Targeting EGFR of triple-negative breast cancer enhances the therapeutic efficacy of paclitaxel- and cetuximab-conjugated nanodiamond nanocomposite
Targeting EGFR of triple-negative breast cancer enhances the therapeutic efficacy of paclitaxel- and cetuximab-conjugated nanodiamond nanocomposite
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DOI：
10.1016/j.actbio.2019.01.025
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发表时间：
2019-03-01
影响因子：
9.7
通讯作者：
Chao, Jui-I
中科院分区：
文献类型：
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作者：
Liao, Wei-Siang;Ho, Yu;Chao, Jui-I
乳腺癌是最常见的恶性肿瘤，也是全世界妇女癌症相关死亡的主要原因。三阴性乳腺癌（TNBC）的特征在于缺乏雌激素受体（ER）、孕激素受体（PR）和人表皮生长因子受体-2（HER 2）。然而，表皮生长因子受体（EGFR）在绝大多数肿瘤细胞中高表达，这为EGFR靶向治疗提供了一个潜在的靶点。纳米金刚石（ND）是一种碳基纳米材料，具有多种优势，包括荧光发射，生物相容性和药物输送应用。在本研究中，我们设计了一种纳米复合物，通过使用ND缀合紫杉醇（PTX）和西妥昔单抗（Cet）用于靶向治疗EGFR阳性的TNBC细胞。ND-PTX在各种人乳腺癌细胞系（MDA-MB-231、MCF-7和BT474）中抑制细胞活力并诱导有丝分裂灾难;相反，单独使用ND不会诱导细胞死亡。ND-PTX对裸鼠移植的人乳腺肿瘤有抑制作用。我们进一步研究了ND-PTX-Cet药物对MDA-MB-231乳腺癌细胞的TNBC的功效。ND-PTX-Cet可特异性结合EGFR，增强EGFR表达的MDA-MB-231细胞的抗肿瘤效应，包括药物摄取水平、有丝分裂灾难和凋亡，但对EGFR阴性的MCF-7细胞无此作用。此外，ND-PTX-Cet增加了活性caspase-3和磷酸化组蛋白H3（Ser 10）的蛋白水平。此外，与ND-PTX相比，ND-PTX-Cet显示出更有效地减小TNBC肿瘤体积。综上所述，这些结果表明，ND-PTX-Cet纳米复合物通过靶向EGFR增强TNBC细胞的有丝分裂灾难和凋亡，这可以为TNBC治疗提供一种可行的策略。因此，迫切需要为TNBC患者开发新的治疗策略。在这里，我们设计了一种纳米复合物，通过靶向TNBC的EGFR来增强ND-缀合的PTX和Cet的治疗功效（ND-PTX-Cet）。有趣的是，我们发现通过ND共递送Cet和PTX在体外和体内增强了EGFR表达的TNBC中的凋亡、有丝分裂灾难和肿瘤抑制。因此，该纳米复合物ND-PTX-Cet可用于靶向EGFR的人TNBC治疗。(C)2019 Acta Materialia Inc.由爱思唯尔有限公司出版。保留所有权利。
Breast cancer is the most common malignancy and a leading cause of cancer-related mortality among women worldwide. Triple-negative breast cancer (TNBC) is characterized by the lack of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2). However, epidermal growth factor receptor (EGFR) is highly expressed in most of the TNBCs, which may provide a potential target for EGFR targeting therapy. Nanodiamond (ND) is a carbon-based nanomaterial with several advantages, including fluorescence emission, biocompatibility, and drug delivery applications. In this study, we designed a nanocomposite by using ND conjugated with paclitaxel (PTX) and cetuximab (Cet) for targeting therapy on the EGFR-positive TNBC cells. ND-PTX inhibited cell viability and induced mitotic catastrophe in various human breast cancer cell lines (MDA-MB-231, MCF-7, and BT474); in contrast, ND alone did not induce cell death. ND-PTX inhibited the xenografted human breast tumors in nude mice. We further investigated ND-PTX-Cet drug efficacy on the TNBC of MDA-MB-231 breast cancer cells. ND-PTX-Cet could specifically bind to EGFR and enhanced the anticancer effects including drug uptake levels, mitotic catastrophe, and apoptosis in the EGFR-expressed MDA-MB-231 cells but not in the EGFR-negative MCF-7 cells. In addition, ND-PTX-Cet increased the protein levels of active caspase-3 and phospho-histone H3 (Ser10). Furthermore, ND-PTX-Cet showed more effective on the reduction of TNBC tumor volume by comparison with ND-PTX. Taken together, these results demonstrated that ND-PTX-Cet nanocomposite enhanced mitotic catastrophe and apoptosis by targeting EGFR of TNBC cells, which can provide a feasible strategy for TNBC therapy.Statement of significanceCurrent TNBC treatment is ineffective against the survival rate of TNBC patients. Therefore, the development of new treatment strategies for TNBC patients is urgently needed. Here, we have designed a nanocomposite by targeting on the EGFR of TNBC to enhance therapeutic efficacy by ND-conjugated PTX and Cet (ND-PTX-Cet). Interestingly, we found that the co-delivery of Cet and PTX by ND enhanced the apoptosis, mitotic catastrophe and tumor inhibition in the EGFR-expressed TNBC in vitro and in vivo. Consequently, this nanocomposite ND-PTX-Cet can be applied for targeting EGFR of human TNBC therapy. (C) 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.