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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

基本信息

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
项目类别：
财政年份：
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

项目摘要

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.

利用超声、高强度聚焦超声（HIFU）或沸腾组织切片法增强药物作用的研究是药物传递、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桥接研究，这些研究是将药物加设备范例带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技术的优化为增强药物输送模式提供了必要的部分，该模式使用MRI温度图来定位能量沉积的位置，并使用实时闭环反馈算法来帮助医生处方和控制能量输送。这种新技术也是按体积交付的，不像谓词技术那样需要线性顺序光栅。核磁共振引导下的低温热疗也可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该方法的安全性。新的临床HIFU热疗系统可以非常快速和按体积对指定组织进行HIFU，这减轻了先前HIFU技术的过多时间要求，这是临床转化的主要障碍。美国国立卫生研究院开发的新工具包括实现体积热疗和体积给药的编程。