Mechanisms of enhanced drug delivery in brain metastases with focused ultrasound-induced blood-tumor barrier disruption.

摘要: Blood-brain/blood-tumor barriers (BBB and BTB) interstitial transport may constitute major obstacles to the of therapeutics in brain tumors. In this study, we examined impact focused ultrasound (FUS) combination with microbubbles on two relevant chemotherapy-based anticancer agents breast cancer metastases at cellular resolution: doxorubicin, a nontargeted chemotherapeutic, ado-trastuzumab emtansine (T-DM1), an antibody-drug conjugate. Using orthotopic xenograft model HER2-positive metastasis quantitative microscopy, demonstrate significant increases extravasation both (sevenfold twofold for doxorubicin T-DM1, respectively), provide evidence increased drug penetration (>100 vs. <20 µm 42 ± 7 12 4 respectively) after application FUS compared control (non-FUS). Integration experimental data physiologically based pharmacokinetic (PBPK) modeling reveals that alleviates vascular enhances convective via increase hydraulic conductivity. Experimental significantly endothelial cell uptake small chemotherapeutic agent. Quantification PBPK transmembrane by more than orders magnitude. indicates selective transvascular through vessel wall pores narrow range sizes (diameter, 10-50 nm). Our work provides framework optimization FUS-drug combinations maximize intratumoral delivery facilitate development strategies treat metastases.