Abstract
Blood-brain/blood-tumor barriers (BBB and BTB) and interstitial transport may constitute major obstacles to the transport of therapeutics in brain tumors. In this study, we examined the impact of focused ultrasound (FUS) in combination with microbubbles on the transport of two relevant chemotherapy-based anticancer agents in HER2-positive breast cancer brain metastases at cellular resolution: doxorubicin, a non-targeted low molecular weight chemotherapeutic, and ado-trastuzumab emtansine (T-DM1), an antibody-drug conjugate. Using an orthotopic xenograft model of HER2-positive breast cancer brain metastasis and quantitative microscopy we demonstrate significant increases in the extravasation of both agents (7-fold and 2-fold for doxorubicin and T-DM1, respectively) and we provide evidence of increased drug penetration (>100µm vs. <20µm and 42 ± 7µm vs. 12 ± 4µm for doxorubicin and T-DM1, respectively) after application of FUS as compared to control (non-FUS). Integration of experimental data with physiologically based pharmacokinetic (PBPK) modeling of drug transport reveals that FUS in combination with microbubbles alleviates vascular barriers and enhances interstitial convective transport via an increase in hydraulic conductivity. Combination of experimental data and PBPK modeling suggests that FUS in combination with microbubbles increases the endothelial cell transmembrane transport and uptake. PBPK modeling indicates a selective increase in transvascular transport of doxorubicin through small vessel-wall pores size with a narrow range (Diameter: 10-50nm). Our work provides a quantitative framework for the optimization of FUS-drug combinations to maximize intratumoral drug delivery and facilitate the development of novel strategies to treat brain metastases.
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