Enhancement of tumor radiation response by ultrasound-driven nanobubble stimulation

项目摘要 放射治疗是癌症治疗的中流砥柱，但挑战依然存在。拟议研究的长期目标是 通过包括扰乱血管的治疗前步骤来改变传统的癌症放射治疗方案 超声激活的放射增敏纳米气泡(NBS)对肿瘤细胞功能的影响。癌症研究的新范式 治疗方案建立在十年前使用商业微泡(MBS)诱导放射增敏的先前工作的基础上 效果。MB的放射增敏作用主要是血管内的，会引起显著的内皮损伤。在……里面 相反，在这里提出的策略中，我们假设NBS也会渗入肿瘤实质，这 除了血管损伤外，还会导致对癌细胞的直接损害显著增加。由此产生的效果 会是血管内和血管外的。用这种方法治疗的肿瘤对辐射的反应会更好，从而降低了有效率 辐射剂量和减少残存肿瘤。该技术还允许靶向肿瘤特定体积 让健康的组织得以幸免。我们已经在体内的初步研究中证明了超声波激活的NB 与MBS相比，肿瘤的扰动导致了显著更大的肿瘤杀伤增强 传统的放射疗法。 这种方法可以显著改进现有的治疗方法，并减少相关的副作用。这在临床上很重要。 对于前列腺癌的治疗，附带损伤和非靶点效应是常见的，并会导致多年的并发症 在很多病人身上。因此，我们提出了一套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疗效。目标1将专注于开发稳定、统一大小的 辐射敏感型国家广播公司。将测量气泡的声学和生物活性，并在肿瘤中进行基线生物分布。 将进行结实小鼠。在目标2中，NBS将在小鼠前列腺模型上进行联合辐射测试 这样才能优化癌症的治疗参数。在与目标2同时进行的目标3中，我们将制定一个 监测早期治疗反应的光声成像方法。这个工具将被用来预测治疗 肿瘤治疗的有效性和完成性在治疗后2小时内。最后，在目标4中，我们将测试 大(兔)人前列腺癌原位模型的联合治疗。 我们已经组建了一个由多学科MPI调查人员组成的团队，并展示了协作工作的记录 在这个领域。该团队包括查尔诺塔博士/博士，他是一位内科科学家，也是最初的MB致敏剂的发现者 目前正在进行临床试验，迈克尔·科利奥斯博士是一位在光声方面拥有丰富经验的医学物理学家 治疗反应和超声物理学的成像和阿加塔·埃克斯纳博士，博士，生物医学工程师，广泛 在用于成像和治疗的纳米气泡的配方和实施方面的专业知识。团队成员正在积极地 合作，共享出版物、赠款和项目，以及向诊所进行技术转换的记录。该队 将确保及时完成拟议的研究并迅速将该方法转化为临床使用。

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.