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.

抽象的 聚焦超声（FUS）是一种未承诺的非侵入性治疗方式，可以永久性地 使用热坏死或机械效应破坏体内深处的组织，目前已批准 用少量的热消融处理必需的和帕金森树。而肿瘤的热消融 FUS已尝试，包括长时间治疗时间和小型治疗 信封限制了这些投资。将FUS与声学活性材料相结合此类微气泡 （MB）超声对比剂，放大局部的FUS能量。这种组合允许非热 通过MBS的惯性空化来产生缺血性病变，消融组织（NTA）。相对大 MB大小（1-3 µm）可以限制进入肿瘤内部的机会。但是，较小的声学材料，例如 随着相移微泡（PSMB，〜200-300 nm），可以更容易地穿透肿瘤并增加NTA 效率，有可能克服治疗时间和治疗包膜的限制。微血管 通过505（b）（2）途径，治疗药（MVT）开发了一种安全，更稳定的基于脂质的MB（MVT- 100）与definity®相比，诱导过敏反应的可能性较小。 MVT随后成为PSMB 来自MVT-100（专利，美国9,427,410b2），并与具有高亲和力的肽配体共轭MB （CD90-MB）。 CD90是胶质母细胞瘤的干细胞标记，MVT已确定CD90结合肽 识别蛋白质的细胞外域。 MVT和合作者在 犹他大学已经表明，在合成大鼠胶质瘤模型上进行的FUS-NTA大大允许 与MB相比，非靶向PSMB的肿瘤渗透更好。在这个阶段I SBIR中，我们将表征 靶向CD90-PSMB并通过进行脑肿瘤的NTA来评估其在体内的选择性和有效性 在生物学相关的动物模型中。我们假设CD90-PSMB将改善导致肿瘤的渗透率 与未靶向的PSMB相比，在改善的肿瘤消融中。我们的主要目标是评估 声学激活的CD90-PSMB优先在肿瘤组织中结合，并与FUS结合 在围绕周围的组织中保留肿瘤的同时，安全有效地烧掉了肿瘤。此应用程序的总体目标 建立在MVT与犹他大学之间的现有合作的基础上，以发展的最终目标 这项技术可为脑肿瘤提供安全，精确，非侵入性和非离子化处理 每年成千上万的患者屈服于脑肿瘤。这个项目被毒死以取得成功 MVT-100平台，并导致用于治疗脑肿瘤的治疗剂的快速发展 人类与Insightec相结合的神经系统结合。