Microbubble Dose Optimization for Image-Guided Drug Delivery

图像引导药物输送的微泡剂量优化

• 批准号: 10438770
• 负责人: Mark Andrew Borden
• 金额: $ 34.52万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-05 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10438770
• 关键词: Acoustics; Acute; Anti-Inflammatory Agents; Area Under Curve; Astrocytes; Blood - brain barrier anatomy; Brain; Brain region; Bypass; Caliber; Cell Adhesion Molecules; Cells; Clinical Trials; Colorado; Communities; Contrast Media; Craniotomy; Definity; Development; Dose; Drug Delivery Systems; Drug Kinetics; Drug Modelings; Drug Targeting; FDA approved; Focused Ultrasound; Formulation; Frequencies; Gases; Gene Delivery; Heat-Shock Proteins 70; Human; Immune; Immune response; In Situ Nick-End Labeling; Infiltration; Inflammatory; Innate Immune Response; Interleukin-1; Interleukin-18; Intravenous; Laboratories; Malignant neoplasm of brain; Mechanics; Mediating; Methods; Microbubbles; Microbubbles Ultrasound Contrast Medium; Microglia; Molecular; Molecular Weight; National Institute of Drug Abuse; Needles; Neurologic; Neurons; Operative Surgical Procedures; Optison; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Physiologic pulse; Physiological; Procedures; Process; Published Comment; Reporting; Research; Research Personnel; Safety; Scheme; Sonication; Sterility; TNF gene; Technology; Testing; Therapeutic; Therapeutic Agents; Tight Junctions; Time; Tissues; Universities; Variant; blood-brain barrier disruption; brain parenchyma; brain tissue; clinical translation; cost; cranium; dosage; image guided; image-guided drug delivery; imaging modality; indexing; lipid nanoparticle; macrophage; nervous system disorder; neurogenesis; non-invasive imaging; pre-clinical research; preclinical study; prospective; receptor; regenerative; response; side effect; transcriptome; trend; ultrasound

The development of new pharmaceuticals for the treatment of brain cancer and neurological disease has outpaced our ability to deliver them safely, largely due to the blood-brain barrier (BBB). Bypassing the BBB to access the brain parenchyma is often highly invasive, involving surgery to remove part of the skull and needle insertion directly into the brain tissue, resulting in lasting damage and significant costs. An alternative, microbubble-assisted focused ultrasound (MB+FUS), is a promising noninvasive, image-guided method of BBB disruption (BBBD) currently undergoing three human clinical trials. MB+FUS induces transient openings in the BBB via acoustically mediated pulsation of 1-10 µm diameter intravenously delivered gas-filled microbubbles, allowing for targeted drug delivery to brain regions as small as 2-3 mm diameter. The safe dosage of these microbubbles has become central to the polarizing debate that is ongoing in the MB+FUS community, and is critical to clinical translation. With recent findings indicating acute sterile immune response (SIR) after MB+FUS BBBD, elucidating the relationship between microbubble dose, pharmacokinetics (PK), ultrasound mechanical index, and MB+FUS-associated tissue effects has become essential. Efforts to do so, however, have been confounded by the product-to-product and batch-to-batch variations in the size, concentration and composition of commercially available microbubble ultrasound contrast agent formulations. Using size-isolated microbubbles (SIMBs) of different monodisperse sizes and uniform composition, our team of researchers at the University of Colorado and NIDA recently discovered that microbubble dosing can be simplified by unifying size and concentration into a single parameter: microbubble volume dose (MVD), which trends linearly with key figures-of-merit for microbubble PK and BBBD magnitude. In this project, we will investigate this effect further in order to create a clear framework for comparing results prospectively and retrospectively between studies performed by different laboratories and different microbubble agents. In Aim 1, we will test the hypothesis that figures-of-merit for PK scale linearly with MVD for FDA-approved ultrasound contrast agents currently used in human clinical trials and most preclinical research, as well as our own SIMBs. We will extend this research to establish a therapeutic window between the minimum MVDs to produce BBBD and acute SIR. In Aim 2, we will test the hypothesis that the minimum MVD required for successful BBBD decreases with increasing mechanical index (MI), which is a unifying ultrasound parameter incorporating frequency and amplitude. The robustness of this relationship will be explored by examining effects of microbubble size (using SIMB), ultrasound frequency and molecular weight of the model drug. Finally, in Aim 3, we will establish a therapeutic window between BBBD (efficacy) and acute SIR (safety) on a diagram of MVD vs. MI, which will help researchers and clinicians in the field to choose appropriate ultrasound and microbubble dose settings for safe BBBD by MB+FUS, and to guide their procedures.

用于治疗脑癌和神经系统疾病的新药物的开发已有 超过了我们安全交付它们的能力，这主要是由于血脑屏障（BBB）。绕过BBB 进入大脑实质通常具有高度侵入性，涉及手术以去除部分头骨和针头 将直接插入脑组织，从而造成持久的损害和巨大的成本。另一种 微气泡辅助聚焦超声（MB+FUS）是BBB的有望无创的，图像引导的方法 目前正在进行三项人类临床试验的破坏（BBBD）。 MB+FUS在 BBB通过声学介导的脉动的1-10 µm直径静脉注射的气体填充微泡， 允许将靶向药物输送到直径为2-3 mm的大脑区域。这些的安全剂量 微泡已经成为MB+FUS社区正在进行的两极分化辩论的核心，并且是 对临床翻译至关重要。最近的发现表明MB+FUS后急性无菌免疫响应（SIR） BBBD，阐明微泡剂量，药代动力学（PK），超声机械之间的关系 指数和MB+FUS相关的组织效应已成为必不可少的。但是，为此努力 由尺寸，集中度和组成的产品到产品和批处理变化混淆 商业可用的微泡超声对比剂公式。 使用不同单分散大小和均匀成分的尺寸分离的微泡（SIMB），我们 科罗拉多大学和NIDA大学的研究人员团队最近发现微气泡的剂量可以是 通过将大小和集中度简化为单个参数：微泡体积剂量（MVD），该参数 趋势与微泡PK和BBBD幅度的关键形象线性趋势。在这个项目中，我们将 进一步调查此效果，以创建一个明确的框架，以前瞻性地比较结果 在不同实验室和不同微泡药进行的研究之间回顾性。在AIM 1中， 我们将测试以FDA批准的超声线性线性的PK量表的假设 当前用于人类临床试验和大多数临床前研究的对比剂以及我们自己的SIMBS。 我们将扩展这项研究，以在最低MVD之间建立一个治疗窗口以生产BBBD 和敏锐的先生。在AIM 2中，我们将测试成功BBBD所需的最低MVD的假设 随着机械指数（MI）的增加而减小，这是一个统一的超声参数编码 频率和放大器。通过检查 微泡大小（使用SIMB），模型药物的超声频率和分子量。最后，在AIM 3中 我们将在MVD图上建立BBBD（功效）和急性SIR（安全）之间的治疗窗口 VS. MI，它将帮助该领域的研究人员和临床医生选择适当的超声波和微泡 MB+FUS安全BBBD的剂量设置，并指导其程序。