Transient and Efficient Vascular Permeability Window for Adjuvant Drug Delivery Triggered by Microbeam Radiation
Background: Microbeam Radiation Therapy (MRT) induces a transient vascular permeability window, which offers a novel drug-delivery system for the preferential accumulation of therapeutic compounds in tumors. MRT is a preclinical cancer treatment modality that spatially fractionates synchrotron X-ray...
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MDPI AG
2021-04-01
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author | Sara Sabatasso Cristian Fernandez-Palomo Ruslan Hlushchuk Jennifer Fazzari Stefan Tschanz Paolo Pellicioli Michael Krisch Jean A. Laissue Valentin Djonov |
author_facet | Sara Sabatasso Cristian Fernandez-Palomo Ruslan Hlushchuk Jennifer Fazzari Stefan Tschanz Paolo Pellicioli Michael Krisch Jean A. Laissue Valentin Djonov |
author_sort | Sara Sabatasso |
collection | DOAJ |
description | Background: Microbeam Radiation Therapy (MRT) induces a transient vascular permeability window, which offers a novel drug-delivery system for the preferential accumulation of therapeutic compounds in tumors. MRT is a preclinical cancer treatment modality that spatially fractionates synchrotron X-rays into micrometer-wide planar microbeams which can induce transient vascular permeability, especially in the immature tumor vessels, without compromising vascular perfusion. Here, we characterized this phenomenon using Chicken Chorioallantoic Membrane (CAM) and demonstrated its therapeutic potential in human glioblastoma xenografts in mice. Methods: the developing CAM was exposed to planar-microbeams of 75 Gy peak dose with Synchrotron X-rays. Similarly, mice harboring human glioblastoma xenografts were exposed to peak microbeam doses of 150 Gy, followed by treatment with Cisplatin. Tumor progression was documented by Magnetic Resonance Imaging (MRI) and caliper measurements. Results: CAM exposed to MRT exhibited vascular permeability, beginning 15 min post-irradiation, reaching its peak from 45 min to 2 h, and ending by 4 h. We have deemed this period the “permeability window”. Morphological analysis showed partially fragmented endothelial walls as the cause of the increased transport of FITC-Dextran into the surrounding tissue and the extravasation of 100 nm microspheres (representing the upper range of nanoparticles). In the human glioblastoma xenografts, MRI measurements showed that the combined treatment dramatically reduced the tumor size by 2.75-fold and 5.25-fold, respectively, compared to MRT or Cisplatin alone. Conclusions: MRT provides a novel mechanism for drug delivery by increasing vascular transpermeability while preserving vessel integrity. This permeability window increases the therapeutic index of currently available chemotherapeutics and could be combined with other therapeutic agents such as Nanoparticles/Antibodies/etc. |
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language | English |
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spelling | doaj.art-946a46ed2da64d37a0803ffee79efd422023-11-21T17:21:29ZengMDPI AGCancers2072-66942021-04-01139210310.3390/cancers13092103Transient and Efficient Vascular Permeability Window for Adjuvant Drug Delivery Triggered by Microbeam RadiationSara Sabatasso0Cristian Fernandez-Palomo1Ruslan Hlushchuk2Jennifer Fazzari3Stefan Tschanz4Paolo Pellicioli5Michael Krisch6Jean A. Laissue7Valentin Djonov8Institute of Anatomy, University of Bern, 3012 Bern, SwitzerlandInstitute of Anatomy, University of Bern, 3012 Bern, SwitzerlandInstitute of Anatomy, University of Bern, 3012 Bern, SwitzerlandInstitute of Anatomy, University of Bern, 3012 Bern, SwitzerlandInstitute of Anatomy, University of Bern, 3012 Bern, SwitzerlandBiomedical Beamline ID17, European Synchrotron Radiation Facility, 38043 Grenoble, FranceBiomedical Beamline ID17, European Synchrotron Radiation Facility, 38043 Grenoble, FranceInstitute of Anatomy, University of Bern, 3012 Bern, SwitzerlandInstitute of Anatomy, University of Bern, 3012 Bern, SwitzerlandBackground: Microbeam Radiation Therapy (MRT) induces a transient vascular permeability window, which offers a novel drug-delivery system for the preferential accumulation of therapeutic compounds in tumors. MRT is a preclinical cancer treatment modality that spatially fractionates synchrotron X-rays into micrometer-wide planar microbeams which can induce transient vascular permeability, especially in the immature tumor vessels, without compromising vascular perfusion. Here, we characterized this phenomenon using Chicken Chorioallantoic Membrane (CAM) and demonstrated its therapeutic potential in human glioblastoma xenografts in mice. Methods: the developing CAM was exposed to planar-microbeams of 75 Gy peak dose with Synchrotron X-rays. Similarly, mice harboring human glioblastoma xenografts were exposed to peak microbeam doses of 150 Gy, followed by treatment with Cisplatin. Tumor progression was documented by Magnetic Resonance Imaging (MRI) and caliper measurements. Results: CAM exposed to MRT exhibited vascular permeability, beginning 15 min post-irradiation, reaching its peak from 45 min to 2 h, and ending by 4 h. We have deemed this period the “permeability window”. Morphological analysis showed partially fragmented endothelial walls as the cause of the increased transport of FITC-Dextran into the surrounding tissue and the extravasation of 100 nm microspheres (representing the upper range of nanoparticles). In the human glioblastoma xenografts, MRI measurements showed that the combined treatment dramatically reduced the tumor size by 2.75-fold and 5.25-fold, respectively, compared to MRT or Cisplatin alone. Conclusions: MRT provides a novel mechanism for drug delivery by increasing vascular transpermeability while preserving vessel integrity. This permeability window increases the therapeutic index of currently available chemotherapeutics and could be combined with other therapeutic agents such as Nanoparticles/Antibodies/etc.https://www.mdpi.com/2072-6694/13/9/2103vascular permeabilitydrug delivery systemmicrobeam radiation therapy (MRT)Chicken Chorioallantoic Membrane (CAM)U-87 Glioblastoma |
spellingShingle | Sara Sabatasso Cristian Fernandez-Palomo Ruslan Hlushchuk Jennifer Fazzari Stefan Tschanz Paolo Pellicioli Michael Krisch Jean A. Laissue Valentin Djonov Transient and Efficient Vascular Permeability Window for Adjuvant Drug Delivery Triggered by Microbeam Radiation Cancers vascular permeability drug delivery system microbeam radiation therapy (MRT) Chicken Chorioallantoic Membrane (CAM) U-87 Glioblastoma |
title | Transient and Efficient Vascular Permeability Window for Adjuvant Drug Delivery Triggered by Microbeam Radiation |
title_full | Transient and Efficient Vascular Permeability Window for Adjuvant Drug Delivery Triggered by Microbeam Radiation |
title_fullStr | Transient and Efficient Vascular Permeability Window for Adjuvant Drug Delivery Triggered by Microbeam Radiation |
title_full_unstemmed | Transient and Efficient Vascular Permeability Window for Adjuvant Drug Delivery Triggered by Microbeam Radiation |
title_short | Transient and Efficient Vascular Permeability Window for Adjuvant Drug Delivery Triggered by Microbeam Radiation |
title_sort | transient and efficient vascular permeability window for adjuvant drug delivery triggered by microbeam radiation |
topic | vascular permeability drug delivery system microbeam radiation therapy (MRT) Chicken Chorioallantoic Membrane (CAM) U-87 Glioblastoma |
url | https://www.mdpi.com/2072-6694/13/9/2103 |
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