Image Guided Focused Ultrasound For Drug Delivery and Tissue Ablation

HIFU项目：使用高强度聚焦超声（HIFU）进行的研究涉及药物输送、癌症治疗、消融（以及过去的纤维瘤治疗和血栓溶解）的各种独特的新应用。为这些临床应用奠定基础需要有针对性的临床前安全性和桥接研究，这些研究是将药物加器械范式带入临床实践所必需的。子宫肌瘤图像引导消融的技术和工艺优化是NIH CC对该技术的首次临床试验，也是美国首次安装一种新的MRI引导HIFU技术，该技术使用MRI温度图来定位能量沉积的位置，并采用实时闭环反馈算法，帮助医生处方和控制能量输送。这种新技术也是按体积输送的，不需要像同品种技术那样进行线性顺序光栅扫描。空化检测进一步提高了这种方法的安全性。新的临床HIFU系统可以非常快速地应用HIFU，这减轻了先前HIFU技术的过度时间要求，这是临床转化的主要障碍。这里开发的新工具包括编程，使体积热疗和体积药物输送。 1.使用低温敏感脂质体（LTSL）增强局部药物沉积：在临床前模型中，我们已经表明，通过将含有药物的LTSL的全身注射和HIFU暴露相结合，肿瘤和肌肉中的局部阿霉素递送得到增强。在肿瘤研究中，将增强的递送与非热敏脂质体进行了比较，并显示出产生改善的抗肿瘤作用。低能量HIFU暴露经过专门设计，可产生仅比体温高出几摄氏度的温度升高，这是非破坏性的，并且会导致脂质体发生相变，使其更具渗透性并能够释放其有效负载。图像引导的热疗也增强了渗透性和灌注。多学科的方法优化这些治疗，以改善空间和时间加热，使用计算机模拟，体外实验和体内研究。与Dieter Haemmerich的合作正在开发一种多参数数学模型，该模型将有限元分析工具与灌注建模，组织生物热效应和已知药物概况相结合，以尝试在翻译之前优化药物加器械方法。增强的局部药物沉积通过非破坏性和破坏性机制发生。热烧蚀还沉积热量，这增加了热敏纳米颗粒的增强的渗透性和保留性以及机械部署。骨和软组织疼痛性肿瘤的I期临床试验处于IRB审查阶段。临床前工作的重点是开发可成像的纳米颗粒剂，理论上可以定义体积药物剂量测定法，从而定义治疗不足的肿瘤风险。这种临床前药物画笔工具将促进和加快这种药物+器械组合的复杂整合。 2.增强肿瘤免疫治疗的诱导效应：各种研究表明，HIFU消融可以增强针对肿瘤的适应性免疫。据推测，除了破坏肿瘤组织，肿瘤相关抗原被释放，可以刺激免疫系统产生这些效果。与NCI MOB合作者一起，我们发表了射频热消融的免疫原性效应，旨在研究进一步的转化机会，以增强癌症的免疫治疗。 3.增强药物溶栓：HIFU和非聚焦超声本身可以增强血栓溶解，正如我们在体外、小动物和大动物模型中所示。提交的工作是关于热敏封装脂质体溶栓剂，可以部署与HIFU。 4.安全性：临床HIFU暴露的安全性和可预测性研究，可能时具有放射学-病理学相关性或与疼痛控制和反应持续时间相关性。HIFU暴露可对辅助治疗和独立治疗产生各种影响。 5.子宫肌瘤消融：完成了MRI引导下“螺旋容积闭环反馈HIFU”治疗子宫肌瘤的I期临床试验的放射学与病理学相关性，作为先导试验。 6. 癌症应用：研究HIFU治疗疼痛性骨转移瘤以及MRI引导的HIFU + IV递送的纳米颗粒脂质体载体中的热部署化疗的方案，以及腹腔镜和机器人递送HIFU的临床转化计划正在进行中。未来的目标是设计一种将HIFU与其他公认的介入肿瘤学区域和局部治疗相结合的方法。部署化疗的可成像脂质体已经在体内显示出能够像“药物画笔”一样在图像引导下局部存款药物。 7.高强度聚焦超声作为前列腺癌的局部治疗已经在NIH的动物模型中进行了研究，并且已经由德克萨斯州达拉斯的合作者转化为临床。 8. UO 1基金最近被批准与儿童国家医学中心的合作者一起评估HIFU治疗儿童实体瘤的效果 9.建议直接在疼痛神经支配水平治疗慢性疼痛，以满足阿片类药物危机时代对新型疼痛治疗的需求。

HIFU projects: The studies being carried out using high intensity focused ultrasound (HIFU) involve a unique variety of novel applications for drug delivery, cancer therapy, ablation, (and in the past, fibroid therapies and thrombolysis). Building a foundation for these clinical applications necessitates directed pre-clinical safety and bridging studies that are requisite to bring drug-plus-device paradigms to clinical practice. The optimization of techniques and technologies for uterine fibroid image guided ablation was the first clinical trial for this technology at NIH CC, and was the first USA install of one of the new MRI-guided HIFU technologies that uses MRI temperature maps to localize where the energy is deposited, with a real-time closed loop feedback algorithms that help the physician prescribe and control the energy delivery. This novel technology is also delivered volumetrically and does not require linear sequential rastering, as did the predicate technology. Cavitation detection further improves the safety of this approach. The new clinical HIFU system can apply HIFU very rapidly, which mitigates the excessive time requirements for prior HIFU technologies, which was a major barrier to clinical translation. New tools developed here include programming to enable volumetric hyperthermia and volumetric drug delivery. 1. Enhanced local drug deposition using low temperature sensitive liposomes (LTSLs): In preclinical models, we have shown that local doxorubicin delivery is enhanced in both tumors and muscle by combining systemic injections of LTSLs containing the drug and HIFU exposures. In the tumor studies, enhanced delivery was compared to non-thermo sensitive liposomes and shown to produce improved anti-tumor effects. Low energy HIFU exposures are tailored to generate temperature elevations that are just a few degrees Celsius above body temperature, which are non-destructive, and which cause a phase