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

项目总结/摘要： 纳米颗粒（NPs）在提供比传统的纳米颗粒更有效和更安全的癌症治疗方面具有巨大的前景。 常用的小分子药物。这是基于研究报告，这些代理人可以 潜在地在实体瘤中实现更大的暴露。然而，这些承诺在很大程度上受到低利率的阻碍。 和低效的肿瘤摄取，其中血浆中只有5-10%的NP实际上从血浆分布到 实体瘤某些肿瘤，如胰腺癌（PaCa），对肿瘤细胞具有更大的固有屏障。 NP的肿瘤递送。因此，迫切需要发现可以显著且安全地增强免疫应答的方法。 NP向肿瘤的总体递送。我们的总体假设是，诱导微束放射治疗（MRT）， 一种新的放射治疗就是这样一种方法。而传统的宽波束辐射（BRT） 适度增强药物递送至肿瘤（0.2- 2倍）。MRT是一种实验性放射治疗， 独特的空间和剂量特性，与传统的BRT截然不同。固体 临床前研究已经证明MRT能够具有超高的治疗比率。我们最近 发现与BRT相反，MRT改变了肿瘤血管系统并增加了肿瘤灌注。我们 假设我们可以利用MRT引起的肿瘤灌注的变化， 与单独的NP或BRT后的NP相比，安全地增强NP向肿瘤的递送。这一假设得到了我们的支持。 乳腺癌基因工程小鼠模型（GEMM）的广泛结果， PEG化脂质体阿霉素（Doxil®; PLD）的给药通过以下方式增强PLD向肿瘤的递送： 前所未有的6- 10倍的幅度，并且通过每周治疗安全地维持增强。 此外，MRT使PLD向乳腺癌GEMM的肿瘤递送增加了4倍， 与BRT相比，这与总体和表达PD-L1的巨噬细胞水平较高相关。我们 在PaCa GEMM中进行的第二项初步研究表明，MRT能够增加PEG-脂质体的肿瘤暴露 伊立替康（Onivyde®，FDA批准用于PaCa治疗）及其活性代谢物SN 38与 只有奥尼维德一个人。这笔赠款将使我们能够将我们突破性的MRT结果转化为PaCa， 到NP的分娩是广泛的，手术切除是唯一的治愈选择，但只有15%的患者 可切除的疾病和MRT + NP方案将是PaCa的术前新辅助治疗的理想方案。 这项工作将由一个多学科研究团队使用新的模型，技术和FDA 批准的药物，可以很容易地转化为临床试验，在3个目标超过5年：AIM 1。评估诱导 MRT增强的NP抗癌药物在PaCa的GEMM中的递送; AIM 2。调查以下因素的机械效应 在PaCa的GEMM中诱导MRT增强的NPs的肿瘤递送; AIM 3.评价诱导MRT增强 NP抗癌药物在PaCa的GEMM中的功效。这项建议旨在克服固有的主要障碍， 在NP向肿瘤的递送中，特别是在PaCa中，其对药物肿瘤递送具有显著的屏障。

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.