Quantification of Focused Ultrasound-Mediated Macromolecular Delivery to Brain Tumors with MRI

Brain metastases, which occur frequently in patients with advanced forms of certain cancers (e.g. breast, lung, melanoma), cause significantly higher patient mortality. Current standards of care include surgery and/or radiotherapy. However, surgical resection is not an option for disseminated and/or inaccessible metastases, and radiotherapy is dose-limited, sometimes ineffective, and linked to cognitive deterioration. Further, blood-borne therapeutics are usually ineffective for brain metastases because of the “blood-tumor barrier” (BTB). The BTB is caused by leaky and dysregulated tumor vasculature, which raises interstitial pressure and diminishes the delivery of convective transport-dependent agents (e.g. biologics). One strategy to enhance drug delivery to brain metastases entails “opening” the BTB by applying focused ultrasound (FUS) after the i.v. microbubble (MB) administration. This technology is advancing rapidly, but is also limited by our limited ability to measure, with high spatial precision, the resultant delivery of biologics to tumor microenvironment after FUS+MB treatment. Immuno-positron emission tomography (ImmunoPET) has sufficient sensitivity to make such measurements, but it does not have sufficient spatial resolution. On the other hand, T1 contrast MRI has excellent spatial resolution and reasonable sensitivity, but it typically entails the use of small molecular weight (~1 kDa) MRI contrast agents that do not model the delivery of larger biologics. Here, we will implement an innovative MRI approach that utilizes quantitative susceptibility mapping (QSM), and later combines it with dynamic contrast-enhanced (DCE) MRI, to provide both the sensitivity and spatial resolution necessary to fill key knowledge gaps. In preliminary studies, this method was able to quantitatively map, with excellent spatiotemporal precision, i.v.-injected model iron oxide nanoparticles (IONPs) as they were delivered to both healthy and tumor bearing brain tissue with FUS+MBs. Our proposal has 2 specific aims. Aim 1 will deploy QSM MRI to investigate whether absolute FUS+MB- mediated delivery of differentially-sized IONPs is affected by dysregulated brain tumor vasculature and microenvironment. We will determine both the magnitude of delivery and the homogeneity of model drug distribution throughout the tumor microenvironment when IONP hydrodynamic diameter is varied (13.5 – 32.2 nm) to cover the size range of common therapeutics. The results will be invaluable for determining dosing with respect to therapeutic size. Aim 2 will then deploy IONP-based DCE MRI to investigate the kinetics of BTB opening and closure with respect to therapeutic agent size. The kinetics of BBB closure after FUS+MBs are fairly well known; however, tumor endothelium is highly dysregulated, so we submit that BBB closure times cannot be extrapolated to the BTB in brain metastases. Achieving this better understanding of BTB closure will be instrumental in treatment plan development and enhancing the efficacy of FUS treatments in the clinic. Project Number: 1R21CA297838-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Richard Price (+1 co-PI) | Institution: UNIVERSITY OF VIRGINIA, CHARLOTTESVILLE, VA | Award Amount: $404,349 | Activity Code: R21 | Study Section: Imaging Guided Interventions and Surgery Study Section[IGIS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11299613