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Targeting folate receptor β positive tumor-associated macrophages in lung cancer with a folate-modified liposomal complex.
Signal Transduction and Targeted Therapy ( IF 40.8 ) Pub Date : 2020-01-22 , DOI: 10.1038/s41392-020-0115-0
Yan Tie 1, 2 , Heng Zheng 3 , Zhiyao He 1 , Jingyun Yang 1, 3 , Bin Shao 1 , Li Liu 1 , Min Luo 1 , Xia Yuan 1 , Yu Liu 1 , Xiangxian Zhang 1 , Hongyi Li 3 , Min Wu 4 , Xiawei Wei 1
Affiliation  

Tumor-associated macrophages (TAMs) facilitate cancer progression by promoting tumor invasion, angiogenesis, metastasis, inflammatory responses, and immunosuppression. Folate receptor β (FRβ) is overexpressed in TAMs. However, the clinical significance of FRβ-positive macrophages in lung cancer remains poorly understood. In this study, we verified that FRβ overexpression in lung cancer TAMs was associated with poor prognosis. We utilized a folate-modified lipoplex comprising a folate-modified liposome (F-PLP) delivering a BIM-S plasmid to target both lung cancer cells and FRβ-positive macrophages in the tumor microenvironment. Transfection of LL/2 cells and MH-S cells with F-PLP/pBIM induced cell apoptosis. Injection of F-PLP/pBIM into LL/2 and A549 lung cancer models significantly depleted FRβ-positive macrophages and reduced tumor growth. Treatment of tumor-bearing mice with F-PLP/pBIM significantly inhibited tumor growth in vivo by inducing tumor cell and macrophage apoptosis, reducing tumor proliferation, and inhibiting tumor angiogenesis. In addition, a preliminary safety evaluation demonstrated a good safety profile of F-PLP/pBIM as a gene therapy administered intravenously. This work describes a novel application of lipoplexes in lung cancer targeted therapy that influences the tumor microenvironment by targeting TAMs.

中文翻译:


用叶酸修饰的脂质体复合物靶向肺癌中叶酸受体 β 阳性肿瘤相关巨噬细胞。



肿瘤相关巨噬细胞(TAM)通过促进肿瘤侵袭、血管生成、转移、炎症反应和免疫抑制来促进癌症进展。叶酸受体 β (FRβ) 在 TAM 中过度表达。然而,FRβ阳性巨噬细胞在肺癌中的临床意义仍知之甚少。在这项研究中,我们证实肺癌 TAM 中 FRβ 过度表达与不良预后相关。我们利用包含叶酸修饰脂质体 (F-PLP) 的叶酸修饰脂质复合物,传递 BIM-S 质粒来靶向肿瘤微环境中的肺癌细胞和 FRβ 阳性巨噬细胞。用 F-PLP/pBIM 转染 LL/2 细胞和 MH-S 细胞诱导细胞凋亡。将 F-PLP/pBIM 注射到 LL/2 和 A549 肺癌模型中可显着耗尽 FRβ 阳性巨噬细胞并减少肿瘤生长。用F-PLP/pBIM治疗荷瘤小鼠,通过诱导肿瘤细胞和巨噬细胞凋亡、减少肿瘤增殖、抑制肿瘤血管生成,显着抑制体内肿瘤生长。此外,初步安全性评估表明,F-PLP/pBIM 作为静脉注射基因疗法具有良好的安全性。这项工作描述了 lipoplex 在肺癌靶向治疗中的一种新应用,通过靶向 TAM 来影响肿瘤微环境。
更新日期:2020-01-22
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