Real-time monitoring of tumor vascular disruption induced by radiofrequency assisted gadofullerene
The anti-vascular therapy has been extensively studied for high performance tumor therapy by suppressing the tumor angiogenesis or cutting off the existing tumor vasculature. We have previously reported a novel anti-tumor treatment technique using radiofrequency (RF)-assisted gadofullerene nanocrystals (GFNCs) to selectively disrupt the tumor vasculature. In this work, we further revealed the changes on morphology and functionality of the tumor vasculature during the high-performance RF-assisted GFNCs treatment in vivo. Here, a clearly evident mechanism of this technique in tumor vascular disruption was elucidated. Based on the H22 tumor bearing mice with dorsal skin flap chamber (DSFC) model and the dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) technique, it was revealed that the GFNCs would selectively inset in the gaps of tumor vasculature due to the innately incomplete structures and unique microenvironment of tumor vasculature, and they damaged the surrounding endothelia cells excited by the RF to induce a phase transition accompanying with size expansion. Soon afterwards, the blood flow of the tumor blood vessels was permanently shut off, causing the entire tumor vascular network to collapse within 24 h after the treatment. The RF-assistant GFNCs technique was proved to aim at the tumor vasculature precisely, and was harmless to the normal vasculature. The current studies provide a rational explanation on the high efficiency anticancer activity of the RF-assisted GFNCs treatment, suggesting a novel technique with potent clinical application.
Keywordsgadofullerene radiofrequency dorsal skin flap chamber dynamic contrast enhanced magnetic resonance imaging tumor vasculature
射频辅助金属富勒烯纳米晶体阻断肿瘤血管作为一项新兴的抗肿瘤技术, 因其高效安全的作用效果, 在癌症治疗的研究发展过程中表现出巨大的应用前景. 本文针对该技术, 提出了对其阻断肿瘤血管的实时原位研究方法, 清晰明确地揭示了高效靶向阻断肿瘤血管的机制. 通过建立小鼠肿瘤背部皮翼视窗模型, 实现了在治疗过程中肿瘤血管和正常血管的形态变化及血流情况的直观监测评价. 同时, 采用临床常用的动态增强磁共振成像手段对肿瘤血管功能进行实时定量评估, 借助相关参数Ktrans, 证明了肿瘤血管在治疗后发生了持续不可逆的破坏. 具体表现为局部肿瘤血管出血、 塌陷, 导致整个肿瘤血管网的血流停止, 切断了肿瘤组织与外界的营养交换, 进而致使肿瘤坏死, 而正常血管并不会受到损伤. 此研究结果是对该技术高效靶向治疗肿瘤的深入研究, 有利于促进其在临床上的转化和应用.
This work was supported by the National Natural Science Foundation of China (51472248 and 51502301), National Major Scientific Instruments and Equipments Development Project (ZDYZ2015-2), and the Key Research Program of the Chinese Academy of Sciences (QYZDJ-SSW-SLH025). We thank Zhentao Zuo for the design of the radiofrequency generator and the help by the State Key Lab of Brain & Cognitive Sciencesin Institute of Biophysics, Chinese Academy of Sciences.
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