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主要的医学问题。动物研究表明，具有微泡的聚焦超声（FUS）可以瞬时破坏血脑屏障（BBB）和血肿瘤屏障（BTB），提供了一种完全非侵入性的方法来改善药物渗透。该技术使得能够使用化疗剂，如阿霉素，如果有效地递送到肿瘤和周围组织，则其在脑肿瘤中具有细胞毒性。使用隐形脂质体或其他方法的药物包封可以增加药物循环时间和肿瘤内递送，同时减少全身副作用。这种封装也可以设计成通过温和的加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，我们建议结合这两种技术，BBB/BTB中断和触发释放联合收割机。我们将通过FUS诱导的BBB/BTB破坏，增强脑肿瘤对低温敏感脂质体（LTS-脂质体）的“泄漏”，该脂质体封装了阿霉素，目前正在进行肝癌和乳腺癌的临床试验。然后，我们将使用相同的FUS装置诱导轻度高温，以从LTS-脂质体中控制释放多柔比星。在实现这一目标之前，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，这种控制可以实现使用被动超声检查，一种方法，可以动态映射的声发射过程中从微泡和评估其频谱内容。这种方法结合特定对象的数值模拟将被用来量化的声发射，我们预计将预测增强的肿瘤渗透性和阿霉素的摄取。接下来，我们将开发出安全地通过经颅FUS在大脑中提供轻度高温的方法。我们将使用数值模拟研究策略，我们将通过实验验证，这将允许在适合触发药物释放的持续时间和窄温度范围（41 ℃ 1 ℃）内进行局部加热，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BBB破坏对肿瘤渗透性和LTS-脂质体保留的影响，量化FUS诱导的热疗对多柔比星释放的影响，并评估多柔比星在脑肿瘤中的渗透。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可以以剂量依赖性方式减少肿瘤生长并增加存活率。通过结合这些靶向药物递送和释放技术，我们将能够优化药物向脑肿瘤的递送，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.