Targeting therapeutic nanoparticles to the glioblastoma resection margin by harnessing postoperative blood-brain barrier disruption.

Abstract

Resection surgery is the first-line therapy for high-grade glioma performed in >70% of patients with glioblastoma, typically within days of suspected diagnosis. Current protocols for follow-on chemoradiotherapy have shown only modest efficacy in eliminating residual disease, leading to inevitable tumor recurrence. There remains a need for approaches to swiftly and effectively treat postoperative residual disease to prevent the rapid early progression of glioblastoma. Using syngeneic preclinical mouse models of glioblastoma resection, we identified spatially and temporally restricted windows of blood-brain barrier disruption localized to the resection margin during the immediate (0 hours) and early (48 to 72 hours) postoperative periods. Intravenous administration of fluorescently labeled, clinically used liposomal nanoparticles during these periods revealed selective accumulation at the postoperative resection margin, with minimal penetration into other regions of the brain with an intact blood-brain barrier. Immunohistological analysis confirmed nanoparticle extravasation in the margin parenchyma, largely interacting with microglial and macrophage populations closely associated with residual tumor cells. Exploiting this, we performed intravenous administration of doxorubicin-loaded liposomes coinciding with the peaks of postoperative blood-brain barrier disruption and demonstrated both enhanced chemotherapy delivery to the brain and, consequently, inhibition of tumor recurrence from a single administration across two glioblastoma models. Overall, this work identifies therapeutically exploitable windows of postoperative blood-brain barrier disruption and demonstrates that appropriately coordinated timing can enable clinically used liposomal nanomedicines to be repurposed for early postoperative therapy in aggressive brain tumors.