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.
The use of chemotherapy for brain tumors has limited use because of poor delivery across the blood-brain and blood-tumor barriers and dose-limiting systemic effects. Focused ultrasound can be used to both disrupt these barriers and to induce local tissue heating. In this project, we will develop a novel therapeutic approach that brings together the therapeutic benefits of a) FUS-mediated blood-brain/blood-tumor barrier disruption and b) FUS-induced mild hyperthermia for controlled release of doxorubicin from thermally-sensitive liposomes to maximize drug delivery to malignant gliomas and surrounding tissues while maintaining a safe systemic dose.
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