Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12 Nishi 6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan.
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12 Nishi 6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan.
J Control Release. 2020 Sep 10;325:235-248. doi: 10.1016/j.jconrel.2020.07.001. Epub 2020 Jul 8.
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 α (HIF-1α), 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.
肿瘤微环境中含有大量肿瘤相关巨噬细胞（TAMs），这些细胞主要为 M2 表型，参与促进肿瘤的功能。靶向 TAMs 以操纵它们并改变其功能可能是癌症治疗的一种新的免疫疗法。这种策略涉及使用小干扰 RNA（siRNA）靶向 TAMs，通过沉默负责其 M2 极化的某些基因来改变它们的功能。在这项研究中，使用脂质纳米颗粒（LNP）制剂靶向并递送至 TAMs 的 siRNA。该 LNP 主要由一种新型的 pH 敏感阳离子脂质组成，称为 CL4H6 脂质，该脂质先前已被优化用于靶向肝细胞。优化后的负载 siRNA 的 CL4H6-LNPs 被选择性地高效摄取，并在裸鼠人肿瘤异种移植模型中的 TAMs 中显示出强烈的基因沉默活性。此外，通过使用优化的负载 siRNA 的 CL4H6-LNPs 靶向 TAMs，在同一肿瘤模型中获得了抗肿瘤治疗反应。通过沉默信号转导和转录激活因子 3（STAT3）和缺氧诱导因子 1α（HIF-1α）获得抗肿瘤治疗反应，导致浸润巨噬细胞（CD11b 细胞）进入肿瘤微环境（TME）的水平增加，以及 M1 巨噬细胞（CD169 细胞）的浓度有增加的趋势。该治疗还导致 TAMs 的促肿瘤功能逆转，主要是血管生成和肿瘤细胞激活，这表现在相关基因表达在 mRNA 水平上的降低。这项研究具有有前途的临床和制药应用前景，可实现新型基于巨噬细胞的癌症免疫疗法。
