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Dataset Description
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Background Focused ultrasound (FUS)-mediated disruption of the blood-brain (BBB) and blood-tumor (BTB) barriers augments drug delivery to the central nervous system; however, relationships between therapeutic dose, size, and delivery to both healthy and tumor tissue with FUS remain poorly defined. Current MRI-based quantification techniques have limited utility for defining such relationships due to insufficient sensitivity offered by macromolecular-sized contrast agents. Purpose To evaluate quantitative susceptibility mapping (QSM) for measuring iron oxide nanoparticle delivery following FUS-mediated BBB/BTB disruption and investigate size-dependent delivery in both healthy murine brain tissue and gliomas. Materials and Methods FUS-mediated BBB/BTB disruption was performed on C57BL/6 mice, either naïve or GL261 tumor-bearing, using albumin-shelled microbubbles. FUS was applied using a standard feedback control approach based on subharmonic and ultraharmonic acoustic emissions levels. Four differentially-sized MRI contrast agents were delivered: 2.3, 13.5, 20.1 and 32.2 nm. Multi-Echo GRE images, taken before and after FUS, were converted to susceptibility maps with the morphology enabled dipole inversion method, and susceptibility differences were converted to agent concentrations. Brain tumor measurements were conducted for the 2.3 and 32.2 nm contrast agents. Results FUS-mediated delivery to the naïve murine brain showed a surprising size-dependence. Delivery initially increases between 2.3 and 13.5 nm before decreasing between 20.1 – 32.2 nm. FUS enhanced brain tumor delivery by 1.50-fold (2.3 nm, p<0.001) and 4.09-fold (32.2 nm, p<0.0001). For identical FUS parameters, absolute delivery to GL261 brain tumors was greater than (2.3 nm) or the same (32.2 nm) as delivery to naïve brain. Conclusions QSM is capable of quantifying the FUS-mediated delivery of differentially-sized model therapeutics to naïve brain and brain tumors. FUS-mediated delivery of therapeutics to naïve brain initially increases between 2.3 and 13.5 nm before decreasing after ~20 nm. Dysregulated glioma vasculature and microenvironment may have an unexpectedly limited influence on total delivery of macromolecules. (2025-05-25)
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