Anti-Tumor Immune Response of Folate-Conjugated Chitosan Nanoparticles Containing the IP-10 Gene in Mice with Hepatocellular Carcinoma
Anti-Tumor Immune Response of Folate-Conjugated Chitosan Nanoparticles Containing the IP-10 Gene in Mice with Hepatocellular Carcinoma
复制标题
含IP-10基因的叶酸缀合壳聚糖纳米粒子对肝细胞癌小鼠的抗肿瘤免疫反应
DOI：
10.1166/jbn.2014.2051
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发表时间：
2014-12-01
影响因子：
2.9
通讯作者：
Lu, Xiaoling
中科院分区：
文献类型：
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作者：
Lai, Chunhui;Yu, Xia;Lu, Xiaoling
免疫疗法是近年来最有前途的肝细胞癌（HCC）新疗法之一。在这项研究中，叶酸缀合的壳聚糖纳米颗粒（FA-CS-NPs）负载了小鼠干扰素γ诱导蛋白10（IP-10）质粒，用于HCC的免疫治疗。用包埋 IP-10 质粒的 FA-CS-NP 处理 H22 荷瘤小鼠，并通过体内光学成像观察靶向效率。采用流式细胞术测量肿瘤中骨髓源性抑制细胞（MDSC）和脾脏中CD4（+）CD25（+）FoxP3（+）T调节细胞（CD4（+）CD25（+）FoxP3（+）Tregs）的数量。使用酶联免疫斑点（ELISPOT）测定来定量干扰素-γ（IFN-γ）阳性细胞的数量。通过免疫组织化学评估IP-10表达、肿瘤血管密度、细胞增殖和凋亡。结果表明，包埋 IP-10 质粒的 FA-CS-NPs 具有抗肿瘤活性，可抑制 H22 荷瘤小鼠的肿瘤生长并延长其生存时间。用 FA-CS-NPs 包埋 IP-10 质粒治疗 H22 荷瘤小鼠可抑制血管生成、促进 IP-10 表达并诱导肿瘤细胞凋亡。与其他实验组的小鼠相比，FA-CS-NPs 包埋的 IP-10 质粒处理小鼠的脾脏中 Treg 比例较低，肿瘤中 MDSC 比例较高，脾脏中 IFN-γ 阳性细胞数量较多。这些数据表明，负载IP-10质粒的叶酸缀合壳聚糖纳米颗粒的基因递送系统可能是HCC免疫治疗的有前途的策略。
Immunotherapy is one of the most promising new therapies for hepatocellular carcinoma (HCC) in recent years. In this study, folate-conjugated chitosan nanoparticles (FA-CS-NPs) were loaded with mouse interferon-gamma-inducible protein-10 (IP-10) plasmid, which were used for immunotherapy in HCC. H22 tumor-bearing mice were treated with FA-CS-NPs entrapped IP-10 plasmid and targeting efficiency was observed by optical imaging in vivo. Flow cytometry was used to measure the number of myeloid- derived suppressor cells (MDSCs) in the tumor and CD4(+)CD25(+)FoxP3(+) T-regulatory cells (CD4(+)CD25(+)FoxP3(+) Tregs) in the spleen. The enzyme-linked immunospot (ELISPOT) assay was used to quantify the number of interferon-gamma (IFN-gamma)-positive cells. IP-10 expression, tumor vessel density, cell proliferation and apoptosis were evaluated by immunohistochemistry. It was shown that FA-CS-NPs entrapped IP-10 plasmid displayed anti-tumor activity with inhibition of tumor growth and prolonging the survival time in H22 tumor-bearing mice. Treatment of H22 tumor-bearing mice with FA-CS-NPs entrapped IP-10 plasmid inhibited angiogenesis and promoted IP-10 expression and induced apoptosis in the tumor. FA-CS-NPs entrapped IP-10 plasmid-treated mice also had a lower proportion of Tregs in the spleen, a higher proportion of MDSCs in the tumor and higher number of IFN-gamma-positive cells in the spleen compared with the mice from the other experimental groups. These data suggested that the gene delivery system of folate-conjugated chitosan nanoparticle loaded with IP-10 plasmid may be a promising strategy for immunotherapy of HCC.