Dual-function nanosystem for synergetic cancer chemo-/radiotherapy through ROS-mediated signaling pathways
Dual-function nanosystem for synergetic cancer chemo-/radiotherapy through ROS-mediated signaling pathways
复制标题
通过 ROS 介导的信号通路进行协同癌症化疗/放疗的双功能纳米系统
DOI：
10.1016/j.biomaterials.2015.01.063
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发表时间：
2015-05-01
期刊：
影响因子：
14
通讯作者：
Chen, Tianfeng
中科院分区：
文献类型：
--
作者：
He, Lizhen;Lai, Haoqiang;Chen, Tianfeng
放射抵抗和放射剂量的限制通常导致乏氧肿瘤的耗竭失败。在此，我们开发了多功能介孔二氧化硅纳米粒子（MSNs）作为一种新的抗癌硒代氨基酸（硒代胱氨酸，SeC）的载体，以实现协同化疗/放疗。这种多功能纳米系统有效地使癌细胞对X射线放射疗法敏感。TAT细胞穿透肽和转铁蛋白与MSN表面的缀合通过受体介导的内吞作用显著增强其在癌细胞中的内化。SeC@MSNs-Tf/TAT可显著增强X射线诱导的宫颈癌细胞生长抑制作用，主要通过死亡受体介导的外源性凋亡途径诱导细胞凋亡。在辐射后，SeC@MSNs-Tf/TAT促进细胞内ROS过量产生，其通过影响p53、ART和MAPKs途径诱导凋亡性细胞死亡。此外，SeC@MSNs-Tf/TAT还通过抑制细胞增殖和诱导细胞凋亡，显著抑制HeLa裸鼠移植瘤的生长。使用小鼠模型研究SeC@MSNs-Tf/TAT纳米颗粒的体内毒性。组织学分析结果显示，纳米颗粒在实验条件下对心、肝、脾、肺和肾等主要器官均未显示出明显的损伤。总之，这项研究证明了一种有效和安全的癌症靶向化疗/放疗的人类癌症的策略。(C)2015爱思唯尔有限公司版权所有。
Radioresistance and limitation of irradiative dosage usually lead to failure in depletion of hypoxic tumors. Herein we developed multifunctional mesoporous silica nanoparticles (MSNs) as a carrier of a novel anticancer selenoamino acid (selenocystine, SeC), to achieve synergistic chemo-/radiotherapy. This multifunctional nanosystem effectively sensitizes cancer cells to X-ray radiotherapy. Conjugation of TAT cell penetrating peptide and transferrin to the surface of MSNs significantly enhances its internalization in cancer cells through receptor-mediated endocytosis. SeC@MSNs-Tf/TAT significantly enhanced X-ray-induced growth inhibition in cervical cancer cells by induction of apoptosis, mainly through death receptor-mediated extrinsic apoptotic pathway. Upon radiation, SeC@MSNs-Tf/TAT promoted intracellular ROS overproduction, which induced apoptotic cell death by affecting p53, ART and MAPKs pathways. Furthermore, SeC@MSNs-Tf/TAT also significantly inhibited HeLa tumor growth in nude mice model through suppression of cell proliferation and induction of apoptosis. In vivo toxicity of the SeC@MSNs-Tf/TAT nanoparticles was investigated using the mouse model. The results of histological analysis revealed that, the nanoparticles did not show any obvious damage to these major organs under the experimental conditions, including heart, liver, spleen, lung and kidney. Taken together, this study demonstrates an effective and safe strategy for cancer-targeted chemo-/radiotherapy of human cancers. (C) 2015 Elsevier Ltd. All rights reserved.