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BSCI-09. MECHANISMS OF ENHANCED DRUG DELIVERY IN BRAIN METASTASES WITH FOCUSED ULTRASOUND-INDUCED BLOOD-TUMOR BARRIER DISRUPTION

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-...

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Autores principales: Ferraro, Gino, Arvanitis, Costas, Askoxylakis, Vasileios, Guo, Yutong, Datta, Meenal, Bernabeu, Miguel, Fukumura, Dai, McDannold, Nathan, Jain, Rakesh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213188/
http://dx.doi.org/10.1093/noajnl/vdz014.007
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author Ferraro, Gino
Arvanitis, Costas
Askoxylakis, Vasileios
Guo, Yutong
Datta, Meenal
Bernabeu, Miguel
Fukumura, Dai
McDannold, Nathan
Jain, Rakesh
author_facet Ferraro, Gino
Arvanitis, Costas
Askoxylakis, Vasileios
Guo, Yutong
Datta, Meenal
Bernabeu, Miguel
Fukumura, Dai
McDannold, Nathan
Jain, Rakesh
author_sort Ferraro, Gino
collection PubMed
description 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: the non-targeted chemotherapeutic doxorubicin and the antibody-drug conjugate ado- trastuzumab emtansine (T-DM1). Using an orthotopic xenograft model of HER2-positive breast cancer brain metastasis and quantitative microscopy we demonstrate multifold 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 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 modelling indicates selective increase in transvascular transport of the non- targeted small chemotherapeutic 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 therapeutic strategies against brain metastases.
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spelling pubmed-72131882020-07-07 BSCI-09. MECHANISMS OF ENHANCED DRUG DELIVERY IN BRAIN METASTASES WITH FOCUSED ULTRASOUND-INDUCED BLOOD-TUMOR BARRIER DISRUPTION Ferraro, Gino Arvanitis, Costas Askoxylakis, Vasileios Guo, Yutong Datta, Meenal Bernabeu, Miguel Fukumura, Dai McDannold, Nathan Jain, Rakesh Neurooncol Adv Abstracts 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: the non-targeted chemotherapeutic doxorubicin and the antibody-drug conjugate ado- trastuzumab emtansine (T-DM1). Using an orthotopic xenograft model of HER2-positive breast cancer brain metastasis and quantitative microscopy we demonstrate multifold 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 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 modelling indicates selective increase in transvascular transport of the non- targeted small chemotherapeutic 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 therapeutic strategies against brain metastases. Oxford University Press 2019-08-12 /pmc/articles/PMC7213188/ http://dx.doi.org/10.1093/noajnl/vdz014.007 Text en © The Author(s) 2019. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Abstracts
Ferraro, Gino
Arvanitis, Costas
Askoxylakis, Vasileios
Guo, Yutong
Datta, Meenal
Bernabeu, Miguel
Fukumura, Dai
McDannold, Nathan
Jain, Rakesh
BSCI-09. MECHANISMS OF ENHANCED DRUG DELIVERY IN BRAIN METASTASES WITH FOCUSED ULTRASOUND-INDUCED BLOOD-TUMOR BARRIER DISRUPTION
title BSCI-09. MECHANISMS OF ENHANCED DRUG DELIVERY IN BRAIN METASTASES WITH FOCUSED ULTRASOUND-INDUCED BLOOD-TUMOR BARRIER DISRUPTION
title_full BSCI-09. MECHANISMS OF ENHANCED DRUG DELIVERY IN BRAIN METASTASES WITH FOCUSED ULTRASOUND-INDUCED BLOOD-TUMOR BARRIER DISRUPTION
title_fullStr BSCI-09. MECHANISMS OF ENHANCED DRUG DELIVERY IN BRAIN METASTASES WITH FOCUSED ULTRASOUND-INDUCED BLOOD-TUMOR BARRIER DISRUPTION
title_full_unstemmed BSCI-09. MECHANISMS OF ENHANCED DRUG DELIVERY IN BRAIN METASTASES WITH FOCUSED ULTRASOUND-INDUCED BLOOD-TUMOR BARRIER DISRUPTION
title_short BSCI-09. MECHANISMS OF ENHANCED DRUG DELIVERY IN BRAIN METASTASES WITH FOCUSED ULTRASOUND-INDUCED BLOOD-TUMOR BARRIER DISRUPTION
title_sort bsci-09. mechanisms of enhanced drug delivery in brain metastases with focused ultrasound-induced blood-tumor barrier disruption
topic Abstracts
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213188/
http://dx.doi.org/10.1093/noajnl/vdz014.007
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