Nano-delivery of salvianolic acid B induces the quiescence of tumor-associated fibroblasts via interfering with TGF-β1/Smad signaling to facilitate chemo- and immunotherapy in desmoplastic tumor
Nano-delivery of salvianolic acid B induces the quiescence of tumor-associated fibroblasts via interfering with TGF-β1/Smad signaling to facilitate chemo- and immunotherapy in desmoplastic tumor
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DOI：
10.1016/j.ijpharm.2022.121953
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发表时间：
2022-07-25
影响因子：
5.8
通讯作者：
Chen, Weidong
中科院分区：
文献类型：
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作者：
Chen, Yunna;Hu, Mengru;Chen, Weidong
肿瘤相关成纤维细胞（TAFs）作为介导促结缔组织增生反应的关键基质细胞，在纳米颗粒有限的穿透和抑制免疫肿瘤微环境中发挥关键作用。在此，我们发现，载丹酚酸B的聚乙二醇化脂质体（PEG-SAB-Lip）可以通过抑制TGF-β 1的分泌来干扰TAFs的活化。在抑制TAFs的活化后，肿瘤中的胶原沉积减少，并且纳米颗粒在肿瘤中的渗透增强。RT-qPCR和免疫荧光染色结果显示肿瘤区域Th 1细胞因子和趋化因子（CXCL 9和CXCL 10）的高表达以及CD 4（+）、CD 8（+）T细胞和M1巨噬细胞的募集。同时，肿瘤区Th 2细胞因子和趋化因子CXCL 13表达降低，MDSCs、TGFAP和M2巨噬细胞数量减少。这些结果与TAF的失活有关。PEG-SAB-Lip与紫杉醇修饰脂质体（PEG-DTX-Lip）联合应用可显著抑制肿瘤生长。此外，PEG-SAB-Lip进一步抑制肿瘤向肺的转移。因此，我们的结果表明PEG-SAB-Lip可以重塑肿瘤微环境并提高纳米颗粒的功效。
As the key stromal cells that mediate the desmoplastic reaction, tumor-associated fibroblasts (TAFs) play a critical role in the limited nanoparticle penetration and suppressive immune tumor microenvironment. Herein, we found that salvianolic acid B-loaded PEGylated liposomes (PEG-SAB-Lip) can interfere with the activation of TAFs by inhibiting the secretion of TGF-beta 1. After inhibiting the activation of TAFs, collagen deposition in tumors was reduced, and the penetration of nanoparticles in tumors was enhanced. The results of RT-qPCR and immunofluorescence staining showed the high expression of Th1 cytokines and chemokines (CXCL9 and CXCL10) and the recruitment of CD4(+), CD8(+) T cells, and M1 macrophages in the tumor area. At the same time, the low expression of Th2 cytokine and chemokine CXCL13, as well as the decrease of MDSCs, Tregs, and M2 macrophages were also observed in the tumor area. These results were related to the inactivation of TAFs. The combined treatment of PEG-SAB-Lip and docetaxel-loaded PEG-modified liposomes (PEG-DTX-Lip) can significantly inhibit tumor growth. Moreover, PEG-SAB-Lip further inhibited tumor metastasis to the lung. Therefore, our results showed that PEG-SAB-Lip can remodel the tumor microenvironment and improve the efficacy of nanoparticles.