Enhancement of tumor radiation response by ultrasound-driven nanobubble stimulation

超声驱动纳米气泡刺激增强肿瘤放射反应

基本信息

批准号：
10671576
负责人：
Gregory Jan Czarnota
金额：
$ 46.52万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-11 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10671576
关键词：
Acoustic Stimulation Acoustics Acute Address Aftercare Animals Antineoplastic Protocols Biodistribution Biological Markers Biomedical Engineering Blood - brain barrier anatomy Blood Vessels Cancer Detection Cell Death Cell physiology Cell surface Cells Clinic Clinical Clinical Trials Collaborations Combined Modality Therapy Contrast Media Data Development Diagnostic Imaging Diameter Doctor of Philosophy Dose Early treatment Endothelium Ensure Evaluation Extravasation Formulation Frequencies Funding Goals Grant Head and Neck Cancer Histologic Hour Image Immunocompromised Host Kinetics Link Malignant neoplasm of prostate Measures Mechanics Mediating Medical Methodology Methods Microbubbles Modeling Modulus Monitor Mus Neoplasms in Vascular Tissue Oryctolagus cuniculus Patients Performance Permeability Pharmaceutical Preparations Physicians Physics Prediction of Response to Therapy Production Prostate Cancer therapy Protocols documentation Publications Radiation Radiation Dose Unit Radiation Oncology Radiation induced damage Radiation therapy Radiation-Sensitizing Agents Radiosensitization Reactive Oxygen Species Research Research Personnel Residual state Resolution Scientist Sensitivity and Specificity Signal Transduction Solid Neoplasm Sonication Techniques Technology Testing Therapeutic Time Tissues Translations Treatment Efficacy Treatment Failure Treatment Step Ultrasonics Vascular Endothelium Work cancer biomarkers cancer cell cancer radiation therapy cancer therapy contrast enhanced effectiveness evaluation experience experimental study human model imaging approach imaging biomarker improved improved outcome in vivo malignant breast neoplasm member meter mouse model multidisciplinary nanobubble neoplastic cell novel photoacoustic imaging physical property predictive marker predictive tools programs prostate cancer model radiation response radio frequency rapid detection receptor research clinical testing response side effect success synergism theranostics tissue oxygenation tool translational approach treatment optimization treatment response tumor ultrasound uptake

项目摘要

Project Summary Radiation is a mainstay of cancer treatment, yet challenges remain. The long term goal of the proposed research is to transform traditional cancer radiation therapy protocols by including a pre-treatment step involving perturbing the vascular and cellular function of tumors with ultrasound-activated radiosensitizing nanobubbles (NBs). The new paradigm in cancer treatment protocol builds upon a decade of prior work that used commercial microbubbles (MBs) to elicit a radiosensitizing effect. The MB radiosensitization effects are primarily intravascular, with significant endothelial damage incurred. In contrast, in the strategy proposed here, we hypothesize that the NBs will also extravasate into the tumor parenchyma, which will result in significant increases in direct damage to the cancer cells, in addition to the vascular damage. Thus the effect will be both intra- and extra-vascular. The tumors treated in this way will respond better to radiation, lowering the effective radiation dose and decreasing residual surviving tumor. The technique further allows targeting of tumor specific volumes allowing healthy tissues to be spared. We have demonstrated in preliminary studies in vivo that ultrasound-activated NB perturbation of tumors results in a significantly greater enhancement in tumor kill compared to MBs when followed by traditional radiation therapy. This approach could markedly improve existing therapies and reduce the associated side-effects. This is clinically important for prostate cancer treatment where collateral damage and off-target effects are common and lead to years of complications in many patients. Therefore, we propose a set of four specific aims to test, develop, optimize, demonstrate and quantify the efficacy of this novel technique in prostate cancer. Aim 1 will focus on the development of stable, uniformly-sized radiosensitizing NBs. The acoustic and bio-activity of the bubbles will be measured, and baseline biodistribution in tumor bearing mice will be carried out. In Aim 2, the NBs will be tested in combination with radiation in a mouse model of prostate cancer so that treatment parameters can be optimized. In Aim 3, carried out concurrently with Aim 2, we will develop a photoacoustic imaging approach for monitoring early treatment response. This tool will be used to predict therapeutic efficacy and completeness of tumor treatment as soon as 2 hours after the therapy. Finally, in Aim 4, we will test the combination approach in a large (rabbit) orthotopic model of human prostate cancer. We have assembled a multidisciplinary MPI team of investigators with a demonstrated track record of collaborative work in this field. The team includes Dr. Czarnota MD/Ph.D., a physician-scientist and discoverer of the original MB sensitizing approach now in clinical trials, Dr. Michael Kolios Ph.D. is a medical physicist with broad experience in photoacoustic imaging for therapy response and ultrasound physics and Dr. Agata Exner, Ph.D., a biomedical engineer with extensive expertise in formulation and implementation of nanobubbles for imaging and therapy. Members of the team are actively collaborating, have shared publications, grants and projects, and record of technology translation to the clinic. The team will ensure timely completion of the proposed research and rapid translation of the approach to clinical use.

