Image Guided Focused Ultrasound For Drug Delivery and Tissue Ablation

HIFU项目：使用高强度聚焦超声(HIFU)进行的研究涉及到药物输送、癌症治疗、消融(以及过去的肌瘤治疗和溶栓)的各种独特的新应用。为这些临床应用建立基础需要有针对性的临床前安全性和衔接研究，这是将药物+设备范例引入临床实践所必需的。对子宫肌瘤图像引导消融技术和技术的优化是NIH CC对这项技术的第一次临床试验，也是美国第一次安装MRI引导的HIFU新技术之一，该技术使用MRI温度图来定位能量储存的位置，并具有实时闭环反馈算法，帮助医生开出处方并控制能量输送。这种新颖的技术也是按体积交付的，并且不需要像谓词技术那样的线性顺序光栅化。气蚀检测进一步提高了这种方法的安全性。新的临床HIFU系统可以非常迅速地应用HIFU，这缓解了以前HIFU技术对时间的过高要求，这是临床翻译的主要障碍。这里开发的新工具包括编程，以实现体积热疗和体积药物输送。 1.使用低温敏感脂质体(LTSLs)增强局部药物沉积：在临床前模型中，我们已经证明，通过全身注射含有药物的LTSLs和HIFU暴露，局部阿霉素在肿瘤和肌肉中的输送都得到了增强。在肿瘤研究中，增强型给药与非热敏性脂质体进行了比较，并显示出更好的抗肿瘤效果。低能量HIFU暴露是量身定做的，可以产生仅比体温高几摄氏度的温度升高，这是非破坏性的，这会导致脂质体中的相变，使它们更具渗透性，能够释放有效载荷。图像引导的热疗也增强了通透性和灌注性。一种多学科的方法通过计算机模拟、体外实验和体内研究来优化这些治疗方法，以改善空间和时间加热。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流建模、组织生物热效应和已知的药物概况相结合，试图在翻译之前优化药物加装置的方法。局部药物沉积增强是通过非破坏性和破坏性机制实现的。热消融还会沉积热量，增加渗透性和保持性，以及热敏性纳米颗粒的机械部署。骨和软组织疼痛肿瘤的I期临床试验正处于IRB审查阶段。临床前工作的重点是开发可成像的纳米颗粒制剂，从理论上定义体积药物剂量学，从而确定肿瘤存在治疗不足的风险。这种临床前药物画笔工具将促进和加速这种药物+设备组合的复杂整合。 2.增强肿瘤免疫治疗的诱导效应：各种研究表明，HIFU消融可增强对肿瘤的获得性免疫。据推测，除了破坏肿瘤组织外，还会释放与肿瘤相关的抗原，从而刺激免疫系统产生这些效应。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，并旨在研究进一步的翻译机会，以加强癌症的免疫治疗。 3.增强药理溶栓：HIFU和非聚焦超声本身可以促进溶栓，这在我们的体外、小动物和大动物模型中已经显示出来。提交的工作是关于热敏性脂质体溶栓剂，可以与HIFU一起部署。 4.安全性：研究临床HIFU照射的安全性和可预测性，尽可能与放射-病理相关，或与疼痛控制和反应持续时间相关。HIFU照射会对辅助治疗和单独治疗产生各种影响。 5.子宫肌瘤消融术：以MRI引导下的“螺旋容积反馈HIFU”治疗子宫肌瘤为先导试验，完成了I期临床试验的放射学与病理学对照研究。 6.癌症应用：研究HIFU治疗疼痛骨转移的方案，以及在MRI引导下的HIFU+热部署化疗在纳米颗粒脂质体载体中输送IV，以及正在进行的腹腔镜和机器人输送HIFU的临床翻译计划。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是未来的目标。体内实验表明，可进行化疗的可成像脂质体能够在图像引导下将药物沉积在焦点上，就像一把“药物画笔”。 7.HIFU作为前列腺癌的局部治疗方法已经在NIH的动物模型中进行了研究，并已由德克萨斯州达拉斯的合作者转化为临床。 8.高强度聚焦超声治疗高血压的研究处于临床前的探索性阶段。

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. Investigation of HIFU for the treatment of hypertension is in exploratory pre-clinical phases.