Development of Novel Acoustic Clusters for Improving Combinatorial Neuroblastoma Therapy

开发新型声学簇以改善神经母细胞瘤组合治疗

• 批准号: 9762494
• 负责人: Sonia Lorena Hernandez
• 金额: $ 38.39万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-12 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762494
• 关键词: 3D ultrasound; Abdomen; Achievement; Acoustics; Acute; Address; Adrenal Glands; Age; Antibodies; Architecture; Area; Birth; Blood Vessels; Caliber; Cancer Model; Chemicals; Child; Child Care; Childhood; Clinical; Contrast Media; Data; Development; Disease-Free Survival; Doxorubicin; Drug Delivery Systems; Drug Targeting; Drug usage; Encapsulated; Excision; Feedback; Fluorocarbons; Focused Ultrasound; Gases; Goals; Incidence; Kidney; Kinetics; Liposomal Doxorubicin; Liposomes; Long-Term Effects; Malignant Childhood Neoplasm; Malignant Neoplasms; Measures; Mediating; Methods; Microbubbles; Modeling; Monitor; Mus; Neuroblastoma; Operative Surgical Procedures; Organ Specificity; Patients; Pediatric Neoplasm; Penetration; Perfusion; Pericytes; Pharmaceutical Preparations; Pharmacotherapy; Property; Relapse; Research; Risk; Site; Solid Neoplasm; Stimulus; Techniques; Technology; Testing; Therapeutic; Time; Toxicity due to chemotherapy; Treatment Efficacy; Tumor Tissue; Ultrasonography; Vascular Permeabilities; Vascular remodeling; base; bevacizumab; cancer diagnosis; chemotherapy; clinically relevant; combinatorial; contrast enhanced; crosslink; demographics; design; dosage; expectation; experience; high risk; humanized monoclonal antibodies; image guided; image-guided drug delivery; improved; in vivo; in vivo monitoring; innovation; insight; mortality; nanoDroplet; novel; novel strategies; novel therapeutics; particle; perfusion imaging; side effect; sonoporation; sound; standard of care; treatment response; tumor; tumor growth; uptake; vessel regression

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.

开发用于改进组合神经母细胞瘤治疗的新型声学簇 摘要：该项目的目的是开发出色的图像引导的交付方法 神经母细胞瘤的化学治疗剂是侵略性实体瘤，造成15％的童年 癌症相关的死亡率。神经母细胞瘤最常见于肾上腺和肾脏，但也发生 腹部的其他区域。与许多肿瘤不同，神经母细胞瘤灌注不佳，需要高剂量 化学疗法，可能对儿童产生有害的短期和长期副作用。目前，没有临床 存在优化体内神经母细胞瘤药物摄取的方法。改善药物输送到肿瘤的方法 需要改善治疗。 在这项研究中，我们提出了一种创新的图像引导的组合药物治疗方法来重塑 使用抗VEGF抗体贝伐单抗（BV），肿瘤脉管系统和治疗神经母细胞瘤，结合 声学递送的脂质体阿霉素（L-Dox）。目前均未指示BV疗法和L-DOX 神经母细胞瘤治疗，但与声音敏感的超声对比剂（UCA）一起，它们具有 显着提高神经母细胞瘤治疗效率的潜力。 BV疗法旨在诱导 血管回归，但是我们和其他人已经证明重复的BV疗法会导致血管 通过周围容器的“库存”在NGP小鼠肿瘤模型中进行重塑，并有可能使它们 通过减少成熟的周细胞覆盖范围，从而损害了血管完整性，更适合药物吸收。 结合BV疗法，我们将测试一个新型平台，以增强使用肿瘤中的药物吸收 超声敏感颗粒，称为“声学簇”（ACS），以最大程度地提高阿霉素的有效载荷 到肿瘤组织。 AC是化学交联的气体填充球（“微泡”，每个直径约为1μm） 在超声场中振动。 AC使用携带脂质体组装，并专门设计 在超声刺激期间，可溶性脂质体封装的药物按需点播。 ACS也可以 透化血管促进释放药物的吸收。我们将测试几种新型图像引导的药物 使用微泡（和纳米光）的ACS进行交付策略，以封装了阿霉素 （有或没有透化血管），以最大程度地吸收肿瘤的药物摄取。策略 简单地释放药物和透化脉管系统是一种新颖的方法，可以使更多 有效的药物靶向并消除了对脂质体内源性肿瘤血管通透性的依赖 封装携带分子的药物，例如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，可提高整体治疗效率。