Controlled Delivery and Release of Chemotherapy in Brain Tumors with FUS

描述（由申请人提供）：恶性神经胶质瘤等脑肿瘤患者的治疗仍然是一个重大的医学问题。动物研究表明，带有微泡的聚焦超声（FUS）可以短暂地破坏血脑屏障（BBB）和血肿瘤屏障（BTB），为提高药物渗透提供了一种完全无创的方法。这项技术使化疗药物如阿霉素的使用成为可能，如果有效地将其输送到肿瘤和周围组织，将对脑肿瘤产生细胞毒性。使用隐形脂质体或其他方法进行药物包封可以增加药物循环时间和肿瘤内给药，同时减少全身副作用。这种包封也可以设计成通过温和的热或其他刺激释放药物内容物，进一步增加局部递送和渗透。在这里，我们建议将BBB/BTB中断和触发释放这两种技术结合起来。我们将通过fus诱导的血脑屏障/BTB破坏，增强脑肿瘤对包裹阿霉素的低温敏感脂质体（lts -脂质体）的“泄漏”，该脂质体目前正在肝脏和乳腺癌的临床试验中。然后，我们将使用相同的FUS装置诱导轻度热疗，以控制阿霉素从lts脂质体中的释放。在此之前，我们需要制定新的策略来控制手术过程，并确保安全有效的结果。首先，我们将开发控制BBB/BTB中断的方法。我们有初步的数据表明，这种控制可以通过被动超声来实现，这种方法既可以动态地绘制超声过程中微气泡发出的声发射，也可以评估其光谱含量。该方法与特定受试者的数值模拟相结合，将用于量化声发射，我们预计将预测增强的肿瘤通透性和阿霉素的摄取。接下来，我们将开发方法，以安全地提供经颅FUS在大脑轻度热疗。我们将研究使用数值模拟的策略，我们将实验验证，这将允许在持续时间和窄温度范围（41°C - 1°C）的局部加热，适合触发药物释放，同时防止对颅骨和邻近正常脑组织的不良影响。为了优化治疗，了解药物的药代动力学以及它们如何受到这些fus诱导效应的影响也很重要。因此，我们将测量FUS诱导的血脑屏障破坏对肿瘤通透性和lts脂质体潴留的影响，量化FUS诱导的热疗对阿霉素释放的影响，并评估阿霉素在脑肿瘤中的渗透。最后，在不同的剂量和时间方案下，我们将确定所提出的方法是否能以剂量依赖的方式减少肿瘤生长和增加生存。通过结合这些靶向药物传递和释放技术，我们将能够优化脑肿瘤的药物传递，同时最大限度地减少全身剂量。

DESCRIPTION (provided by applicant): The treatment of patients with brain tumors such as malignant glioma remains a major medical problem. Research in animals has shown that focused ultrasound (FUS) with microbubbles can transiently disrupt the blood-brain barrier (BBB) and the blood-tumor barrier (BTB), offering a completely noninvasive approach to improve drug penetration. This technique enables the use of chemotherapy agents such as doxorubicin that would be cytotoxic in brain tumors if effectively delivered to the tumor and surrounding tissue. Drug encapsulation using stealth liposomes or other methods can increase drug circulation times and intratumoral delivery while reducing systemic side effects. This encapsulation can also be designed to release the drug contents by mild heat or other stimuli, further increasing local delivery and penetration. Here, we propose to combine these two technologies, BBB/BTB disruption and triggered release. We will enhance brain tumor "leakiness" to low-temperature-sensitive liposomes (LTS-liposomes) encapsulating doxorubicin, currently in clinical trials for liver and breast cancer, via FUS-induced BBB/BTB disruption. We will then use the same FUS device to induce mild hyperthermia for controlled release of doxorubicin from the LTS-liposomes. Before this can be achieved, we need to develop new strategies to control the procedure and ensure a safe and effective result. First, we will develop methods to control the BBB/BTB disruption. We have preliminary data that suggest that this control can be achieved using passive ultrasonography, a method that can both dynamically map the acoustic emissions originating from microbubbles during sonications and assess their spectral content. This method combined with subject-specific numerical simulations will be used to quantify the acoustic emissions, which we expect will predict the enhanced tumor permeability and doxorubicin uptake. Next, we will develop methods to safely provide mild hyperthermia in the brain with transcranial FUS. We will investigate strategies using numerical simulations, which we will validate experimentally, that will permit focal heating at the duration and narrow temperature range (41�C �1�C) suitable for triggered drug release while preventing adverse effects in the skull and adjacent normal brain tissues. To optimize the treatment, it will also be important to understand the drug pharmacokinetics and how they are affected by these FUS-induced effects. Therefore, we will measure the impact of the FUS-induced BBB disruption to the tumor permeability and retention of the LTS-liposomes, quantify the impact of the FUS induced hyperthermia on the doxorubicin release, and assess doxorubicin penetration in brain tumor. Finally, under different dosing and timing schemes, we will determine if the proposed method can reduce tumor growth and increase survival in a dose-dependent manner. By combining these targeted drug delivery and release technologies, we will be able to optimize drug delivery to brain tumors while minimizing the systemic dose.