Translational use of focused ultrasound to increase blood-tumor barrier permeability as a mechanism to increase drug accumulation into brain metastases of breast cancer

项目概述：一旦癌症扩散，大约20%的时间将转移到 个脑袋最常见的脑转移瘤起源于肺、乳腺和/或皮肤。大脑 转移常常直到神经系统症状明显时才被诊断出来， 这通常意味着严重的疾病负担。传统治疗包括手术切除 和放射治疗的疗效很低，这可以通过低的两年生存率来证明。 百分之八点一与血脑屏障相比，血肿瘤屏障（BTB）虽然被破坏， 仍然是限制90%病变中有效药物蓄积的物理化学屏障。我们 长期目标是暂时破坏BTB并增强药物在BTB内的积累。 转移性脑损伤我们假设BTB的破坏将允许药物 在病变内积累细胞毒性浓度，增加化疗疗效 并延长总体生存期。经颅低强度聚焦超声（LiFUS）已被 以前用于神经系统疾病，以非侵入性地增加药物在 利用内皮细胞之间增加的细胞旁转运来控制大脑。本研究 建议研究LiFUS暴露对标准化疗药物BTB渗透性的影响 以增加小鼠的肿瘤细胞毒性和存活率。要做到这一点，我们首先需要控制 LiFUS介导的BTB破坏。第一个具体目标将阐明关键LiFUS参数 包括空化剂量、功率和持续时间对BTB渗透性以及脑/病变的影响 化疗药物的积累。还将测量存活率和肿瘤进展 使用这种模式，每周完成一次治疗。第二个具体目标将 阐明由超声波引起的潜在长期血管变化。具体地说， 我们将在五个时间点（24小时-7天）评估与BTB不可或缺的五种蛋白质， 未处理和处理动物中的两个剂量空化剂量。两种外排转运蛋白（P-gp、BCRP） 将评价表达和外排底物的能力。三种紧密连接蛋白 将被评估用于表达和定位。这两个阶段合在一起， 为治疗转移性CNS病变提供了一种新的治疗策略， LiFUS对潜在血管机制的影响。

Project Summary: Once a cancer has disseminated approximately 20% of the time it will go to brain. The most common brain metastases originate from lung, breast and or skin. Brain metastases often are often not diagnosed until neurological symptoms are pronounced, which usually indicates a significant disease burden. Traditional therapy including surgical resection and radiation therapy have a low degree of efficacy as evidenced by a low two-year survival of 8.1%. The blood-tumor barrier (BTB) while disrupted compared to the blood-brain barrier, remains a physicochemical barrier limiting effective drug accumulation in 90% of lesions. Our long-term goal is to temporarily disrupt the BTB and enhance drug accumulation within metastatic brain lesions. We hypothesize that disruption of the BTB will allow drugs to accumulate at cytotoxic concentrations within the lesions, increasing chemotherapeutic efficacy and prolonging overall survival. Transcranial low intensity focused ultrasound (LiFUS) has been previously used in neurological disorders to non-invasively increase drug accumulation within the brain using increased paracellular transport between endothelial cells. In this study, we propose the investigation of LiFUS exposure on BTB permeability of standard chemotherapies in order to increase tumor cytotoxicity and survival in mice. To do this, we first need to control LiFUS mediated BTB disruption. The first specific aim will elucidate key LiFUS parameters including cavitation dose, power and duration on BTB permeability as well as brain/lesion accumulation of chemotherapeutics. Survival and tumor progression will also be measured using this model, with weekly treatments being completed. The second specific aim will elucidate potential long-term vascular changes induced by the ultrasound waves. Specifically, we will evaluate five proteins that are integral to the BTB, over five time points (24h – 7d), with two doses cavitation doses in naive and treated animals. Two efflux transporters (P-gp, BCRP) will be evaluated for expression and the ability to efflux substrates. Three tight junction proteins will be evaluated for expression and localization. Together, these two phases will potentially provide a novel therapeutic strategy for treating metastatic CNS lesions and understanding the effect of LiFUS on the underlying vascular mechanisms.