Targeting integrins with RGD-conjugated gold nanoparticles in radiotherapy decreases the invasive activity of breast cancer cells.
Targeting integrins with RGD-conjugated gold nanoparticles in radiotherapy decreases the invasive activity of breast cancer cells.
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DOI：
10.2147/ijn.s137833
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发表时间：
2017
影响因子：
8
通讯作者：
Nam JM
中科院分区：
文献类型：
--
作者：
Wu PH;Onodera Y;Ichikawa Y;Rankin EB;Giaccia AJ;Watanabe Y;Qian W;Hashimoto T;Shirato H;Nam JM
金纳米粒子（AuNPs）最近作为用于增强各种癌症中的放射治疗效果的临床药剂而引起关注。虽然放射治疗是癌症的标准治疗方法，但侵袭性复发和转移是重要的临床问题。几项研究表明，辐射通过激活涉及整合素和纤连蛋白（FN）的分子机制促进癌细胞的侵袭。在这项研究中，聚乙二醇化金纳米颗粒（P-AuNPs）与Arg-Gly-Asp（RGD）肽（RGD/P-AuNPs）缀合，以靶向表达RGD结合整合素（如α5-和α v-整合素）的癌细胞。在MDA-MB-231细胞的晚期内体和溶酶体中，RGD/P-AuNPs更有效地内化并与整合素共定位。在MDA-MB-231细胞中，与单独的辐射相比，RGD/P-AuNP和辐射的组合降低了癌细胞活力并增加了DNA损伤。此外，在存在RGD/P-AuNPs的情况下，放射处理后的乳腺癌细胞系的侵袭活性被显著抑制。微阵列分析显示，在辐射细胞中FN的表达被抑制由联合使用的RGD/P-AuNPs。FN和下游信号传导的减少可能涉及通过RGD/P-AuNPs抑制辐射诱导的侵袭活性。我们的研究表明，RGD/P-AuNPs可以靶向整合素过度表达的癌细胞，通过抑制侵袭性活动以及敏化来改善放射治疗。因此，这些发现提供了一个可能的临床策略，使用金纳米粒子治疗浸润性乳腺癌放疗后。
Gold nanoparticles (AuNPs) have recently attracted attention as clinical agents for enhancing the effect of radiotherapy in various cancers. Although radiotherapy is a standard treatment for cancers, invasive recurrence and metastasis are significant clinical problems. Several studies have suggested that radiation promotes the invasion of cancer cells by activating molecular mechanisms involving integrin and fibronectin (FN). In this study, polyethylene-glycolylated AuNPs (P-AuNPs) were conjugated with Arg–Gly–Asp (RGD) peptides (RGD/P-AuNPs) to target cancer cells expressing RGD-binding integrins such as α5- and αv-integrins. RGD/P-AuNPs were internalized more efficiently and colocalized with integrins in the late endosomes and lysosomes of MDA-MB-231 cells. A combination of RGD/P-AuNPs and radiation reduced cancer cell viability and increased DNA damage compared to radiation alone in MDA-MB-231 cells. Moreover, the invasive activity of breast cancer cell lines after radiation treatment was significantly inhibited in the presence of RGD/P-AuNPs. Microarray analyses revealed that the expression of FN in irradiated cells was suppressed by combined use of RGD/P-AuNPs. Reduction of FN and downstream signaling may be involved in suppressing radiation-induced invasive activity by RGD/P-AuNPs. Our study suggests that RGD/P-AuNPs can target integrin-overexpressing cancer cells to improve radiation therapy by suppressing invasive activity in addition to sensitization. Thus, these findings provide a possible clinical strategy for using AuNPs to treat invasive breast cancer following radiotherapy.