Controlled Delivery and Release of Chemotherapy in Brain Tumors with FUS

描述(申请人提供)：恶性胶质瘤等脑肿瘤患者的治疗仍然是一个主要的医学问题。在动物身上的研究表明，带有微泡的聚焦超声(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提高药物的渗透性。这项技术使化疗药物的使用成为可能，例如阿霉素，如果有效地输送到肿瘤和周围组织，这些药物将对脑肿瘤产生细胞毒性。使用隐形脂质体或其他方法包裹药物可以增加药物循环次数和肿瘤内给药，同时减少全身副作用。这种胶囊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，进一步增加局部传递和渗透。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BBB/BTB中断，将脑瘤的渗漏增强到包裹阿霉素的低温敏感脂质体(LTS-脂质体)，目前阿霉素正处于肝癌和乳腺癌的临床试验中。然后，我们将使用相同的FUS设备来诱导轻微热疗，以控制阿霉素从其脂质体中的释放。在实现这一目标之前，我们需要制定新的战略来控制这一过程，并确保安全有效的结果。首先，我们将制定控制BBB/BTB中断的方法。我们有初步数据表明，这种控制可以使用被动超声检查来实现，这是一种既可以动态绘制声学检查过程中微泡发出的声发射图，又可以评估其频谱含量的方法。这种方法结合特定对象的数值模拟将被用来量化声发射，我们预计这将预测肿瘤渗透性增强和阿霉素摄取。下一步，我们将开发通过经颅FUS在大脑中安全地提供轻度热疗的方法。我们将使用数值模拟来研究策略，我们将通过实验进行验证，这种策略将允许在适合触发药物释放的持续时间和窄温度范围(41�C�1�C)进行焦点加热，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诱导效应的影响也是重要的。因此，我们将测量FUS诱导的血脑屏障破坏对肿瘤通透性和脂质体滞留的影响，量化FUS诱导的高温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够以一种剂量依赖的方式减少肿瘤生长并提高生存率。通过结合这些靶向药物输送和释放技术，我们将能够优化脑肿瘤的药物输送，同时将全身剂量降至最低。

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.