Pulsed Focused Ultrasound (pFUS) exposures and devices for tissue permeabilization without contrast agents

脉冲聚焦超声 (pFUS) 曝光和无需造影剂的组织透化装置

• 批准号: 9397455
• 负责人: Tatiana Khokhlova
• 金额: $ 47.75万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9397455
• 关键词: Acoustics; Acute; Address; Animal Model; Antineoplastic Agents; Blood Vessels; Cancer Patient; Cell Density; Characteristics; Clinical; Consensus; Contrast Media; Data; Dependence; Detection; Devices; Dextrans; Diagnostic; Doxorubicin; Drug Delivery Systems; Drug Exposure; Drug Transport; Dyes; Family suidae; Feedback; Fibrosis; Focused Ultrasound; Focused Ultrasound Therapy; Frequencies; Gel; Generations; Geometry; Goals; Image; Investigation; Kidney; Label; Liver; Malignant Neoplasms; Malignant neoplasm of prostate; Mechanics; Modeling; Molecular Weight; Mus; Pancreas; Penetration; Pericytes; Pharmaceutical Preparations; Photography; Physiologic pulse; Procedures; Prostate Adenocarcinoma; Protocols documentation; Public Health; Rattus; Reporting; Series; Shapes; Shock; Smooth Muscle Myocytes; Solid; Solid Neoplasm; Spatial Distribution; Speed; Techniques; Technology; Therapeutic; Tissues; Transducers; Treatment Protocols; Tumor Tissue; Ultrasonography; Validation; Work; base; cancer survival; chemotherapeutic agent; chemotherapy; experimental study; improved; in vivo; indexing; interstitial; millisecond; neoplastic cell; pancreatic neoplasm; pressure; subcutaneous; targeted agent; time interval; tumor; uptake

ABSTRACT Cavitation induced by ultrasound combined with systemically administered ultrasound contrast agents (UCAs) has been extensively studied over the past decade, and successfully applied to the delivery of a number of different drugs to solid tumours. A limitation of this approach is that the UCAs are confined to blood vessels and the perivascular space, which limits their access to poorly vascularized regions of a tumor. Increased interstitial pressure, high tumor cell density, and stromal barriers further inhibit drug delivery. Inducing de novo cavitation throughout tumor tissue using pulsed focused ultrasound (pFUS) would thus be very beneficial for overcoming these barriers to drug penetration. However, according to current consensus in the field, the focal pressure levels required to nucleate and sustain inertial cavitation are substantially higher than for UCA-enhanced ultrasound and can only be achieved with high-power, highly focused transducers with a large footprints. This limits the practicality of this approach. Our preliminary data indicate that the inertial cavitation activity that results in tissue permeabilization can be achieved at lower peak negative pressures if a shock front develops in the focal waveform, due to nonlinear propagation effects. Further, we have demonstrated that the relationship between the shock amplitude and peak negative pressure is primarily determined by the F-number of a FUS transducer, with less focused transducers producing shocks at the lowest peak negative pressure values. We also showed that shocked waveforms can be achieved using diagnostic ultrasound probes at relatively low mechanical index (MI ~ 4-6) at relevant depth in attenuative tissue. The overall goal of this proposal is to develop feedback controlled pFUS treatment protocols for drug delivery to solid tumours that can be implemented using small footprint, (potentially diagnostic) ultrasound probes. Such permeabilization procedures could be performed just prior to the administration of chemotherapy on any tumor that can be imaged with ultrasound. To achieve our goal, we propose to determine the dependence of the focal waveform metrics and associated cavitation activity on the shape and frequency of the transducer through numerical modelling and a series of experiments in transparent tissue-mimicking gel phantoms and ex vivo tissues (Specific Aims 1 and 2 correspondingly). Direct observation of bubble dynamics using high-speed photography in transparent gels will be correlated with active and passive cavitation detection observations for use in subsequent experiments in tissue. The optimized pFUS treatment protocols will then be applied to healthy porcine tissues (liver, kidney and pancreas), and to subcutaneous Dunning rat prostatic adenocarcinoma, and will be followed by systemic administration of fluorescent labelled dextrans of different molecular weights (Specific Aim 3). The permeabilization effect will be evaluated acutely from the absolute concentration and distribution of the dextrans in tissue. The durability of pFUS-induced permeabilization will be evaluated in a short survival study in rats, by varying the time interval pFUS application and dye administration.

抽象的 超声结合全身超声造影剂 (UCA) 诱导空化 在过去的十年中得到了广泛的研究，并成功应用于许多 治疗实体瘤的药物不同。这种方法的局限性在于 UCA 仅限于血管和 血管周围空间，这限制了它们进入肿瘤血管化不良的区域。增加插页式广告 压力、高肿瘤细胞密度和基质屏障进一步抑制药物输送。诱发从头空化 因此，使用脉冲聚焦超声（pFUS）遍及肿瘤组织将非常有利于克服 这些药物渗透的障碍。然而，根据该领域目前的共识，焦点压力水平 成核和维持惯性空化所需的能量远高于 UCA 增强超声 并且只能通过具有大占地面积的高功率、高度聚焦的传感器来实现。这限制了 这种方法的实用性。我们的初步数据表明，惯性空化活动导致组织 如果在焦点处出现激波前沿，则可以在较低的峰值负压下实现透化 波形，由于非线性传播效应。此外，我们还证明了之间的关系 冲击幅度和峰值负压主要由 FUS 传感器的 F 数决定， 焦点较少的传感器在最低峰值负压值下产生冲击。我们还展示了 使用诊断超声探头可以在相对较低的机械指数下实现冲击波形 (MI ~ 4-6) 在衰减组织的相关深度。该提案的总体目标是开发反馈 用于向实体瘤输送药物的受控 pFUS 治疗方案可以使用小型药物来实施 足迹，（潜在诊断）超声波探头。这种透化程序只需进行 在对任何可以用超声波成像的肿瘤进行化疗之前。为了实现我们的 目标，我们建议确定焦点波形指标和相关空化活动的依赖性 通过数值建模和一系列实验来确定换能器的形状和频率 透明的模仿组织的凝胶体模和离体组织（相应的具体目标 1 和 2）。直接的 使用透明凝胶中的高速摄影观察气泡动力学将与活性相关 以及用于后续组织实验的被动空化检测观察。优化后的 pFUS 然后将治疗方案应用于健康的猪组织（肝脏、肾脏和胰腺），并 皮下注射 Dunning 大鼠前列腺腺癌，然后全身给药 不同分子量的荧光标记葡聚糖（具体目标 3）。通透效果将是 根据组织中葡聚糖的绝对浓度和分布进行敏锐评估。耐久性 pFUS 诱导的透化作用将在大鼠的短期生存研究中通过改变时间间隔进行评估 pFUS 应用和染料管理。