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: 9973211
• 负责人: Mark Andrew Borden
• 金额: $ 35.23万
• 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/9973211
• 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; Ultrasonography; 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

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.

治疗脑癌和神经系统疾病的新药物的开发已取得进展 我们无法安全地运送它们，这主要是由于血脑屏障（BBB）的影响。绕过 BBB 进入脑实质通常是高度侵入性的，需要手术切除部分头骨和针头 直接插入脑组织，导致持久的损伤和巨大的成本。另一种选择， 微泡辅助聚焦超声 (MB+FUS) 是一种有前途的非侵入性图像引导 BBB 方法 破坏（BBBD）目前正在进行三项人体临床试验。 MB+FUS 诱导瞬时开放 BBB 通过静脉内输送直径为 1-10 µm 的声学脉动充气微泡， 允许将药物靶向输送至直径小至 2-3 毫米的大脑区域。这些药物的安全剂量 微泡已成为 MB+FUS 界正在进行的两极分化争论的核心，并且 对临床转化至关重要。最近的研究结果表明 MB+FUS 后出现急性无菌免疫反应 (SIR) BBBD，阐明微泡剂量、药代动力学（PK）、超声力学之间的关系 指数，MB+FUS 相关的组织效应已变得至关重要。然而，这样做的努力已经 因产品与产品之间以及批次与批次之间的尺寸、浓度和成分差异而造成混淆 市售的微泡超声造影剂制剂。 使用不同单分散尺寸和均匀成分的尺寸隔离微泡 (SIMB)，我们 科罗拉多大学和 NIDA 的研究小组最近发现，微泡剂量可以 通过将尺寸和浓度统一为一个参数来简化：微泡体积剂量 (MVD)，其中 趋势与微泡 PK 和 BBBD 大小的关键品质因数呈线性关系。在这个项目中，我们将 进一步研究这种影响，以便创建一个清晰的框架来前瞻性地比较结果 不同实验室和不同微泡剂进行的研究之间进行回顾性研究。在目标 1 中， 我们将检验以下假设：FDA 批准的超声检查的 PK 品质因数与 MVD 成线性关系 目前用于人体临床试验和大多数临床前研究的造影剂，以及我们自己的 SIMB。 我们将扩展这项研究，以建立产生 BBBD 的最小 MVD 之间的治疗窗口 和急性 SIR。在目标 2 中，我们将检验成功 BBBD 所需的最小 MVD 的假设 随着机械指数 (MI) 的增加而减小，机械指数是一个统一的超声参数，结合了 频率和幅度。将通过检查以下因素的影响来探讨这种关系的稳健性： 微泡尺寸（使用 SIMB）、超声频率和模型药物的分子量。最后，在目标 3 中， 我们将在 MVD 图上建立 BBBD（功效）和急性 SIR（安全性）之间的治疗窗口 与 MI，这将帮助该领域的研究人员和临床医生选择合适的超声和微泡 MB+FUS 的安全 BBBD 剂量设置，并指导其程序。