Glioblastoma (GBM) is the most prevalent and aggressive primary brain tumor in adults, characterized by rapid proliferation and invasive infiltration into normal brain tissue. Despite maximal resection and temozolomide (TMZ) chemotherapy, over 80% of GBM cases recur near the resection margin, highlighting the need for improved therapeutic strategies. The blood–brain barrier (BBB) remains a major obstacle to effective drug delivery, limiting TMZ penetration into infiltrative tumor regions. This study explores the potential of focused ultrasound (FUS) to transiently open the BBB, optimizing TMZ delivery to GBM-infiltrated brain regions before tumor neovascularization, and investigates its impact on tumor progression and survival in an orthotopic xenograft mouse model. Human primary GBM tumorspheres (TS15-88) were implanted into the striatum of 4- to 8-week-old male athymic nude mice to establish an orthotopic xenograft model. FUS was applied 1 week post-implantation, followed by intraperitoneal TMZ administration. BBB permeability was assessed using Evans blue extravasation, gadolinium-enhanced T1-weighted magnetic resonance imaging (MRI), and ZO-1 tight junction protein expression. GBM infiltration into the brain was confirmed using ZEB-1 and hematoxylin and eosin staining. Bioluminescence imaging and Kaplan–Meier survival analysis were used to evaluate the therapeutic effects of combined FUS and TMZ treatment. MRI and Evans blue staining confirmed that BBB integrity was preserved in the tumor-only group, suggesting that tumor-induced neovascularization had not yet developed at the time of treatment. However, FUS-mediated BBB opening significantly enhanced Evans blue extravasation and reduced ZO-1 expression, indicating transient and localized BBB disruption. FUS-TMZ combination therapy significantly suppressed tumor growth, as evidenced by bioluminescence imaging, and prolonged survival compared to that with TMZ alone. Additionally, applying FUS in the early treatment phase (1-day group) showed a trend toward better tumor suppression and survival outcomes compared to that at later time points. Our findings suggest that integrating FUS with standard TMZ chemotherapy during the early treatment phase may enhance drug penetration into infiltrative tumor regions, leading to improved tumor control and survival outcomes. These results highlight the clinical potential of FUS as an adjunct therapy to optimize TMZ efficacy, particularly in patients with early-stage GBM.
Shin et al. (Mon,) studied this question.
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