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: 9891989
• 负责人: Sonia Lorena Hernandez
• 金额: $ 35.71万
• 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/9891989
• 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; 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.

新型声学簇的发展改善神经母细胞瘤组合治疗