Minibeam Radiation Therapy Enhanced Delivery of Nanoparticle Anticancer Agents to Pancreatic Cancer Tumors

项目摘要/摘要： 纳米粒子(NPs)在提供比传统药物更有效、更安全的癌症治疗方面前景广阔 常用的小分子药物。这是基于研究报告，这些代理人可以 可能在实体肿瘤中获得更大的曝光率。然而，这些承诺在很大程度上受到低点的阻碍。 以及低效的肿瘤摄取，血浆中只有5%-10%的NPs实际上是从血浆分布到 实体瘤。某些肿瘤，如胰腺癌(PACA)，甚至有更大的固有障碍 NPs的肿瘤递送。因此，迫切需要发现能够显著且安全地增强 NPs向肿瘤的整体输送。我们的总体假设是感应微束放射治疗(MRT)， 一种新颖的放射治疗，就是这样一种方法。然而，仅常规宽束辐射(BRT) 适度增强对肿瘤的药物输送(0.2至2倍)。MRT是一种实验性的放射疗法， 独特的空间和剂量学特征，与传统BRT截然不同。实心 临床前研究表明，MRT具有超高的治愈率。我们最近 研究发现，与BRT相比，MRT可以改变肿瘤的血管系统，增加肿瘤的血流灌注。我们 假设我们可以利用MRT引起的肿瘤血流灌注的变化来显著和 与单独或BRT后的NPs相比，安全地增强NP对肿瘤的递送。这一假设得到了我们的 乳腺癌基因工程小鼠模型(GEMM)在诱导MRT之前的广泛结果 给药聚乙二醇化脂质体阿霉素(Doxil®；PLD)通过以下途径增强PLD对肿瘤的输送 史无前例的6到10倍的增长，每周治疗安全地维持了这种增强。 此外，MRT使乳腺癌肿瘤向GEM输送PLD的增加了4倍， 这与与BRT相比，巨噬细胞总数和PD-L1表达水平更高有关。我们的 PACA GEMMS的第二项先导研究表明，MRT能够增加聚乙二醇脂质体对肿瘤的暴露 伊立替康(Onivyde®，FDA批准用于PACA治疗)及其活性代谢物SN38是&gt；的4倍 只有ONIVYDE一个人这笔赠款将使我们能够将我们开创性的捷运结果转换到Paca，在那里障碍 对于NP的分娩是广泛的，手术切除是唯一的治疗选择，但只有15%的患者 可切除病变和MRT+NP方案是PACA术前新辅助治疗的理想方案。 这项工作将由一个使用新模型、新技术和FDA的多学科研究团队进行 可在5年内在3个目标内转化为临床试验的已批准药物：目标1.评估诱导 MRT促进NP类抗癌药物在PACA的GEMM中的传递；目的2.探讨MRT的作用机制 诱导MRT增强NPs在PACA GEM中的肿瘤递送；目的3.评估诱导MRT增强 NP类抗癌药物在PACA GEMM中的疗效这项提议旨在克服固有的主要障碍 在NP对肿瘤的传递中，特别是在PACA中，它对药物肿瘤的传递有很大的障碍。

PROJECT SUMMARY / ABSTRACT: Nanoparticles (NPs) hold great promise for delivering more effective and safer cancer treatment than the small molecule drugs that are commonly used. This is based on studies reporting that these agents can potentially achieve greater exposure in solid tumors. However, these promises are largely hampered by a low and inefficient tumor uptake in which only 5-10% of NPs in the plasma are actually distributed from plasma to solid tumors. Certain tumors, such as pancreatic cancer (PaCa), have even greater inherent barriers to the tumor delivery of NPs. Thus, there is a strong need to discover methods that can significantly and safely enhance the overall delivery of NPs to tumors. Our overall hypothesis is that induction minibeam radiation therapy (MRT), a novel radiation treatment, is such a method. Whereas, conventional broad beam radiation (BRT) only moderately enhances drug delivery to tumors (0.2- to 2-fold). MRT is an experimental radiation therapy with unique spatial and dosimetric characteristics that are drastically different from conventional BRT. Solid preclinical studies have demonstrated that MRT is capable of an ultra-high therapeutic ratio. We recently discovered that MRT, in contrast to BRT, modifies tumor vasculature and increases tumor perfusion. We hypothesize that we can take advantage of the changes in tumor perfusion induced by MRT to significantly and safely enhance NP delivery to tumors compared to NPs alone or after BRT. This hypothesis is supported by our extensive results in genetically engineered mouse models (GEMMs) of breast cancer where induction MRT prior to administration of PEGylated liposomal doxorubicin (Doxil®; PLD) enhanced the delivery of PLD to tumors by an unprecedented magnitude of 6- to 10-fold and the enhancement was sustained safely with weekly treatments. In addition, MRT produced a 4-fold greater increase in the tumor delivery of PLD to GEMMs of breast cancer, which was associated with higher levels of overall and PD-L1 expressing macrophages compared to BRT. Our 2nd pilot study in PaCa GEMMs showed that MRT was able to increase the tumor exposure of PEG-liposomal irinotecan (Onivyde®, FDA approved for PaCa treatment) and its active metabolite SN38 by >4-fold compared to Onivyde alone. This grant will allow us to translate our ground breaking MRT results to PaCa where the barriers to NP delivery are extensive, surgical resection is the only curative option but only 15% of patients have resectable disease and the MRT + NP regimen would be ideal for pre-surgical neoadjuvant treatment of PaCa. This work will be performed by a multidisciplinary research team using novel models, technologies and FDA approved drugs that can be readily translated to clinical trials in 3 aims over 5 yrs: AIM 1. Evaluate induction MRT-enhanced delivery of NP anticancer drugs in GEMMs of PaCa; AIM 2. Investigate mechanistic effects of induction MRT-enhanced tumor delivery of NPs in GEMMs of PaCa; AIM 3. Evaluate induction MRT-enhanced efficacy of NP anticancer drugs in GEMMs of PaCa. This proposal aims to overcome the inherent major barriers in NP delivery to tumors, especially in PaCa, which has significant barriers to drug tumor delivery.