Modulation of pericytes by a fusion protein comprising of a PDGFRβ-antagonistic affibody and TNFα induces tumor vessel normalization and improves chemotherapy
Modulation of pericytes by a fusion protein comprising of a PDGFRβ-antagonistic affibody and TNFα induces tumor vessel normalization and improves chemotherapy
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由 PDGFR β 拮抗性亲和体和 TNF α 组成的融合蛋白对周细胞的调节诱导肿瘤血管正常化并改善化疗
DOI：
10.1016/j.jconrel.2019.03.018
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发表时间：
2019-05-28
影响因子：
10.8
通讯作者：
Lu, Xiaofeng
中科院分区：
文献类型：
--
作者：
Fan, Qing;Tao, Ze;Lu, Xiaofeng
抗癌药物的递送受到结构和功能异常的肿瘤血管的阻碍，这就需要通过药物来介导血管正常化。目前血管正常化策略主要集中在对内皮细胞（ECs）的直接调节上，但这常常会影响正常组织中的血管。调节内皮细胞支持细胞，如周细胞（PCs），是一个新方向。在此，我们通过将血小板衍生生长因子受体β（PDGFRβ）拮抗亲合体Z(PDGFRβ)与肿瘤坏死因子α（TNFα）融合，制备出一种融合蛋白Z - TNFα。由于融合的Z(PDGFRβ)对PDGFRβ具有亲和力，Z - TNFα可结合PDGFRβ阳性的周细胞，而不结合PDGFRβ阴性的内皮细胞。低剂量（1微克/小鼠）的Z - TNFα处理可重塑肿瘤血管，从而降低血管通透性并增加血管灌注。结果显示，Z - TNFα处理改善了阿霉素（DOX）的递送并增强了其抗肿瘤效果，这表明Z - TNFα诱导了肿瘤血管的正常化。从机制上讲，Z - TNFα介导的肿瘤血管正常化可能归因于周细胞分泌血管内皮生长因子（VEGF）的减少以及周细胞中细胞间黏附分子 - 1（ICAM - 1）表达的升高，这可能抑制内皮细胞的增殖和迁移，同时引发血管周围巨噬细胞与周细胞之间的相互作用。这些结果表明，肿瘤相关周细胞可被视为血管正常化的新型靶细胞，Z - TNFα有可能开发成为一种潜在的抗肿瘤联合治疗工具。
The delivery of anticancer drugs is hampered by tumor vessels with abnormal structure and function, which requires that vessel normalization be mediated by pharmaceutics. The current strategies for vessel normalization focus on direct modulation of endothelial cells (ECs), which frequently affect vessels in normal tissues. Modulating EC-supporting cells, such as pericytes (PCs), is a new direction. Here, we produced a fusion protein, Z-TNF alpha, by fusing the platelet-derived growth factor receptor beta (PDGFR beta)- antagonistic affibody Z(PDGFR beta) to tumor necrosis factor alpha (TNF alpha). Owing to the affinity of fused Z(PDGFR beta) for PDGFR beta, Z-TNF alpha binds PDGFR beta(+) PCs but not PDGFR beta(-) ECs. Low-dose (1 mu g/mouse) Z-TNF alpha treatment remodeled the tumor vessels, thus reducing vessel permeability and increasing vessel perfusion. As a result, the Z-TNF alpha treatment improved the delivery of doxorubicin (DOX) and enhanced its antitumor effect, indicating that Z-TNF alpha induced normalization of tumor vessels. Mechanically, the tumor vessel normalization mediated by Z-TNF alpha might be attributed to the reduction of vascular endothelial growth factor (VEGF) secretion by PCs and the elevated expression of intercellular cell adhesion molecule-1 (ICAM-1) in PCs, which might suppress the proliferation and migration of ECs and simultaneously trigger interaction between perivascular macrophages and PCs. These results demonstrated that tumor-associated PCs could be considered novel target cells for vessel normalization, and Z-TNF alpha might be developed as a potential tool for antitumor combination therapy.