Image Guided Focused Ultrasound For Drug Delivery and Tissue Ablation

用于药物输送和组织消融的图像引导聚焦超声

• 批准号: 10920175
• 负责人: Bradford Wood
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10920175
• 关键词: Ablation; Acceleration; Algorithms; Animals; Annual Reports; Back; Benign; Biological; Bladder; Bladder irrigation procedure; Body Temperature; Cancer Vaccines; Cell Death; Chemosensitization; Child; Clinic; Clinical; Clinical Trials; Computer Simulation; Contrast Media; Cryosurgery; Dendritic Cells; Deposition; Detection; Development; Device or Instrument Development; Devices; Doxorubicin; Drug Delivery Systems; Drug Regulations; Electroporation; Emerging Technologies; Endothelial Cells; Engineering; Feedback; Finite Element Analysis; Focused Ultrasound; Focused Ultrasound Therapy; Foundations; Future; Gel; Goals; Grant; Heating; Hyperthermia; Image; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunologic Factors; Immunologic Stimulation; Immunomodulators; Immunotherapy; In Vitro; Industry; Infrastructure; Injections; Institutional Review Boards; Investigation; Irrigation; Lasers; Liposomes; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Maps; Mechanics; Medical center; Methods; Mitomycins; Modeling; Muscle; Natural Immunity; Operative Surgical Procedures; Pathology; Perfusion; Permeability; Pharmaceutical Preparations; Pharmacotherapy; Phase Transition; Physicians; Physiologic pulse; Polyvinyls; Pre-Clinical Model; Prostate; Prostate Cancer therapy; Publishing; Radiosensitization; Research; Risk; Robotics; Rodent; Safety; Saline; Solid Neoplasm; System; Technology; Temperature; Thermal Ablation Therapy; Thermometry; Time; Tissues; Translating; Translations; Tumor Antigens; Tumor Tissue; Ultrasonic Therapy; United States National Institutes of Health; Universities; Up-Regulation; Urology; Uterine Fibroids; Vaccines; Validation; Visualization; Water; Work; adaptive immunity; antitumor effect; cancer immunotherapy; cancer therapy; checkpoint inhibition; chemotherapy; clinical application; clinical practice; clinical translation; cold temperature; comparative; design; dosimetry; electric field; image guided; image-guided drug delivery; immune activation; immune modulating agents; immune resistance; immune stimulant; immunogenic; immunoregulation; improved; in vivo; in vivo Model; interdisciplinary approach; liposome vector; mathematical model; multimodality; nano; nanoDroplet; nanoparticle; neoplasm immunotherapy; new technology; non-invasive imaging; novel; pre-clinical; preclinical safety; preclinical study; radio frequency; technology/technique; tool; translational potential; treatment optimization; treatment planning; tumor; ultrasound; ultrasound ablation; vaccine delivery; vector

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.

使用超声波、高强度聚焦超声波 (HIFU) 或沸腾组织解剖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进行图像引导药物输送。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输送的技术和技术的优化为增强药物输送范式提供了必要的部分，这些范式使用 MRI 温度图来定位能量沉积的位置，并通过实时闭环反馈算法来帮助医生规定并控制能量输送。这项新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。 MRI 引导的低温热疗还可用于细胞死亡以外的生物效应，例如免疫激活或免疫调节。空化检测进一步提高了该方法的安全性。新的临床 HIFU 热疗系统可以非常快速地将 HIFU 应用于规定的组织，从而减轻了先前 HIFU 技术的过多时间要求，这是临床转化的主要障碍。 NIH 开发的新工具包括实现体积热疗和体积药物输送的编程。 在临床前模型和临床试验模型中使用低温敏感脂质体（LTSL）增强局部药物沉积的设计、验证和部署。过去，我们已经证明，通过将含有药物的 LTSL 全身注射和 HIFU 暴露相结合，可以增强肿瘤和肌肉中的局部阿霉素递送。在肿瘤研究中，与非热敏脂质体相比，增强的递送被证明可以产生改善的抗肿瘤效果。低能量 HIFU 照射经过专门设计，可产生仅比体温高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。图像引导热疗还可以增强渗透性和灌注。多学科方法利用计算机模拟、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。过去开发了一种多参数数学模型，将有限元分析工具与灌注模型、组织生物热效应和已知药物概况相结合，试图在翻译之前优化药物加设备方法。通过非破坏性和破坏性机制增强局部药物沉积。热烧蚀还沉积热量，从而增强热敏纳米粒子的渗透性和保留性以及机械部署。临床前工作此前主要集中于开发可成像的纳米颗粒制剂，理论上可以定义体积药物剂量测定，从而确定处于治疗不足风险的肿瘤。这种临床前药物画笔工具为过去的模型提供了这种药物+设备组合的复杂集成的信息。最近的研究重点是基于 HIFU 的作用可能会增强检查点抑制等免疫疗法。 与其他方法（例如 RFA 热消融或冷冻消融或 IRE）相比，HIFU 增强肿瘤免疫治疗的效果在很大程度上仍不清楚。研究表明HIFU消融可以增强针对肿瘤的先天性和适应性免疫。据推测，除了破坏肿瘤组织之外，肿瘤相关抗原的释放也可以刺激免疫系统产生这些作用。多年来，我们与 NCI MOB 合作者一起发表了有关射频热消融及其与树突状细胞注射或癌症疫苗递送相结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，以增强癌症的免疫疗法。 之前的 UO1 资助（参见年度报告 CL-090074）与国家儿童医学中心的合作者一起评估了 HIFU 对实体瘤的治疗效果。 HIFU、超声组织解剖、IRE、PEF 和冷冻消融能够将免疫抵抗性免疫“冷”肿瘤转化为“热”或免疫活性肿瘤。电穿孔、脉冲电场、冷冻消融和超声组织解剖等其他转化机会将被考虑用于临床部署。 将气泡作为药物递送部署载体的新尝试正在开始，包括利用超声波和气泡进行免疫调节以及气泡凝胶和药物洗脱珠上的气泡，作为增强可视化和药物递送的方法，特别是对于阿霉素和免疫调节剂。 NCI 泌尿科将于 2024 财年开始一项热水膀胱冲洗临床试验，以部署静脉注射 LTSL 并结合膀胱内丝裂霉素治疗膀胱癌。这可能会为未来的 LTSL 研究提供信息。

项目成果

Combination therapy with local radiofrequency ablation and systemic vaccine enhances antitumor immunity and mediates local and distal tumor regression.

局部射频消融和全身疫苗的联合治疗可增强抗肿瘤免疫力并介导局部和远端肿瘤消退。

• 发表时间: 2013
• 影响因子: 3.7
• 作者: Gameiro, Sofia R;Higgins, Jack P;Dreher, Matthew R;Woods, David L;Reddy, Goutham;Wood, Bradford J;Guha, Chandan;Hodge, James W
• 通讯作者: Hodge, James W

Liposomal doxorubicin plus radiofrequency ablation for complete necrosis of a hepatocellular carcinoma.

脂质体阿霉素联合射频消融治疗肝细胞癌完全坏死。

• 发表时间: 2013-06
• 作者: Hong, C W;Libutti, S K;Wood, B J
• 通讯作者: Wood, B J