Augmented Blood-Tumor Barrier Permeability and Enhanced Doxorubicin Delivery in Rat Brain Tumor Models Through Additional Focused Ultrasound Stimulation

Focused ultrasound (FUS) has emerged as a promising technique for temporarily disrupting the blood-brain barrier (BBB) and blood-tumor barrier (BTB) to enhance the delivery of therapeutic agents. Despite its potential, optimizing FUS to maximize drug delivery while minimizing adverse effects remains a significant challenge. In this study, we evaluated a novel FUS protocol that incorporates additional FUS stimulation without microbubbles (MBs) ("FUS protocol") prior to conventional BBB disruption with MBs ("BBBD protocol") in a rat brain tumor model (n = 35). This approach aimed to validate its effectiveness in enhancing BBB/BTB disruption and facilitating doxorubicin delivery. T1-weighted contrast-enhanced and dynamic contrast-enhanced (DCE) MRI demonstrated significant increases in signal intensity and permeability (Ktrans) in the tumor region under the "FUS + BBBD protocol”, with 2.65-fold and 2.08-fold increases, respectively, compared to the non-sonicated contralateral region. These values were also elevated compared to the conventional "BBBD protocol" by 1.45-fold and 1.25-fold, respectively. Furthermore, doxorubicin delivery in the targeted region increased by 1.91-fold under the "FUS + BBBD protocol”, compared to a 1.44-fold increase using the conventional "BBBD protocol”. This novel FUS approach offers a promising, cost-effective strategy for enhancing drug delivery to brain tumors. While further studies are required to assess its applicability with different chemotherapeutics and tumor types, it holds significant potential for improving brain tumor treatment in both preclinical and clinical settings.