Stapf Marcus, Teichgräber Ulf, Hilger Ingrid
Department of Experimental Radiology, Institute of Diagnostic and Interventional Radiology, Jena University Hospital, Friedrich-Schiller University Jena, Jena, Germany.
Int J Nanomedicine. 2017 Apr 6;12:2793-2811. doi: 10.2147/IJN.S120969. eCollection 2017.
Heat-based approaches have been considered as promising tools due to their ability to directly eradicate tumor cells and/or increase the sensitivity of tumors to radiation- or chemotherapy. In particular, the heating of magnetic nanoparticles (MNPs) via an alternating magnetic field can provide a handy alternative for a localized tumor treatment. To amplify the efficacy of magnetically induced thermal treatments, we elucidated the superior tumor-destructive effect of methotrexate-coupled MNPs (MTX/MNPs) in combination with magnetic heating (nanochemothermia) over the thermal treatment alone. Our studies in a murine bladder xenograft model revealed the enormous potential of nanochemothermia for a localized and relapse-free destruction of tumors which was superior to the thermal treatment alone. Nanochemothermia remarkably fostered the reduction of tumor volume. It impaired proapoptotic signaling (eg, p-p53), cell survival (eg, p-ERK1/2), and cell cycle (cyclins) pathways. Additionally, heat shock proteins (eg, HSP70) were remarkably affected. Moreover, nanochemothermia impaired the induction of angiogenic signaling by decreasing, for example, the levels of VEGF-R1 and MMP9, although an increasing tumor hypoxia was indicated by elevated Hif-1α levels. In contrast, tumor cells were able to recover after the thermal treatments alone. In conclusion, nanochemothermia on the basis of MTX/MNPs was superior to the thermal treatment due to a modification of cellular pathways, particularly those associated with the cellular survival and tumor vasculature. This allowed very efficient and relapse-free destruction of tumors.
基于热的方法因其能够直接根除肿瘤细胞和/或提高肿瘤对放疗或化疗的敏感性而被视为有前景的工具。特别是，通过交变磁场加热磁性纳米颗粒（MNPs）可为局部肿瘤治疗提供一种便捷的替代方法。为了增强磁诱导热处理的效果，我们阐明了甲氨蝶呤偶联的磁性纳米颗粒（MTX/MNPs）与磁热疗（纳米化疗）联合使用比单独热处理具有更优异的肿瘤破坏效果。我们在小鼠膀胱异种移植模型中的研究揭示了纳米化疗在局部无复发地破坏肿瘤方面具有巨大潜力，其优于单独的热处理。纳米化疗显著促进了肿瘤体积的减小。它损害了促凋亡信号通路（如p-p53）、细胞存活信号通路（如p-ERK1/2）和细胞周期（细胞周期蛋白）通路。此外，热休克蛋白（如HSP70）也受到显著影响。而且，纳米化疗通过降低例如VEGF-R1和MMP9的水平来损害血管生成信号的诱导，尽管Hif-1α水平升高表明肿瘤缺氧增加。相比之下，肿瘤细胞在单独热处理后能够恢复。总之，基于MTX/MNPs的纳米化疗由于对细胞通路的改变，特别是与细胞存活和肿瘤血管相关通路的改变，优于热处理。这使得肿瘤能够被非常有效地无复发地破坏。
