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Proc Natl Acad Sci U S A. 2018 Sep 11;115(37):E8717-E8726. doi: 10.1073/pnas.1807105115. Epub 2018 Aug 27.

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

Author information

1
School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332; costas.arvanitis@gatech.edu jain@steele.mgh.harvard.edu.
2
Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332.
3
Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
4
School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332.
5
Department of Chemical and Biological Engineering, Tufts University, Medford, MA 02155.
6
Centre for Medical Informatics, Usher Institute, University of Edinburgh, Edinburgh EH16 4UX, United Kingdom.
7
Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
8
Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114; costas.arvanitis@gatech.edu jain@steele.mgh.harvard.edu.

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 breast cancer brain metastases at cellular resolution: doxorubicin, a nontargeted 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 (sevenfold and twofold for doxorubicin and T-DM1, respectively), and we provide evidence of increased drug penetration (>100 vs. <20 µm and 42 ± 7 vs. 12 ± 4 µm for doxorubicin and T-DM1, respectively) after the application of FUS compared with 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. Experimental data demonstrate that FUS in combination with microbubbles enhances significantly the endothelial cell uptake of the small chemotherapeutic agent. Quantification with PBPK modeling reveals an increase in transmembrane transport by more than two orders of magnitude. PBPK modeling indicates a selective increase in transvascular transport of doxorubicin through small vessel wall pores with a narrow range of sizes (diameter, 10-50 nm). Our work provides a quantitative framework for the optimization of FUS-drug combinations to maximize intratumoral drug delivery and facilitate the development of strategies to treat brain metastases.

KEYWORDS:

blood–brain/blood–tumor barrier; brain tumor; drug transport; focused ultrasound; pharmacokinetics

PMID:
30150398
PMCID:
PMC6140479
[Available on 2019-03-11]
DOI:
10.1073/pnas.1807105115
[Indexed for MEDLINE]

Conflict of interest statement

Conflict of interest statement: R.K.J. received an honorarium from Amgen and consultant fees from Merck, Ophthotech, Pfizer, SPARC, SynDevRx, and XTuit; owns equity in Enlight, Ophthotech, SynDevRx, and XTuit; served on the Board of Directors of XTuit; and serves on the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, and Tekla World Healthcare Fund. Neither any reagent nor any funding from these organizations was used in this study.

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