Combined Cancer Therapy with RF Ablation and Drug-Loaded Nanopreparations

射频消融与载药纳米修复联合治疗肿瘤 我们的目标是通过合理地结合影像引导和微创影像引导来提高肿瘤的破坏力 辅助纳米疗法射频(RF)热消融。我们建议匹配加载的 我们的纳米修复材料中的试剂，以利用热消融产生的关键机制，包括细胞 应激和细胞凋亡，以及更多外周热休克蛋白(HSP)的产生，以及使用纳米地毯 增强了射频诱导的热疗，以帮助克服多药耐药性。 因此，目前的提案最初将涵盖含有强大的促凋亡剂的纳米修复材料 紫杉醇(Aim 1)等药物，GLA和BSO(Aim 2)等细胞应激诱导剂，以及藜芦素a 已知的热休克蛋白下调调节剂(目标3)。总的来说，我们将坚持已被证明是成功的战略。 对于我们将射频消融结合多西他滨的范例从IDEA通过动物研究翻译到 临床实践。对于每一种建议的纳米制剂，这种循序渐进的方法将包括在体内：1) 表征和优化与我们的系统最相关的参数(即佐剂剂量， 相关动物模型中的热剂量、治疗间隔时间和最大效果的时间 (R3230大鼠乳腺腺癌及M109肺多药耐药表达和缺失突变体 2)肿瘤破坏、药物摄取和热剂量学终点与拟议相关机制的相关性；以及3)不同拟议纳米辅助疗法单独和联合应用之间两个主要终点凝血直径和动物存活率的比较(目标5)。此外，我们还建议加载临床相关的成像标记，以确定相关纳米修复的MR成像的空间分布与由此导致的肿瘤破坏之间的相关性(目标4)。 总体而言，这一综合方法将使我们能够确定合适的纳米制剂与射频消融预期的未来临床试验相结合，特别是对肺、肝、乳腺和MDR肿瘤的临床试验。

Combined Cancer Therapy with RF Ablation and Drug-Loaded Nanopreparations Our goal is to improve tumor destruction by rationally combining image-guided, minimally invasive imageguided radiofrequency (RF) thermal ablation with adjunctive nanotherapies. We propose to match the loaded agents within our nanopreparations to exploit key mechanisms generated by thermal ablation including cell stress and apoptosis, and more peripherally heat shock protein (HSP) production, as well as use nanodrug enhanced RF-induced hyperthermia to help overcome multidrug resistance. Accordingly, the current proposal will initially cover nanopreparations containing powerful proapoptotic agents such as paclitaxel (Aim 1), cell stress inducers such as GLA and BSO (Aim 2), and quercitin a known down-regulator of HSP (Aim 3). In general, we will adhere to a strategy that has proven successful for our translation of the paradigm of RF ablation combined with Doxil from idea through animal studies to clinical practice. For each proposed nanoagent, this step-wise approach will include in vivo: 1) characterization and optimization of the parameters most relevant to our system (i.e. adjuvant dosing, thermal dosing, interval timing of therapies, and the timing of maximal effect) in relevant animal models (R3230 rat mammary adenocarcinoma, and the MDR expressed and absent variants of M109 lung carcinoma, and Daoy medulloblastoma in mice); 2) correlation of endpoints of tumor destruction, drug uptake, and thermal dosimetry with the proposed relevant mechanisms; and 3) comparison of the two primary endpoints coagulation diameter and animal survival among the different proposed adjuvant nanotherapies alone and in combination (Aim 5). We additionally propose loading of clinically relevant imaging markers that will enable determination of correlation between spatial distribution at MR imaging of the relevant nanopreparations and resultant tumor destruction (Aim 4). Overall, this comprehensive approach will enable us to identify appropriate nanoagents for combination with RF ablation anticipated future clinical trials particularly for lung, liver, breast, and MDR tumors.