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:
  • 金额:
    $ 35.23万
  • 依托单位:
  • 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

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

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Mark Andrew Borden其他文献

Mark Andrew Borden的其他文献

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{{ truncateString('Mark Andrew Borden', 18)}}的其他基金

Endoskeletal nanodrops for x-ray acoustic dosimetry
用于 X 射线声剂量测定的内骨骼纳米滴
  • 批准号:
    10429759
  • 财政年份:
    2022
  • 资助金额:
    $ 35.23万
  • 项目类别:
Endoskeletal nanodrops for x-ray acoustic dosimetry
用于 X 射线声剂量测定的内骨骼纳米滴
  • 批准号:
    10660977
  • 财政年份:
    2022
  • 资助金额:
    $ 35.23万
  • 项目类别:
Peritoneal Oxygen Delivery For The Treatment Of Acute Respiratory Distress Syndrome
腹膜供氧治疗急性呼吸窘迫综合征
  • 批准号:
    10556430
  • 财政年份:
    2020
  • 资助金额:
    $ 35.23万
  • 项目类别:
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
  • 财政年份:
    2019
  • 资助金额:
    $ 35.23万
  • 项目类别:
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:
    10438770
  • 财政年份:
    2019
  • 资助金额:
    $ 35.23万
  • 项目类别:
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:
    10652332
  • 财政年份:
    2019
  • 资助金额:
    $ 35.23万
  • 项目类别:
Ultrasound Molecular Imaging to Assess Therapeutic Response
超声分子成像评估治疗反应
  • 批准号:
    9053460
  • 财政年份:
    2015
  • 资助金额:
    $ 35.23万
  • 项目类别:
Ultrasound Molecular Imaging to Assess Therapeutic Response
超声分子成像评估治疗反应
  • 批准号:
    9274263
  • 财政年份:
    2015
  • 资助金额:
    $ 35.23万
  • 项目类别:
Ultrasound Molecular Imaging to Assess Therapeutic Response
超声分子成像评估治疗反应
  • 批准号:
    9440982
  • 财政年份:
    2015
  • 资助金额:
    $ 35.23万
  • 项目类别:
Targeted Microbubbles for Noninvasive Measurement of Tumor VEGF Levels
用于无创测量肿瘤 VEGF 水平的靶向微泡
  • 批准号:
    8702492
  • 财政年份:
    2014
  • 资助金额:
    $ 35.23万
  • 项目类别:

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