Simultaneous Thermal and Osmotic Stresses in Tumor Ablation: Imaging and Biology

摘要 肝细胞癌是一种致命的疾病，也是美国增长最快的癌症类型。多数 病人不适合做手术，药物治疗只是在最近才取得有限的存活率。 服用索拉非尼2-3个月的疗效。这种药价格昂贵，而且有许多副作用，限制了它的 接受和影响。局部治疗原位肿瘤同样有局限性，尽管 生存福利通常更长。现有治疗方法的主要临床缺点，如消融和 栓塞术治疗不彻底，局部复发。在目前的建议中，我们寻求利用 酸和碱之间的放热化学反应，在高温下放出热量和盐 杀灭肿瘤组织的浓度。我们假设同时的热和渗透的结合 压力在杀死肿瘤细胞方面非常有效，而且这个过程可以成像和控制。第一个目标是 我们建议进行mri温度成像来绘制热剂量图，结合多梯度回波。 回想化学位移成像，以高时间分辨率绘制盐，以及钠磁共振成像，以绘制 钠在处理体积中的浓度。在第二个目标中，我们将进行体外实验 肿瘤细胞株以了解细胞如何对这种联合应激做出反应并询问可能的途径 为未来的干预做准备。在最终目的中，我们建议使用兔VX2肿瘤模型在体内测试这一概念， 它足够大，可以进行热成像和钠成像。

Abstract Hepatocellular carcinoma is a lethal disease and the fastest growing type of cancer in the United States. Most patients are not candidates for surgery and medical therapy has only recently achieved a limited survival benefit of 2-3 months with sorafenib. This drug is costly and has a number of side effects limiting its acceptance and impact. Locoregional therapies treating tumor in situ likewise have limitations, although the survival benefit is generally longer. Major clinical weaknesses of existing therapies such as ablation and embolization are incomplete treatment and local recurrence. In the current proposal, we seek to harness the exothermic chemical reaction between an acid and a base to release heat and a salt at high local concentration to kill tumor tissue. We hypothesize that the combination of simultaneous thermal and osmotic stress is highly effective in killing tumor cells and that the process can be imaged and controlled. In the first aim we propose to perform MRI temperature imaging to map the thermal dose, combined with multi-gradient echo recall chemical shift imaging to map the salt with high temporal resolution, and sodium MRI to map the concentration of the sodium in the treated volume. In the second aim we will perform in vitro experiments on tumor cell lines to understand how cells respond to this kind of combined stress and interrogate likely pathways for future intervention. In the final aim we propose to test the concept in vivo using the rabbit VX2 tumor model, which is large enough to allow for the thermal and sodium imaging.