Image Guided Focused Ultrasound For Drug Delivery and Tissue Ablation

使用超声、高强度聚焦超声（HIFU）或沸腾组织破坏来增强药物作用的研究是药物递送、癌症治疗和消融的新应用。过去对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递送。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。用于图像引导组织消融和图像引导药物递送的技术和工艺的优化为药物递送范例的增强提供了必要的部分，所述药物递送范例使用MRI温度图来定位能量沉积的位置，并具有实时闭环反馈算法，所述实时闭环反馈算法帮助医生开处方并控制能量递送。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。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。空化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地将HIFU体积地施加到规定的组织，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。NIH开发的新工具包括编程，以实现体积热疗和体积药物输送。 在临床前模型和临床试验模型中，设计、验证和部署了使用低温敏感脂质体（LTSL）的增强的局部药物沉积。在过去，我们已经表明，局部多柔比星的交付是增强在肿瘤和肌肉的全身注射的LTSL含有药物和HIFU曝光。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照射量身定制，以产生仅高于体温几摄氏度的温度升高，这是非破坏性的，并且引起脂质体的相变，使其更具渗透性并能够释放其有效载荷。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。过去开发了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分布相结合，以尝试在转换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。临床前工作以前集中在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，从而定义治疗不足的肿瘤风险。这种临床前药物画笔工具已经告知了过去关于这种药物+器械组合的复杂整合的模型。最近的努力集中在基于HIFU的作用可能增强免疫治疗如检查点抑制的方式上。 与其他方法（如RFA的热消融或冷冻消融或IRE）相比，HIFU如何增强肿瘤的免疫治疗在很大程度上仍不清楚。研究表明，高强度聚焦超声消融可以增强机体对肿瘤的天然免疫和适应性免疫。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。多年来，我们与NCI MOB合作，发表了关于射频热消融及其与树突状细胞注射或癌症疫苗递送组合的免疫原性效应的文章。我们的目标是研究进一步的转化机会，以增强癌症的免疫治疗。 先前的UO 1资助（见年度报告CL-090074）与儿童国家医学中心的合作者一起评估了HIFU治疗实体瘤的效果。HIFU、超声组织摧毁术、IRE、PEF和冷冻消融具有将免疫抗性免疫“冷”肿瘤转化为“热”或免疫活性肿瘤的能力。将考虑电穿孔、脉冲电场、冷冻消融和超声组织破坏的其他平移机会用于临床部署。 作为药物递送的部署载体的气泡的新努力正在开始，包括用超声和气泡以及药物洗脱珠上的气泡凝胶和气泡的免疫调节，作为增强可视化和药物递送的方法，特别是对于多柔比星和免疫调节剂。 临床试验将于2024财年开始，由NCI Urology进行热水膀胱冲洗，以部署IV给药的LTSL联合膀胱内丝裂霉素治疗膀胱癌。这可能会为未来的LTSL研究提供信息。

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.