Microbubble Dose Optimization for Image-Guided Drug Delivery

用于治疗脑癌和神经系统疾病的新药的开发， 超过了我们安全递送它们的能力，这主要是由于血脑屏障（BBB）。将BBB转换为 进入脑实质通常是高度侵入性的，涉及手术以移除部分颅骨和针头。 直接插入脑组织，导致持久的损伤和显著的成本。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 目前正在进行三项人体临床试验。MB+FUS诱导了 BBB通过声学介导的1-10 µm直径的静脉内递送的充气微泡的脉动， 允许靶向药物递送到直径小至2-3 mm的脑区域。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， 对临床翻译至关重要。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）、超声机械 指数，MB+ FUS相关的组织效应变得至关重要。然而，这样做的努力一直是 受到产品间和批次间尺寸、浓度和组成差异的混淆 市售的微泡超声造影剂制剂。 使用不同单分散尺寸和均匀组成的尺寸隔离微泡（SIMBs）， 科罗拉多大学和NIDA的一个研究小组最近发现，微泡剂量可以 通过将尺寸和浓度统一为单个参数来简化：微泡体积剂量（MVD）， 与微泡PK和BBBD量级的关键品质因数呈线性趋势。在这个项目中，我们将 进一步研究这一影响，以便为前瞻性比较结果建立一个明确的框架， 不同实验室和不同微泡剂进行的研究之间的回顾性比较。在目标1中， 我们将检验以下假设：对于FDA批准的超声，PK的优值与MVD呈线性关系 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。 我们将扩大这项研究，以建立一个治疗窗口之间的最低MVD产生BBBD 急性SIR。在目标2中，我们将检验成功BBBD所需的最小MVD 随着机械指数（MI）的增加而减小，机械指数（MI）是统一的超声参数， 频率和振幅。这种关系的稳健性将通过检查 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（有效性）和急性SIR（安全性）之间的治疗窗口 vs. MI，这将有助于该领域的研究人员和临床医生选择合适的超声和微泡 通过MB+FUS进行安全BBBD的剂量设置，并指导其程序。

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.