Microbubble Dose Optimization for Image-Guided Drug Delivery

图像引导药物输送的微泡剂量优化

基本信息

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
项目类别：
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

项目摘要

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输送它们，这主要是由于绕过了血脑屏障 (BBB)。进入脑实质通常是高度侵入性的，手术需要切除部分头骨并涉及针头直接插入脑组织，导致持久的损伤和巨大的成本。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。 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。微泡已成为 MB+FUS 界正在进行的两极分化争论的核心，并且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然而，MB+FUS 相关的组织效应已变得至关重要。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。研究这种进一步的影响，以便创建一个清晰的框架来前瞻性地比较结果在目标 1 中，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。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 之间的治疗窗口在目标 2 中，我们将测试成功 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，结合了将通过检查频率和幅度的影响来探讨这种关系的稳健性。最后，在目标 3 中，微泡尺寸（使用 SIMB）、超声频率和模型药物的分子量。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维护者选择合适的超声波和微泡 MB+FUS 的安全 BBBD 剂量设置，并指导其程序。