Magnetic nanoparticle-mediated hyperthermia therapy induces tumour growth inhibition by apoptosis and Hsp90/AKT modulation
Magnetic nanoparticle-mediated hyperthermia therapy induces tumour growth inhibition by apoptosis and Hsp90/AKT modulation
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DOI：
10.3109/02656736.2015.1075072
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发表时间：
2015-11-17
影响因子：
3.1
通讯作者：
Pandey, Badri N.
中科院分区：
文献类型：
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作者：
Shetake, Neena G.;Kumar, Amit;Pandey, Badri N.
目的：我们评估了油酸功能化 Fe3O4 磁性纳米粒子（MN-OA）在体内条件下的热疗功效，并阐明了抑制肿瘤生长的潜在机制。材料和方法：使用 TUNEL 测定、蛋白质印迹 (WB)、免疫荧光 (IF) 染色和组织病理学检查等技术，在小鼠纤维肉瘤肿瘤模型 (WEHI-164) 中评估 MN-OA 介导的磁热疗 (MHT) 抑制肿瘤生长的功效和机制。此外，分别通过普鲁士蓝染色和血清生化分析研究了MN-OA在肿瘤/其他靶器官中的生物分布及其对正常器官功能的影响。结果：通过测量肿瘤体积以及对来自荧光素酶转染的 WEHI-164 细胞的肿瘤进行体内成像，确定 MN-OA 诱导的 MHT 显着抑制肿瘤生长。组织病理学分析显示，在接受 MHT 治疗的肿瘤中，存在严重的细胞凋亡和肿瘤细胞增殖减少，TUNEL 测定进一步证实了这一点，Ki-67 的表达降低，裂解的 caspase-3 水平升高。此外，通过 WB 和 IF 染色研究，在用 MHT 治疗的肿瘤中，热应激标志物 Hsp90 及其客户蛋白 AKT/PKB 的表达分别减少了约 50% 和 80%。血清分析表明 MN-OA 的毒性很小（就肝肾功能而言），这进一步与靶器官中 MN-OA 的最小积累相关。结论：这些结果表明细胞凋亡和 Hsp90/AKT 调节参与 MN-OA 介导的 MHT 诱导的肿瘤生长抑制。
Purpose: We have evaluated the hyperthermia efficacy of oleic acid-functionalised Fe3O4 magnetic nanoparticles (MN-OA) under in vivo conditions and elucidated the underlying mechanism of tumour growth inhibition. Materials and methods: The efficacy and mechanism of tumour growth inhibition by MN-OA-mediated magnetic hyperthermia therapy (MHT) was evaluated in a murine fibrosarcoma tumour model (WEHI-164) using techniques such as TUNEL assay, Western blotting (WB), immunofluorescence (IF) staining and histopathological examination. In addition, bio-distribution of MN-OA in tumour/other target organs and its effect on normal organ function were studied by Prussian blue staining and serum biochemical analysis, respectively. Results: MN-OA-induced MHT resulted in significant inhibition of tumour growth as determined by measurement of tumour volume, as well as by in vivo imaging of tumour derived from luciferase-transfected WEHI-164 cells. Histopathology analysis showed presence of severe apoptosis and reduced tumour cells proliferation, which was further confirmed by TUNEL assay, reduced expression of Ki-67 and enhanced level of cleaved caspase-3, in tumours treated with MHT. Moreover, expression of heat stress marker, Hsp90 and its client protein, AKT/PKB was reduced by approximate to 50 and 80%, respectively, in tumours treated with MHT as studied by WB and IF staining. Serum analysis suggested insignificant toxicity of MN-OA (in terms of liver and kidney function), which was further correlated with minimal accumulation of MN-OA in target organs. Conclusions: These results suggest the involvement of apoptosis and Hsp90/AKT modulation in MN-OA-mediated MHT-induced tumour growth inhibition.