权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10190853
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/10190853
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.

用于治疗脑癌和神经系统疾病的新药的开发