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: 10341157
• 负责人: Sonia Lorena Hernandez
• 金额: $ 35.73万
• 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/10341157
• 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; aggressive therapy; base; bevacizumab; cancer diagnosis; chemotherapy; clinically relevant; combinatorial; contrast enhanced; crosslink; delivery vehicle; 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; ultrasound; 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.

开发新型声学簇以改善神经母细胞瘤组合治疗 摘要：该项目的目标是开发卓越的图像引导方法来交付 神经母细胞瘤的化疗，神经母细胞瘤是一种侵袭性实体瘤，约占儿童期的 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 腹部的其他区域。与许多肿瘤不同，神经母细胞瘤灌注不良，需要高剂量 化疗可能会对儿童产生有害的短期和长期副作用。目前临床上尚无 存在优化神经母细胞瘤体内药物摄取的方法。改善肿瘤药物递送的方法 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组合药物治疗方法来重塑 使用抗 VEGF 抗体贝伐珠单抗 (BV) 联合治疗肿瘤脉管系统和治疗神经母细胞瘤 声学递送脂质体阿霉素（L-DOX）。 BV 疗法和 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）一起使用 显着提高神经母细胞瘤治疗效果的潜力。 BV 疗法旨在诱导 血管退化，然而我们和其他人已经证明重复的 BV 治疗会导致血管退化 通过“选择”周围血管并可能使它们在 NGP 小鼠肿瘤模型中进行重塑 通过减少成熟周细胞的覆盖从而损害血管完整性，更容易吸收药物。 与 BV 疗法相结合，我们将测试一种新的平台，利用该平台来增强肿瘤的药物摄取 超声敏感颗粒，称为“声簇”(AC)，专门用于最大限度地提高阿霉素的有效负载 至肿瘤组织。 AC 是化学交联的充气球体（“微泡”，每个直径约 1 μm）， 在超声波场中振动。 AC 使用载药脂质体组装，并经过专门设计 在超声刺激期间按需溶解脂质体封装的药物。 AC还可以 使血管通透，促进释放药物的吸收。我们将测试几种新颖的图像引导药物 使用基于微泡（和纳米液滴）的 AC 来“释放”封装的阿霉素的递送策略 （有或没有通透血管）以最大限度地提高肿瘤中的药物摄取。的策略 同时释放药物和透化脉管系统是一种新颖的方法，它将使更多 高效药物靶向，消除脂质体对内源性肿瘤血管通透性的依赖 封装的药物携带分子，例如 L-DOX。本研究开发的技术是 适用于多种药物和癌症，以提高整体治疗效果。