Controlled drug delivery and release in brain tumors with focused ultrasound

Several passive and active strategies based on different nanoparticle (NP) formulations have been proposed for improving drug delivery in brain tumors. Despite improved NP designs, drug accumulation in brain tumors remains very low. In this talk, we will present two different strategies to improve the penetration of therapeutic agents in brain tumors. The first uses transcranial focused ultrasound (FUS) in combination with microbubbles to overcome the vascular barriers of brain tumors. Our findings indicate that ultrasonically actuated microbubbles can increase the interstitial convective transport (Pe_non-FUS ≈ 0.1 to Pe_FUS ≈ 20), in addition to alleviating the vascular barriers, and improve the extravasation of fluorescently labeled NPs (∼40 nm in diameter) in healthy mice brain and mice brain tumor models. The second strategy employs transcranial MR guided focused ultrasound (MRgFUS) combined with low temperature sensitive liposomes loaded with doxorubicin (LTS-Dox ∼ 100 nm in diameter). Using an optimized MRgFUS system and closed-loop methods for controlled transcranial hyperthermia (∼10 min), we were able to significantly increase doxorubicin uptake in LTS-Dox + FUS group as compared to LTS-Dox and free Dox groups (<0.01) in mice brain tumor model. Our results demonstrate that these therapeutic strategies provide unique opportunities to improve the delivery of NPs and their cargo in the brain and brain tumor microenvironment.