Toward real-time prediction and validation of ultrasonic hyperthermia profiles

描述（由申请人提供）：我们已经证明使用轻度热疗的超声药物释放是可行的。在这里，我们的目标是开发快速的方法来预测和验证轻度超声热疗加热的区域，开发将用于临床治疗计划的方法。在这种治疗方法中，注射温度敏感的药物递送颗粒，并允许其在感兴趣的区域内积累，通常超过6-24小时。然后超声波通过感兴趣的体积进行扫描，使局部温度在短时间内升高2-40摄氏度，释放药物并大大增加其局部浓度。为了实现这一目标，在初步工作中制订了下列组成部分：具有增强稳定性的可激活药物传递载体，集成在临床超声系统中的先进超声换能器，用于监测载体外壳和核心的正电子发射断层扫描（PET）和光学成像探针，跟踪颗粒和封装药物的方法，使用成像数据作为输入的药代动力学模型，以及靶向肿瘤细胞和肿瘤血管的脂质eg肽。应用我们的新基础设施，我们已经证明我们可以：将大量携带药物的颗粒靶向肿瘤（全身给药后每克注射剂量的23%），获得载体的高（高达33 dB）靶背景比图像，在感兴趣的区域内释放模型药物，同时对释放进行光学成像，并通过超声增强药物疗效。为了将这项技术转化为临床，必须生成用于治疗计划和验证的算法和软件。在这里，我们的具体目标是：首先，开发快速计算不同光束几何形状和扫描协议的有效场和温度分布的方法；其次，在仿真中验证场和温度曲线；第三，证明药物在植入肿瘤模型中的快速有效释放。利用位移和热应变的辐射力估计来估计梁的位置。公共卫生相关性：目前，美国每4例死亡中就有1例死于癌症。现有的预防和治疗方案受到各种药物毒性概况的限制。因此，为了提高药物治疗的疗效和降低药物治疗的毒性，人们已经投入了大量的努力来开发基于纳米技术的方法。超声波可以用于远程和选择性地从纳米颗粒中释放药物，甚至可以在组织深处释放药物。为了将超声给药转化为临床，我们在这里开发了预测和验证整个体积的超声强度和温度分布的方法。

DESCRIPTION (provided by applicant): We have demonstrated that ultrasonic drug release using mild hyperthermia is feasible. Here, our goal is to develop fast methods to predict and validate the region that is heated with mild ultrasound hyperthermia, developing methods that will be used in clinical treatment planning. In this treatment methodology, temperature sensitive drug delivery particles are injected and allowed to accumulate within a region of interest, typically over 6-24 hours. Ultrasound is then scanned through the volume of interest to locally increase the temperature by 2-40C for a short period, releasing a drug and greatly increasing its local concentration. In order to accomplish this goal, the following components have been developed in preliminary work: activatable drug delivery vehicles with enhanced stability, advanced ultrasound transducers integrated within a clinical ultrasound system, positron emission tomography (PET) and optical imaging probes to monitor the vehicle shell and core, methods to track particles and the encapsulated drug, a pharmacokinetic model using imaging data as the inputs, and lipoPEGpeptides targeted to tumor cells and tumor vasculature. Applying our new infrastructure, we have demonstrated that we can: target a significant fraction of drug-carrying particles to tumors (~up to 23% of the injected dose per gram following systemic administration), obtain a high (up to 33 dB) target to background ratio image of the vehicles, release model drugs within the region of interest while imaging the release optically, and enhance drug efficacy with ultrasound. In order to translate this technology into the clinic, algorithms and software for treatment planning and validation must be generated. Here, our specific aims are: first, develop fast methods to calculate the effective field and temperature distribution for varied beam geometries and scanning protocols; second, validate the field and temperature profiles in phantom; third, demonstrate rapid and effective drug release in implanted tumor models. Radiation force estimates of displacement and thermal strain are used to estimate the beam location. PUBLIC HEALTH RELEVANCE: Currently, one in 4 deaths in the United States is due to cancer. Available options for preemption and treatment are limited by the toxicity profiles of various drugs. As a result, substantial efforts have been directed to develop nanotechnology-based methods for increasing the efficacy and decreasing the toxicity of drug therapies. Ultrasound can be used to release a drug from a nanoparticle remotely and selectively, even within deep within tissues. In order to translate ultrasonic drug delivery into the clinic, here we develop methods to predict and validate ultrasound intensity and temperature profiles over an entire volume.