Enhancement of tumor radiation response by ultrasound-driven nanobubble stimulation

项目摘要 放射治疗是癌症治疗的主要手段，但挑战依然存在。拟议研究的长期目标是 通过包括涉及扰动血管的预治疗步骤来改变传统的癌症放射治疗方案， 和肿瘤的细胞功能与超声激活的放射增敏纳米泡（NB）。癌症的新范式 治疗方案建立在十年前的工作，使用商业微泡（MB），以引起放射增敏 效果MB的放射增敏作用主要是血管内的，引起显著的内皮损伤。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， 将导致除了血管损伤之外，对癌细胞的直接损伤显著增加。因此， 将是血管内和血管外的。以这种方式治疗的肿瘤将对辐射产生更好的反应，降低有效的放射性。 放射剂量和减少残余存活肿瘤。该技术还允许靶向肿瘤特异性体积 使健康的组织得以保留。我们已经在体内初步研究中证明，超声激活的NB 与MB相比，肿瘤的扰动导致肿瘤杀伤的显著更大增强， 传统的放射治疗。 这种方法可以显着改善现有的治疗方法，并减少相关的副作用。这在临床上很重要 对于前列腺癌治疗，其中附带损伤和脱靶效应是常见的，并导致多年的并发症 在许多患者中。因此，我们提出了一套四个具体目标，以测试，开发，优化，演示和量化 这种新技术在前列腺癌中的疗效。目标1将专注于开发稳定、大小一致的 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。 将进行荷瘤小鼠。在目标2中，将在前列腺增生的小鼠模型中测试NB与辐射的组合。 癌症，从而可以优化治疗参数。在目标3中，与目标2同时进行，我们将制定一个 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 肿瘤治疗的有效性和完整性在治疗后2小时内就可以得到确认。最后，在目标4中，我们将测试 在人前列腺癌的大（兔）原位模型中，使用组合方法。 我们已经组建了一个多学科的MPI调查团队，该团队具有合作工作的良好记录 在该领域该团队包括Czarnota博士，他是一位物理学家兼科学家，也是最初的MB致敏作用的发现者， 迈克尔·科利奥斯博士（Michael Kolios Ph.D.）是一位医学物理学家， 成像治疗反应和超声物理学和Agata Exner博士，博士，生物医学工程师， 在成像和治疗的纳米气泡的制定和实施的专业知识。团队成员积极 合作，共享出版物，赠款和项目，以及向诊所翻译技术的记录。球队 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.