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Magnetic Enhancement of Stem Cell–Targeted Delivery into the Brain Following MR-Guided Focused Ultrasound for Opening the Blood–Brain Barrier
Focused ultrasound (FUS)-mediated blood–brain barrier disruption (BBBD) can enable even large therapeutics such as stem cells to enter the brain from the bloodstream. However, the efficiency is relatively low. Our previous study showed that human neural progenitor cells (hNPCs) loaded with superpara...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
SAGE Publications
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5657739/ https://www.ncbi.nlm.nih.gov/pubmed/28933214 http://dx.doi.org/10.1177/0963689717715824 |
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author | Shen, Wei-Bin Anastasiadis, Pavlos Nguyen, Ben Yarnell, Deborah Yarowsky, Paul J. Frenkel, Victor Fishman, Paul S. |
author_facet | Shen, Wei-Bin Anastasiadis, Pavlos Nguyen, Ben Yarnell, Deborah Yarowsky, Paul J. Frenkel, Victor Fishman, Paul S. |
author_sort | Shen, Wei-Bin |
collection | PubMed |
description | Focused ultrasound (FUS)-mediated blood–brain barrier disruption (BBBD) can enable even large therapeutics such as stem cells to enter the brain from the bloodstream. However, the efficiency is relatively low. Our previous study showed that human neural progenitor cells (hNPCs) loaded with superparamagnetic iron oxide nanoparticles (SPIONs) in culture were attracted by an external magnetic field. In vivo, enhanced brain retention was observed near a magnet mounted on the skull in a rat model of traumatic brain injury, where BBBD also occurs. The goal of the current study was to determine whether magnetic attraction of SPION-loaded hNPCs would also enhance their retention in the brain after FUS-mediated BBBD. A small animal magnetic resonance imaging (MRI)-guided FUS system operating at 1.5 MHz was used to treat rats (∼120 g) without tissue damage or hemorrhage. Evidence of successful BBBD was validated with both radiologic enhancement of gadolinium on postsonication TI MRI and whole brain section visualization of Evans blue dye. The procedure was then combined with the application of a powerful magnet to the head directly after intravenous injection of the hNPCs. Validation of cells within the brain was performed by staining with Perls’ Prussian blue for iron and by immunohistochemistry with a human-specific antigen. By injecting equal numbers of iron oxide (SPIONs) and noniron oxide nanoparticles–loaded hNPCs, each labeled with a different fluorophore, we found significantly greater numbers of SPIONs-loaded cells retained in the brain at the site of BBBD as compared to noniron loaded cells. This result was most pronounced in regions of the brain closest to the skull (dorsal cortex) in proximity to the magnet surface. A more powerful magnet and a Halbach magnetic array resulted in more effective retention of SPION-labeled cells in even deeper brain regions such as the striatum and ventral cortex. There, up to 90% of hNPCs observed contained SPIONs compared to 60% to 70% with the less powerful magnet. Fewer cells were observed at 24 h posttreatment compared to 2 h (primarily in the dorsal cortex). These results demonstrate that magnetic attraction can substantially enhance the retention of stem cells after FUS-mediated BBBD. This procedure could provide a safer and less invasive approach for delivering stem cells to the brain, compared to direct intracranial injections, substantially reducing the risk of bleeding and infection. |
format | Online Article Text |
id | pubmed-5657739 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | SAGE Publications |
record_format | MEDLINE/PubMed |