项目概要放射是癌症治疗的主要手段，但挑战仍然存在。拟议研究的长期目标是通过包括扰动血管的预处理步骤来改变传统的癌症放射治疗方案和超声激活放射增敏纳米气泡（NB）的肿瘤细胞功能。癌症的新范例治疗方案建立在十年前的工作基础上，该工作使用商业微泡（MB）来引发放射增敏影响。 MB 放射增敏作用主要是血管内的，会引起显着的内皮损伤。在相反，在这里提出的策略中，我们假设 NB 也会外渗到肿瘤实质中，这除了血管损伤之外，还会导致对癌细胞的直接损伤显着增加。这样的效果将是血管内和血管外的。以这种方式治疗的肿瘤将对放射反应更好，从而降低有效剂量辐射剂量和减少残留存活肿瘤。该技术进一步允许靶向肿瘤特定体积让健康组织免受伤害。我们已经在体内初步研究中证明，超声激活的 NB 与 MB 相比，扰动肿瘤可显着增强肿瘤杀灭效果传统放射治疗。这种方法可以显着改善现有疗法并减少相关副作用。这在临床上很重要用于前列腺癌治疗，附带损害和脱靶效应很常见，并会导致多年的并发症在许多患者中。因此，我们提出了一组四个具体目标来测试、开发、优化、演示和量化这项新技术在前列腺癌中的功效。目标 1 将重点发展稳定、大小统一的放射增敏 NB。将测量气泡的声学和生物活性，以及肿瘤中的基线生物分布将进行生育小鼠。在目标 2 中，将在小鼠前列腺模型中结合辐射对 NB 进行测试癌症，以便优化治疗参数。在与目标 2 同时进行的目标 3 中，我们将开发一个用于监测早期治疗反应的光声成像方法。该工具将用于预测治疗治疗后 2 小时即可观察肿瘤治疗的有效性和完整性。最后，在目标 4 中，我们将测试人类前列腺癌大型（兔）原位模型中的组合方法。我们组建了一支多学科 MPI 研究人员团队，具有良好的协作记录在这个领域。该团队包括医学博士/博士 Czarnota 博士，他是一位医师科学家，也是原始 MB 致敏剂的发现者 Michael Kolios 博士博士表示，该方法目前正在进行临床试验。是一位在光声方面拥有丰富经验的医学物理学家 Agata Exner 博士是一位生物医学工程师，拥有广泛的研究成果，可用于治疗反应和超声物理成像。用于成像和治疗的纳米气泡的配制和实施方面的专业知识。团队成员积极主动合作，共享出版物、赠款和项目以及临床技术翻译记录。团队将确保及时完成拟议的研究并将该方法快速转化为临床使用。