DDEL-16. Opening the blood-brain barrier with focused ultrasound for drug delivery: a meta-analysis of pharmacokinetic determinants

Abstract BACKGROUND Focused ultrasound mediated blood-brain barrier opening (FUS-BBBO) enables safe, local, reversible, and minimally invasive BBB-opening for improving drug delivery to brain tumors and other brain pathologies. However, determinants of FUS-BBBO-mediated drug delivery remain poorly understood, complicating clinical translation. We hypothesized that both drug-specific and biological system-related properties influence the magnitude and time course of FUS-BBBO-mediated drug delivery enhancement. METHODS We conducted a literature search to identify studies that (1) applied FUS-BBBO for therapeutic drug delivery to the brain and (2) reported a quantitative metric of local drug delivery enhancement in the brain by FUS-BBBO, termed the FUS-BBBO Amplification Ratio (FAR). Study-level mean FAR values were (a) correlated to physicochemical properties of the delivered drugs, (b) compared across different species as a proxy for biological system properties, and (c) analyzed over time for individual drugs. RESULTS More than 60 studies reported FUS-BBBO delivery of 37 different drugs across six species. Agents were administered in both healthy animals and patients and animals with nine neurological disorders, predominantly neuro-oncological, including (diffuse midline) high-grade gliomas and brain metastases. High molecular weight (HMW) drugs (>10 kDa) showed significantly higher FAR values than low molecular weight (LMW) drugs (< 1 kDa) (p<0.05). Among LMW drugs, poor intrinsic BBB penetration, as indicated by lower Central Nervous System Multiparameter Optimization scores, correlated with higher FAR values (p<0.05). FAR values did not significantly differ between species. Temporal FAR profiles revealed drug-specific patterns in delivery enhancement. CONCLUSION HMW drugs and poorly brain-penetrant LMW drugs benefit most from FUS-BBBO-mediated delivery. Drug-specific patterns in FAR time-courses suggest the importance of drug administration timing, relative to FUS, in optimizing therapy. The consistency of FAR across species supports translational robustness. These findings advocate for pharmacokinetics-informed drug selection and personalized delivery strategies in future preclinical and clinical FUS-BBBO-mediated drug delivery studies.