaodi Liu Qi Zhang Yixia Liang Shiyu Xiong Yan Cai Jincheng Cao Yanni Xu Xiaolin Xu Ye Wu Qiang Lu Xiaoding Xu Baoming Luo Department of Ultrasound Laboratory of Ultrasound Imaging and DrugWest China HospitalSichuan UniversityChengdu 610041China Department of Ultrasound Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China Department of Ultrasound Central People's Hospital of ZhanjiangZhanjiang 524045China

cell infiltration and proliferation in tumor tissues are the main factors that significantly affect the therapeutic outcomes of cancer *** evidence has shown that interferon-gamma(IFN)could enhance CXCL9 secretion from macrophages to recruit T cells,but Siglec15 expressed on TAMs can attenuate T cell ***,targeted regulation of macrophage function could be a promising strategy to enhance cancer immunotherapy via concurrently promoting the infiltration and proliferation of T cells in tumor *** herein developed reductionresponsive nanoparticles(NPs)made with poly(disulfide amide)(PDSA)and lipid-poly(ethylene glycol)(lipid-PEG)for systemic delivery of Siglec15 siRNA(siSiglec15)and IFN for enhanced cancer *** intravenous administration,these cargo-loaded could highly accumulate in the tumor tissues and be efficiently internalized by tumor-associated macrophages(TAMs).With the highly concentrated glutathione(GSH)in the cytoplasm to destroy the nanostructure,the loaded IFN and si-Siglec15 could be rapidly released,which could respectively repolarize macrophage phenotype to enhance CXCL9 secretion for T cell infiltration and silence Siglec15 expression to promote T cell proliferation,leading to significant inhibition of hepatocellular carcinoma(HCC)growth when combining with the immune checkpoint *** strategy developed herein could be used as an effective tool to enhance cancer immunotherapy.

关键词： Nanoparticles Tumor-associated macrophages macrophage repolarization T cell infiltration T cell proliferation Cancer immunotherapy Siglec15 Hepatocellular carcinoma

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A Redox-responsive Prodrug Nanogel of TLR7/8 Agonist for Improved Cancer Immunotherapy

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Chinese Journal of Polymer Science 2023年第1期41卷 32-39页

作者： Kai-Shuo Wang Yu-Feng Jin Qi-Song Tong Yong-Cong Huang Zhen-Lin Gao Sui-Juan Zheng Jing-Yang Zhang Jun Wang Jin-Zhi Du School of Medicine South China University of TechnologyGuangzhou510006China School of Biomedical Sciences and Engineering Guangzhou International CampusSouth China University of TechnologyGuangzhou511442China National Engineering Research Center for Tissue Restoration and Reconstruction South China University of TechnologyGuangzhou510006China Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education and Guangdong Provincial Key Laboratory of Biomedical EngineeringSouth China University of TechnologyGuangzhou510006China

The existence of tumor immunosuppressive microenvironment(TIME)is the major determinant for the poor efficacy of current tumor ***-associated macrophages(TAMs)tend to become tumor-promoting M2-like phenotype and hinder immune response in solid *** of TAMs from M2 to anti-tumor M1 phenotype is robust for remodeling the ***,we developed a redox-responsive nanogel as the delivery system of Toll-like receptor 7 and 8(TLR7/8)agonist(R848)prodrug for potent cancer *** nanogel(denoted as R848-Gel)was obtained by emulsion polymerization of HSEMA and R848 prodrug(R848-HSEMA),whose size was appropriate 100 nm.R848-Gel could be internalized by macrophages and dendritic cells in vitro,and effectively repolarized M2 into M1 macrophages and promoted the maturation of antigen-presenting *** vivo study indicated that the R848-Gel showed a stronger tumor inhibitory effect and no drastic body weight change compared with free *** cell analysis after the treatment indicated that R848-Gel was helpful to activating the *** summary,this study provides a simple but effective vehicle for R848 to improve cancer immunotherapy.

关键词： Nanogel Drug delivery Tumor-associated macrophage macrophage repolarization Cancer immunotherapy

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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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Nano Research 2022年第1期15卷 510-518页

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 Institutes for Life Sciences School of MedicineSouth China University of TechnologyGuangzhou 510006China School of Biomedical Sciences and Engineering Guangzhou International CampusSouth China University of TechnologyGuangzhou 511442China National Engineering Research Center for Tissue Restoration and Reconstruction Key Laboratory of Biomedical Engineering oj Guangdong ProvinceSouth China University of TechnologyGuangzhou 510006China Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education Innovation Center for Tissue Restoration and ReconstructionSouth China University of TechnologyGuangzhou 510006China

Tumor associated macrophages(TAMs)tend to exhibit tumor-promoting M2 phenotype and contribute to the development of immunosuppressive microenvironment of solid *** 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 *** 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 *** the 4T1 orthotopic breast cancer model,G4-DEEA@R848 showed a stronger tumor inhibitory effect than free *** 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 *** 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

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