Development of Novel Acoustic Clusters for Improving Combinatorial Neuroblastoma Therapy

用于改进神经母细胞瘤联合治疗的新型声学簇的开发 摘要：该项目的目标是开发卓越的图像引导的交付方法 神经母细胞瘤的化疗药物，这是一种侵袭性的实体肿瘤，占儿童的15% 与癌症相关的死亡率。神经母细胞瘤最常发生在肾上腺和肾脏，但也 腹部的其他部位。与许多肿瘤不同，神经母细胞瘤的血流很差，需要高剂量的治疗。 化疗可能会对儿童产生有害的短期和长期副作用。目前，还没有临床上 存在优化神经母细胞瘤体内药物摄取的方法。改善对肿瘤药物输送的方法 是改善治疗所必需的。 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来重塑 肿瘤血管生成和治疗神经母细胞瘤，使用抗血管内皮生长因子抗体贝伐单抗联合 阿霉素声学脂质体(L-DOX)。BV疗法和L-DOX目前都不适用于 神经母细胞瘤的治疗，但与声敏超声造影剂(UCA)一起使用时， 极大地提高神经母细胞瘤治疗效果的潜力。BV疗法的设计是为了诱导 血管退化，然而，我们和其他人已经证明，重复的BV治疗会导致血管 NGP小鼠肿瘤模型“共选”周围血管并潜在地使其重塑 通过减少成熟周细胞的覆盖率从而损害血管的完整性，更容易被药物摄取。 结合BV疗法，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(ACS)，以最大限度地增加阿霉素的有效载荷 肿瘤组织。AC是化学交联的充气球体(“微泡”，每个直径约1μm) 在超声场中振动。AC是用携带药物的脂质体组装的，是专门设计的 在超声刺激过程中按需溶解脂质体包裹的药物。ACS还可以 使血管通透，便于吸收释放的药物。我们将测试几种新型的图像引导药物 基于微泡(和纳米微滴)的ACS“包埋”阿霉素胶囊的给药策略 (具有和不具有通透性血管)，以最大限度地提高肿瘤的药物摄取。中国企业的战略 同时释放药物和渗透血管系统是一种新的方法，将使更多 高效靶向药物并消除脂质体对内源性肿瘤血管通透性的依赖 微囊化载药分子，如L多柔比星。这项研究中开发的技术将是 适用于多种药物和癌症，有助于提高整体治疗效果。

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.