transition in the liposomes making them more permeable and able to release their payload. The image guided hyperthermia enhances permeability and perfusion as well. A multi-disciplinary approach optimizes these treatments for improving spatial and temporal heating using computer simulations, in vitro experimentation, and in vivo studies. Collaborations with Dieter Haemmerich are developing a multi-parametric mathematical model that combines finite element analysis tools with perfusion modeling, tissue bioheat effects and known drug profiles to try to optimize the drug-plus-device approach prior to translation. Enhanced local drug deposition occurs through non-destructive and destructive mechanisms. Thermal ablation also deposits heat that adds to enhanced permeability and retention as well as mechanical deployment of heat-sensitive nanoparticles. Phase I clinical trials for bone and soft tissue painful tumors are at the IRB review stage. Preclinical work has focused on development of image-able nanoparticle agents that could theoretically define volumetric drug dosimetry, thus defining tumor at risk for undertreatment. This preclinical drug paintbrush tool will facilitate and expedite the intricate integration of this drug + device combination. 2. Induced effects for enhancing immunotherapy of tumors: Various studies have shown that HIFU ablation can enhance adaptive immunity against tumors. It is hypothesized that in addition to destroying tumor tissue, tumor associated antigens are being released that can stimulate the immune system to create these effects. With NCI MOB collaborators, we published on the immunogenic effects of radiofrequency thermal ablation, and aim to study further translational opportunities to enhance immunotherapies for cancer. 3. Enhanced pharmacologic thrombolysis: HIFU and non focused ultrasound itself can enhance thrombolysis as has been shown in our in vitro, small animal, and large animal models. Work is submitted on heat sensitive encapsulated liposomal thrombolytics, that could be deployed with HIFU. 4. Safety: Studies on the safety and predictability of clinical HIFU exposures with radiology - pathology correlation where possible or correlation with pain control and duration of response. HIFU exposures can produce a variety of effects for both adjunct and stand alone treatments. 5. Fibroid Ablation: Radiology to pathology correlation for Phase I clinical trial was completed for the use of MRI-guided "Spiral volumetric closed loop feedback HIFU" for the treatment of uterine fibroids as a pilot trial. 6. Cancer applications: Protocols to study HIFU for painful bone metastases as well as MRI-guided HIFU + heat deployed chemotherapy in a nanoparticle liposomal vector delivered IV, and plans are ongoing for clinical translation of laparoscopically and robotically delivered HIFU. Devising a methodology for combining HIFU with other accepted interventional oncology regional and local therapies is a future goal. Image-able liposomes that deploy chemotherapy have been shown in vivo to be able to deposit drug focally with image guidance, like a "drug paintbrush". 7. HIFU as a local therapy for prostate cancer has been investigated in animal models here at NIH, and has been translated to clinic by collaborators in Dallas, TX. 8. A UO1 grant has recently been approved to evaluate HIFU for pediatric solid tumors with collaborators at Childrens National Medical Center 9. Proposals to treat chronic pain directly at pain innervation levels in efforts to meet the needs for newer pain treatments in this era of opioid crisis.