Image Guided Focused Ultrasound For Drug Delivery and Tissue Ablation

使用超声波、高强度聚焦超声(HIFU)或沸腾组织摩擦来增强药物效果的研究是药物输送、癌症治疗和消融的新应用。过去HIFU应用的努力包括癌症和良性组织消融，以及利用可成像载体的图像引导药物输送。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。图像引导组织消融和图像引导药物传递的技术和技术的优化为药物传递范式的改进提供了必要的部分，该范例使用MRI温度图来定位能量储存的位置，并使用实时闭环反馈算法来帮助医生处方和控制能量传递。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。MRI引导的低温热疗也可以用于细胞死亡以外的生物效应，如免疫激活或免疫调节。气蚀检测进一步提高了这种方法的安全性。新的临床HIFU热疗系统可以非常快速和大量地将HIFU应用于指定的组织，这缓解了先前HIFU技术对时间的过高要求，这是临床翻译的主要障碍。美国国立卫生研究院开发的新工具包括编程，以实现容量热疗和容量药物输送。 设计、验证和部署了在临床前模型和临床试验模型中使用低温敏感脂质体(LTSLs)增强局部药物沉积。在过去，我们已经证明，通过全身注射含有阿霉素的LTSL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，并会导致脂质体中的相变，使其更具渗透性，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。过去开发了一个多参数的数学模型，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分布相结合，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。临床前的工作以前专注于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。这个临床前药物画笔工具已经向过去的模型提供了关于这种药物+设备组合的复杂集成的信息。最近的努力集中在基于HIFU的行动可能加强免疫治疗的方式，如检查点抑制。 HIFU增强的肿瘤免疫治疗与其他方法相比，如RFA的热消融或冷冻消融，或IRE，在很大程度上仍未确定。研究表明，HIFU消融可以增强针对肿瘤的先天免疫和获得性免疫。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。在过去的几年里，我们与NCI MOB的合作者一起，发表了射频热消融及其与树突状细胞注射或癌症疫苗注射的联合应用的免疫促进作用。我们的目标是研究进一步的翻译机会，以加强癌症的免疫治疗。 先前的一项UO1拨款(见CL-090074年度报告)与儿童国家医学中心的合作者一起评估了高强度聚焦超声治疗实体肿瘤。HIFU、超声组织学、IRE、PEF和冷冻消融术有能力将免疫抵抗型免疫“冷”肿瘤转变为“热”或免疫活跃的肿瘤。电穿孔、脉冲电场、冷冻消融和超声组织检查的其他翻译机会将被考虑用于临床部署。 以气泡作为药物输送载体的新努力正在开始，包括用超声波和气泡进行免疫调节，以及在药物洗脱微珠上使用气泡凝胶和气泡，以此作为增强可视化和药物输送的方法，特别是对阿霉素和免疫调节剂。 一项临床试验将在2014财年开始，以NCI泌尿科的热水膀胱冲洗为开端，部署静脉注射的LTSL，结合膀胱内丝裂霉素治疗膀胱癌。这可能会为未来的LTSL研究提供参考。

The studies being carried out using ultrasound, high intensity focused ultrasound (HIFU) or boiling histotripsy to enhance drug effects are novel applications for drug delivery, cancer therapy, and ablation. Past efforts for HIFU applications have included cancer and benign tissue ablation, as well as image guided drug delivery with image-able vectors. 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 image guided tissue ablation and image guided drug delivery provides the requisite parts for enhancement of drug delivery paradigms that use 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. MRI-guided low temperature hyperthermia can also be prescribed for biologic effects other than cell death, such as immune activation or immunomodulation. Cavitation detection further improves the safety of this approach. The new clinical HIFU hyperthermia system can apply HIFU very rapidly and volumetrically to the prescribed tissue, which mitigates the excessive time requirements for prior HIFU technologies, which was a major barrier to clinical translation. New tools developed at NIH include programming to enable volumetric hyperthermia and volumetric drug delivery. The enhanced local drug deposition using low temperature sensitive liposomes (LTSLs) in preclinical models and in clinical trial models was designed, validated and deployed. In the past, 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. A multi-parametric mathematical model was developed in the past 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. Preclinical work had previously 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 had informed past models on the intricate integration of this drug + device combination. Recent efforts have focused on the way that HIFU based actions might potentiate immunotherapies such as check point inhibition. It largely remains undefined how HIFU enhanced immunotherapy of tumors compares to other methods such as thermal ablation from RFA or cryoablation, or IRE. Studies have shown that HIFU ablation can enhance innate and 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 over years gone by, we published on the immunogenic effects of radiofrequency thermal ablation and its combination with dendritic cell injection or with cancer vaccine delivery. We aim to study further translational opportunities to enhance immunotherapies for cancer. A prior UO1 grant (see annual report CL-090074) evaluated HIFU for solid tumors with collaborators at Childrens National Medical Center. HIFU, ultrasound histotripsy, IRE, PEF and cryoablation have the ability to convert immune-resistant immune "cold" tumors into "hot" or immune active tumors. Other translational opportunities for electroporation, pulsed electrical fields, cryoablation, and ultrasound histotripsy will be considered for clinical deployment. Novel efforts into bubbles as deployment vectors for drug delivery are beginning, including immunomodulation with ultrasound and bubbles as well as bubble gels and bubbles on drug eluting beads, as methods to enhance visualization and drug delivery, especially for doxorubicin and immunomodulators. A clinical trial will begin FY24 with NCI Urology for hot water bladder irrigations to deploy the IV administered LTSL, combined with intra-bladder Mitomycin for Bladder Cancer. This may inform future LTSL studies.