Enhanced Antitumor Activity of EGFP-EGF1-Conjugated Nanoparticles by a Multitargeting Strategy
Enhanced Antitumor Activity of EGFP-EGF1-Conjugated Nanoparticles by a Multitargeting Strategy
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通过多靶点策略增强 EGFP-EGF1 共轭纳米颗粒的抗肿瘤活性
DOI：
10.1021/acsami.6b00036
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发表时间：
2016-04-13
影响因子：
9.5
通讯作者：
Pang, Zhiqing
中科院分区：
文献类型：
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作者：
Zhang, Bo;Jiang, Ting;Pang, Zhiqing
肿瘤间质细胞与肿瘤实质细胞相互作用促进肿瘤生长已被越来越多的人所认识。因此，我们推测同时向实质细胞和基质细胞递送治疗剂可能更有效地治疗肿瘤。组织因子（TF）广泛存在于肿瘤组织中，在肿瘤实质细胞和基质细胞（包括新生血管细胞、肿瘤相关的成纤维细胞和肿瘤相关的巨噬细胞）中都有大量表达，这表明TF可能是一种同时向多种细胞递送药物的良好靶点。EGFP-EGF 1是一种融合蛋白，来源于TF的天然配体因子VII。它保留了特异性TF结合能力，但不引起凝血。在本研究中，EGFP-EGF 1修饰的纳米粒（ENP）被构建为多靶向药物递送系统。蛋白结合实验显示EGFP-EGF 1能与A549肿瘤细胞及其他基质细胞如新生血管细胞、肿瘤相关成纤维细胞、肿瘤相关巨噬细胞等良好结合。与未修饰的纳米颗粒（NP）相比，A549细胞和这些基质细胞对ENP的摄取显著增强，但过量的游离EGFP-EGF 1抑制ENP的摄取。此外，当紫杉醇（PTX）负载时，ENP比Taxol和NP诱导更多的A549肿瘤细胞凋亡。在体内，通过体内成像，ENP更特异性地在TF过表达的A549肿瘤中积累，主要是未被VII因子占据的区域和靶向肿瘤实质细胞以及通过免疫荧光染色的不同类型的基质细胞。用载有PTX的ENP（ENP-PTX）治疗显著降低了裸鼠中的A549肿瘤生长，而NP-PTX和紫杉醇治疗的小鼠对治疗的反应较低。此外，H&E和TUNEL染色显示ENP-PTX诱导更严重的肿瘤坏死和更广泛的细胞凋亡。总之，本研究表明ENP可以通过TF靶向肿瘤中的多种关键细胞类型，这可以用于提高抗癌药物的治疗效果。
Tumor stromal cells have been increasingly recognized to interact with tumor parenchyma cells and promote tumor growth. Therefore, we speculated that therapeutics delivery to both parenchyma cells and stromal cells simultaneously might treat a tumor more effectively. Tissue factor (TF) was shown to be extensively located in a tumor and was abundantly sited in both tumor parenchyma cells and stromal cells including neo-vascular cells, tumor-associated fibroblasts, and tumor-associated macrophages, indicating it might function as a favorable target for drug delivery to multiple cell types simultaneously. EGFP-EGF1 is a fusion protein derived from factor VII, the natural ligand of TF. It retains the specific TF binding capability but does not cause coagulation. In the present study, a nanoparticle modified with EGFP-EGF1 (ENP) was constructed as a multitargeting drug delivery system. The protein binding experiment showed EGFP-EGF1 could bind well to A549 tumor cells and other stromal cells including neo-vascular cells, tumor-associated fibroblasts, and tumor-associated macrophages. Compared with unmodified nanoparticles (NP), ENP uptake by A549 cells and those stromal cells was significantly enhanced but inhibited by excessive free EGFP-EGF1. In addition, ENP induced more A549 tumor cell apoptosis than Taxol and NP when paclitaxel (PTX) was loaded. In vivo, ENP accumulated more specially in TF-overexpressed A549 tumors by in vivo imaging, mainly regions unoccupied by factor VII and targeted tumor parenchyma cells as well as different types of stromal cells by immunofluorescence staining. Treatment with PTX-loaded ENP (ENP-PTX) significantly reduced the A549 tumor growth in nude mice while NP-PTX- and Taxol-treated mice had lower response to the therapy. Furthermore, H&E and TUNEL staining revealed that ENP-PTX induced more severe tumor necrosis and more extensive cell apoptosis. Altogether, the present study demonstrated that ENP could target multiple key cell types in tumors through TF, which could be utilized to improve the therapeutic effect of anticancer drugs.