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 超声诱导的空化与全身施用的超声对比剂（UCAS）结合 在过去的十年中，已经广泛研究了 对实体瘤的不同药物。这种方法的局限性是UCA仅限于血管和 血管周空间限制了它们进入肿瘤血管化较差的区域。增加的间隙 压力，高肿瘤细胞密度和基质屏障进一步抑制药物递送。诱导从头空化 因此，使用脉冲聚焦超声（PFU）在整个肿瘤组织中将非常有益于克服 这些药物渗透的障碍。但是，根据当前在现场的共识，局灶性压力水平 成核和维持惯性空化所需的要高于UCA增强超声 并且只能通过具有较大足迹的高功率，高度专注的传感器来实现。这限制了 这种方法的实用性。我们的初步数据表明，导致组织的惯性空化活动 如果局灶性发生冲击战线，则可以在较低的峰值负压下实现通透性 波形，由于非线性传播效应。此外，我们已经证明了 冲击振幅和峰值负压主要由FUS换能器的F指定器确定 在较低的峰值负压值下，焦点较少的换能器产生冲击。我们也表明 使用诊断超声探针在相对较低的机械指数中可以实现令人震惊的波形 （MI〜4-6）在衰减组织中相关的深度。该提案的总体目标是发展反馈 可以使用小的PFU治疗方案，用于将药物输送到实体瘤 足迹，（可能诊断）超声探针。可以仅执行此类通透程序 在对任何可以用超声进行成像的肿瘤进行化学疗法之前。实现我们的 目标，我们建议确定焦距指标和相关的空化活动的依赖性 通过数值建模和一系列实验在传感器的形状和频率上 透明的组织模拟凝胶幻像和离体组织（特定目的1和2相应地）。直接的 使用高速摄影在透明凝胶中观察气泡动力学将与活动相关 和被动空化检测观察结果，用于在组织中进行后续实验。优化的PFU 然后，治疗方案将应用于健康的猪组织（肝脏，肾脏和胰腺），并将其应用于 皮下Dunning大鼠前列腺腺癌，然后全身给药 荧光标记的不同分子量的右旋体（特定目标3）。透化效应将是 从组织中葡聚糖的绝对浓度和分布进行敏锐的评估。耐用性 PFU诱导的透化将在大鼠的短期生存研究中评估，通过改变时间间隔 PFUS应用和染料给药。