期刊
JOURNAL OF CONTROLLED RELEASE
卷 325, 期 -, 页码 235-248出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2020.07.001
关键词
Cancer immunotherapy; Gene silencing; Lipid nanoparticle; Tumor-associated macrophages; Short interfering RNA
资金
- Japan Society for Promotion of Science (JSPS) KAKENHI [15K20831, 17H05052, 18K19889]
- Special Education and Research Expenses from the Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- Grants-in-Aid for Scientific Research [17H05052, 18K19889, 15K20831] Funding Source: KAKEN
The tumor-microenvironment contains large numbers of tumor-associated macrophages (TAMs) which are largely M2 phenotypes and are involved in pro-tumorous functions. Targeting TAMs so as to manipulate them and to modify their functions could be a novel immunotherapy for the treatment of cancer. Such a strategy would involve targeting TAMs with short interfering RNA (siRNA) to modify their functions by silencing certain genes that are responsible for their M2 polarization. In this study, a lipid nanoparticle (LNP) formulation was used to target and deliver siRNA to TAMs. The LNP was mainly composed of a novel, pH-sensitive cationic lipid, referred to as the CL4H6 lipid, which had previously been optimized to target hepatocytes. The optimized siRNA-loaded CL4H6-LNPs were selectively and efficiently taken up and showed strong gene silencing activity in TAMs in a human tumor xenograft model in nude mice. Furthermore, an anti-tumor therapeutic response in the same tumor model was obtained by targeting TAMs using the optimized siRNA-loaded CL4H6-LNPs. The anti-tumor therapeutic response was obtained through the silencing of the signal transducer and activator of transcription 3 (STAT3) and hypoxia inducible factor 1 alpha (HIF-1 alpha), which resulted in an increase in the level of infiltrated macrophage (CD11b +/- cells) into the tumor-microenvironment (TME) as well as a tendency to increase the concentration of M1 macrophages (CD169 +/- cells). The treatment also resulted in reversing the pro-tumorous functions of TAMs-mainly angiogenesis and tumor cell activation-, as evidenced by a decrease in the related gene expression at the mRNA level. This research has promising clinical and pharmaceutical applications for achieving novel macrophage-based cancer immunotherapy.
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