Selectivity and Efficacy of CD90-targeted Phase Shift Microbubbles for HIFU-mediated Non-Thermal Ablation of Brain Tumors.

CD90 靶向相移微泡对 HIFU 介导的脑肿瘤非热消融的选择性和功效。

• 批准号: 10547718
• 负责人: Emmanuelle Joelle Meuillet
• 金额: $ 39.76万
• 依托单位: MICROVASCULAR THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10547718
• 关键词: Acoustics; Adult; Affinity; Animal Model; Animals; Binding; Brain; Brain Neoplasms; Cause of Death; Cells; Clinic; Clinical; Clinical Trials; Collaborations; Definity; Development; Diagnosis; Disease; Effectiveness; Exposure to; Extracellular Domain; Extracellular Protein; FDA approved; Family suidae; Fluorescent Dyes; Focused Ultrasound; Focused Ultrasound Therapy; Frequencies; Gases; Glioblastoma; Glioma; Goals; Histology; Human; Image; In Vitro; Investigation; Ionizing radiation; Label; Lead; Legal patent; Lesion; Ligands; Lipids; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Mechanics; Mediating; Microbubbles; Microbubbles Ultrasound Contrast Medium; Modality; Modeling; Necrosis; Operative Surgical Procedures; Outcome; Parkinsonian Disorders; Particle Size; Pathway interactions; Patients; Penetration; Peptides; Phase; Physiologic pulse; Positioning Attribute; Property; Rattus; Reaction; Research Design; Small Business Innovation Research Grant; Spinal Cord; Survival Rate; System; Technology; Therapeutic; Thermal Ablation Therapy; Time; Tissues; Translating; Tremor; Tumor Tissue; Ultrasonic Therapy; Universities; Utah; base; chemotherapy; clinically relevant; clinically translatable; cranium; experience; experimental study; improved; improved outcome; in vivo; ischemic lesion; minimally invasive; neoplastic cell; nonhuman primate; novel; porcine model; pressure; rapid testing; safety study; stem cell biomarkers; theranostics; tumor; tumor ablation; uptake

ABSTRACT Focused Ultrasound (FUS) is a promising non or minimally invasive treatment modality that can permanently destroy tissue deep within the body using thermal necrosis or mechanical effects and is currently FDA approved to treat essential and Parkinsonian tremor with small thermal ablations. While thermal ablation of tumors with FUS has been attempted, several critical challenges, including long treatment times and small treatment envelopes, have limited these investigations. Combining FUS with acoustically active materials such microbubble (MB) ultrasound contrast agents, amplifies the FUS energy locally. This combination allows for non-thermal ablation (NTA) of tissues by creating ischemic lesions through inertial cavitation of the MBs. The relatively large MB size (1-3 µm) can limit access to the interior of tumors. However, smaller acoustically active materials, such as phase shift microbubbles (PSMB, ~200-300 nm), can more easily penetrate tumors and increase NTA efficiency, potentially overcoming both treatment time and treatment envelope limitations. Microvascular Therapeutics (MVT) has, via the 505(b)(2) pathway, developed a safe and more stable lipid-based MB (MVT- 100) less likely to induce anaphylactoid reactions as compared to Definity®. MVT has subsequently made PSMB from MVT-100 (Patent, US 9,427,410B2) and conjugated MB with a peptide ligand with high affinity for CD90 (CD90-MB). CD90 is a stem cell marker of glioblastoma, and MVT has identified a CD90-binding peptide that recognizes the protein's extracellular domain. Preliminary studies performed by MVT and collaborators at the University of Utah have shown that FUS-NTA performed on a syngeneic rat glioma model allowed for substantially better tumor penetration of non-targeted PSMB compared to MB. In this Phase I SBIR, we will characterize targeted CD90-PSMB and evaluate their selectivity and effectiveness in vivo by performing NTA of brain tumors in a biologically relevant animal model. We hypothesize that CD90-PSMB will improve tumor penetration resulting in improved tumor ablation compared to untargeted PSMB. Our main objective is to evaluate the ability of acoustically activated CD90-PSMB to preferentially conjugate in tumor tissue, and when combined with FUS, safely and efficiently ablate the tumor while sparing surrounding tissues. The overall objectives of this application are to build on the existing collaboration between MVT and University of Utah with the ultimate goal to develop this technology to provide a safe, precise, non-invasive and non-ionizing treatment of brain tumors for the tens of thousands of patients succumbing to brain tumors every year. This project is poised to succeed based on the MVT-100 platform, and to lead to the rapid development of a theranostic agent for treatment of brain tumors in humans in combination with the ExAblate Neuro system by InSightec.

摘要 聚焦超声（FUS）是一种有前途的非侵入性或微创治疗方式， 利用热坏死或机械效应破坏体内深层组织，目前已获得FDA批准 用小型热消融治疗原发性震颤和帕金森震颤。虽然肿瘤的热消融 FUS已经尝试，几个关键的挑战，包括治疗时间长和治疗量小 信封，限制了这些调查。将FUS与声学活性材料如微泡结合 (MB)超声造影剂局部放大FUS能量。这种组合允许非热 通过MB的惯性空化产生缺血性损伤来进行组织消融（NTA）。相对大的 MB大小（1-3 µm）可以限制进入肿瘤内部。然而，较小的声学活性材料，例如 作为相移微泡（PSMB，~200-300 nm），可以更容易地穿透肿瘤并增加NTA 效率，潜在地克服治疗时间和治疗包络限制。微血管 Therapeutics（MVT）通过505（B）（2）途径，开发了一种安全且更稳定的脂质基MB（MVT-1）。 100)与DESIGN ®相比，不太可能诱发过敏样反应。MVT随后使PSMB 来自MVT-100（专利，US 9，427，410 B2）并与对CD 90具有高亲和力的肽配体缀合的MB （CD90-MB）。CD 90是胶质母细胞瘤的干细胞标志物，MVT已经鉴定了一种CD 90结合肽， 识别蛋白质的胞外区MVT和合作者在 犹他州大学的研究表明，在同基因大鼠神经胶质瘤模型上进行的FUS-NTA允许实质性地减少神经胶质瘤的发生。 与MB相比，非靶向PSMB的肿瘤渗透性更好。在第一阶段SBIR中，我们将描述 靶向CD 90-PSMB，并通过脑肿瘤NTA评估其体内选择性和有效性 在生物学相关的动物模型中。我们假设CD 90-PSMB将改善肿瘤渗透， 与非靶向PSMB相比，改善了肿瘤消融。我们的主要目标是评估 声学激活的CD 90-PSMB优先在肿瘤组织中结合，当与FUS结合时， 安全有效地切除肿瘤，同时保留周围组织。本申请的总体目标 是建立在MVT和犹他州大学之间现有的合作，最终目标是发展 这项技术提供了一个安全，精确，非侵入性和非电离治疗脑肿瘤的数十年， 每年都有成千上万的病人死于脑瘤该项目有望取得成功， MVT-100平台，并导致用于治疗脑肿瘤的治疗诊断剂的快速开发， 人类与InSightec的Experimate Neuro系统相结合。