spelling | pubmed-56577392017-11-08 Magnetic Enhancement of Stem Cell–Targeted Delivery into the Brain Following MR-Guided Focused Ultrasound for Opening the Blood–Brain Barrier Shen, Wei-Bin Anastasiadis, Pavlos Nguyen, Ben Yarnell, Deborah Yarowsky, Paul J. Frenkel, Victor Fishman, Paul S. Cell Transplant Traumatic Brain Injury Focused ultrasound (FUS)-mediated blood–brain barrier disruption (BBBD) can enable even large therapeutics such as stem cells to enter the brain from the bloodstream. However, the efficiency is relatively low. Our previous study showed that human neural progenitor cells (hNPCs) loaded with superparamagnetic iron oxide nanoparticles (SPIONs) in culture were attracted by an external magnetic field. In vivo, enhanced brain retention was observed near a magnet mounted on the skull in a rat model of traumatic brain injury, where BBBD also occurs. The goal of the current study was to determine whether magnetic attraction of SPION-loaded hNPCs would also enhance their retention in the brain after FUS-mediated BBBD. A small animal magnetic resonance imaging (MRI)-guided FUS system operating at 1.5 MHz was used to treat rats (∼120 g) without tissue damage or hemorrhage. Evidence of successful BBBD was validated with both radiologic enhancement of gadolinium on postsonication TI MRI and whole brain section visualization of Evans blue dye. The procedure was then combined with the application of a powerful magnet to the head directly after intravenous injection of the hNPCs. Validation of cells within the brain was performed by staining with Perls’ Prussian blue for iron and by immunohistochemistry with a human-specific antigen. By injecting equal numbers of iron oxide (SPIONs) and noniron oxide nanoparticles–loaded hNPCs, each labeled with a different fluorophore, we found significantly greater numbers of SPIONs-loaded cells retained in the brain at the site of BBBD as compared to noniron loaded cells. This result was most pronounced in regions of the brain closest to the skull (dorsal cortex) in proximity to the magnet surface. A more powerful magnet and a Halbach magnetic array resulted in more effective retention of SPION-labeled cells in even deeper brain regions such as the striatum and ventral cortex. There, up to 90% of hNPCs observed contained SPIONs compared to 60% to 70% with the less powerful magnet. Fewer cells were observed at 24 h posttreatment compared to 2 h (primarily in the dorsal cortex). These results demonstrate that magnetic attraction can substantially enhance the retention of stem cells after FUS-mediated BBBD. This procedure could provide a safer and less invasive approach for delivering stem cells to the brain, compared to direct intracranial injections, substantially reducing the risk of bleeding and infection. SAGE Publications 2017-06-30 2017-07 /pmc/articles/PMC5657739/ /pubmed/28933214 http://dx.doi.org/10.1177/0963689717715824 Text en © The Author(s) 2017 http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). |
spellingShingle | Traumatic Brain Injury Shen, Wei-Bin Anastasiadis, Pavlos Nguyen, Ben Yarnell, Deborah Yarowsky, Paul J. Frenkel, Victor Fishman, Paul S. Magnetic Enhancement of Stem Cell–Targeted Delivery into the Brain Following MR-Guided Focused Ultrasound for Opening the Blood–Brain Barrier |
title | Magnetic Enhancement of Stem Cell–Targeted Delivery into the Brain Following MR-Guided Focused Ultrasound for Opening the Blood–Brain Barrier |
title_full | Magnetic Enhancement of Stem Cell–Targeted Delivery into the Brain Following MR-Guided Focused Ultrasound for Opening the Blood–Brain Barrier |
title_fullStr | Magnetic Enhancement of Stem Cell–Targeted Delivery into the Brain Following MR-Guided Focused Ultrasound for Opening the Blood–Brain Barrier |
title_full_unstemmed | Magnetic Enhancement of Stem Cell–Targeted Delivery into the Brain Following MR-Guided Focused Ultrasound for Opening the Blood–Brain Barrier |
title_short | Magnetic Enhancement of Stem Cell–Targeted Delivery into the Brain Following MR-Guided Focused Ultrasound for Opening the Blood–Brain Barrier |
title_sort | magnetic enhancement of stem cell–targeted delivery into the brain following mr-guided focused ultrasound for opening the blood–brain barrier |
topic | Traumatic Brain Injury |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5657739/ https://www.ncbi.nlm.nih.gov/pubmed/28933214 http://dx.doi.org/10.1177/0963689717715824 |
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