Microbubble Dose Optimization for Image-Guided Drug Delivery

治疗脑癌和神经疾病的新药的开发已经 超过了我们安全运送它们的能力，这在很大程度上是由于血脑屏障(BBB)。绕过BBB以 进入脑实质通常是高度侵入性的，需要手术移除部分头骨和针头。 直接植入脑组织，导致持久的损害和巨大的成本。另一种选择， 微泡辅助聚焦超声(MB+FUS)是一种很有前途的无创、图像引导的血脑屏障检查方法。 破坏(BBBD)目前正在进行三项人体临床试验。MB+FUS诱导大鼠脑内一过性开放 通过直径1-10微米的声学脉动，静脉注射充气微泡， 允许将药物定向输送到直径小至2-3毫米的大脑区域。这些药物的安全剂量 微泡已经成为MB+FUS社区正在进行的两极分化辩论的核心，而且 对临床翻译至关重要。最近的发现表明MB+FUS后的急性不育免疫反应(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，与MB+FUS相关的组织效应已变得必不可少。然而，这样做的努力一直是 产品与产品之间以及批次与批次之间在大小、浓度和组成上的差异 商业上可用的微泡超声造影剂配方。 使用不同单分散尺寸和均匀组成的尺寸隔离微泡(SIMB)，我们的 科罗拉多大学和NIDA的研究团队最近发现，微泡剂量可以 通过将大小和浓度统一为单个参数进行简化：微泡体积剂量(MVD)，它 趋势与微泡PK和BBBD大小的关键优值成线性关系。在这个项目中，我们将 进一步调查这一影响，以便建立一个明确的框架，以便前瞻性地比较结果和 回顾不同实验室和不同微泡剂进行的研究。在目标1中， 我们将检验PK分级的优值系数与FDA批准的超声的MVD呈线性关系的假设 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，在产生BBBD的最小MVD之间建立一个治疗窗口 和敏锐的先生。在目标2中，我们将检验以下假设：成功的BBBD所需的最小MVD 随机械指数(MI)增加而减小，该指数是一个统一的超声参数 频率和幅度。这种关系的稳健性将通过检查以下因素的影响来探讨 模型药物的微泡大小(使用SIMB)、超声频率和分子质量。最后，在目标3中， 我们将在MVD图上建立BBBD(有效)和急性SIR(安全性)之间的治疗窗口 VS 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的剂量设置，并指导他们的手术。

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.