Image Guided Focused Ultrasound For Drug Delivery and Tissue Ablation

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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 soon in clinical models will be reported separately this year. 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 UO1 grant is ongoing (see annual report CL-090074) to evaluate HIFU eventually for solid tumors with collaborators at Childrens National Medical Center. HIFU, ultrasound histotripsy, IRE, and cryoablation have the ability to convert immune-resistant immune "cold" tumors into "hot" or immune active tumors. Other translational opportunities for electroporation, cruoablation, and ultrasound histotripsy will be considered for clinical deployment.