Combined Cancer Therapy with RF Ablation and Drug-Loaded Nanopreparations

射频消融和载药纳米制剂的联合癌症治疗 我们的目标是通过合理结合影像引导、微创影像引导 射频（RF）热消融与连续纳米疗法。我们建议将装载的 我们的纳米制剂中的试剂，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）产生，以及使用纳米药物 增强射频诱导的热疗，以帮助克服多药耐药性。 因此，当前的提案最初将涵盖含有强效促细胞凋亡的纳米修复 药物如紫杉醇（Aim 1），细胞应激诱导剂如GLA和BSO（Aim 2），和槲皮素a 已知HSP的下调因子（Aim 3）。总的来说，我们将坚持一项已被证明是成功的战略 我们将射频消融与Doxil结合的范例从想法通过动物研究转化为 临床实践对于每种提出的纳米剂，这种逐步的方法将包括体内： 表征和优化与我们的系统最相关的参数（即佐剂剂量， 热剂量、治疗的间隔时间和最大效应的时间 （R3230大鼠乳腺癌，以及M109肺转移瘤的MDR表达和缺失变体） 癌和小鼠Daoy髓母细胞瘤）; 2）肿瘤破坏、药物摄取和热剂量测定的终点与提出的相关机制的相关性;和3）单独和组合的不同提出的辅助纳米疗法之间的两个主要终点凝血直径和动物存活率的比较（目的5）。我们还提出了临床相关成像标记物的加载，这将使得能够确定相关纳米修复的MR成像的空间分布与所产生的肿瘤破坏之间的相关性（目标4）。 总的来说，这种全面的方法将使我们能够确定适当的纳米药物与射频消融结合预期未来的临床试验，特别是肺，肝，乳腺和MDR肿瘤。

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.