Development of Novel Acoustic Clusters for Improving Combinatorial Neuroblastoma Therapy

新型声学簇的开发用于改善神经母细胞瘤的组合治疗 总结：本项目的目标是开发上级图像引导的方法， 神经母细胞瘤是一种侵袭性实体瘤，占儿童的15%。 癌症相关死亡率。神经母细胞瘤最常见于肾上腺和肾脏，但也 腹部的其他部位。与许多肿瘤不同，神经母细胞瘤灌注差，需要高剂量的 化疗，这可能会对儿童产生有害的短期和长期副作用。目前，没有临床 存在优化神经母细胞瘤体内药物摄取的方法。改善药物递送至肿瘤的方法 来改善治疗效果 在这项研究中，我们提出了一种创新的图像引导组合药物治疗方法，以重塑 肿瘤脉管系统和治疗神经母细胞瘤，使用抗VEGF抗体贝伐单抗（BV）与 声学递送的脂质体阿霉素（L-DOX）。BV治疗和L-DOX目前均不适用于 神经母细胞瘤治疗，但与声敏超声造影剂（UCA）一起，他们有 有可能显著提高神经母细胞瘤的治疗效果。BV治疗旨在诱导 然而，我们和其他人已经证明，重复BV治疗会导致血管退化， NGP小鼠肿瘤模型通过周围血管的“共同选择”进行重构，并可能使它们 通过减少成熟的周细胞覆盖从而损害血管完整性而更易于药物摄取。 结合BV治疗，我们将测试一种新的平台，用于增强肿瘤中的药物摄取， 超声敏感颗粒，称为“声学簇”（AC），以最大化阿霉素的有效载荷， 肿瘤组织。AC是化学交联的充气球（“微泡”，每个直径约1 μm）， 在超声波场中振动。AC的组装使用载药脂质体和专门设计的 以在超声刺激期间按需溶解脂质体包封的药物。AC还可以 使血管透化，促进释放的药物的摄取。我们将测试几种新的图像引导药物 使用基于微泡（和纳米液滴）的AC“撑开”包封的阿霉素的递送策略 (with并且不渗透血管）以使肿瘤中的药物摄取最大化。战略 同时释放药物和透化脉管系统是一种新的方法， 有效的药物靶向性和消除对内源性肿瘤血管通透性的依赖 包封的药物携带分子，如L-DOX。这项研究中开发的技术将是 适用于广泛的药物和癌症，以提高整体治疗效果。 第7页 项目概要/摘要

Development of Novel Acoustic Clusters for Improving Combinatorial Neuroblastoma Therapy Summary: The goal of this project is to develop superior image-guided methods of delivering chemotherapeutics to neuroblastoma, which are aggressive solid tumors responsible for 15% of childhood cancer related mortalities. Neuroblastoma most commonly arises in the adrenal gland and kidneys, but also other areas of the abdomen. Unlike many tumors, neuroblastomas are poorly perfused, requiring high-dosage chemotherapy, which can have deleterious short and long-term side effects in children. Currently, no clinical methods exist to optimize drug uptake in neuroblastoma in vivo. Methods of improving drug delivery to tumors are needed to improve therapy. In this study, we propose an innovative image-guided combinatorial drug therapy approach to remodel the tumor vasculature and treat neuroblastoma, using anti-VEGF antibody, bevacizumab (BV), in combination with acoustically delivered liposomal doxorubicin (L-DOX). Neither BV therapy nor L-DOX are currently indicated for neuroblastoma treatment, but together with sound-sensitive ultrasound contrast agents (UCA's) they have the potential to dramatically improve neuroblastoma treatment efficacy. BV therapy was designed to induce vascular regression, however we and others have demonstrated that repetitive BV therapy causes vascular remodeling in NGP mouse tumor models by “cooption” of surrounding vessels and potentially making them more amenable to drug uptake by reducing mature pericyte coverage thereby compromising vascular integrity. In combination with BV therapy, we will test a novel platform for enhancing drug uptake in tumors utilizing ultrasound sensitive particles, called “Acoustic Clusters” (ACs), to maximize payload of doxorubicin specifically to tumor tissue. ACs are chemically crosslinked gas-filled spheres (“microbubbles”, ~1 μm diameter each) that vibrate in an ultrasound field. AC's are assembled using drug carrying liposomes and are specifically designed to solubilize liposome-encapsulated drugs on-demand during ultrasound stimulation. ACs can also permeabilize blood vessels facilitating uptake of released drugs. We will test several novel image-guided drug delivery strategies using microbubble (and nanodroplet) based ACs to “uncage” encapsulated doxorubicin (with and without permeabilizing blood vessels) to maximize drug uptake in tumors. The strategy of simultaneously releasing drugs and permeabilizing vasculature is a novel approach that will enable more efficient drug targeting and eliminate the reliance on endogenous tumor vascular permeability for liposome encapsulated drug carrying molecules, such as L-DOX. The techniques developed in this study would be applicable to a wide range of drugs and cancers toward improving overall treatment efficacies. Page 7 Project Summary/Abstract