High-frequency ultrasound-guided intrathecal injections in a young mouse model: Targeting the central nervous system in drug delivery

Sun Eui Choi; Anum Rahman; Tiffany Ayoub; Owen Botelho; Gail Lee; Lisa M Gazdzinski; Anne L Wheeler; Rosanna Weksberg; Sharon L Guger; Russell J Schachar; Shinya Ito; Johann Hitzler; Brian J Nieman

doi:10.1016/j.jneumeth.2022.109778

High-frequency ultrasound-guided intrathecal injections in a young mouse model: Targeting the central nervous system in drug delivery

J Neurosci Methods. 2023 Feb 15:386:109778. doi: 10.1016/j.jneumeth.2022.109778. Epub 2022 Dec 23.

Authors

Affiliations

¹ Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada; Translational Medicine, Hospital for Sick Children Research Institute, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada. Electronic address: suneui.choi@sickkids.ca.
² Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada; Translational Medicine, Hospital for Sick Children Research Institute, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
³ Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada; Translational Medicine, Hospital for Sick Children Research Institute, Toronto, ON, Canada.
⁴ Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada; Neuroscience and Mental Health, Hospital for Sick Children Research Institute, Toronto, ON, Canada.
⁵ Neuroscience and Mental Health, Hospital for Sick Children Research Institute, Toronto, ON, Canada; Department of Physiology, University of Toronto, Toronto, ON, Canada.
⁶ Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada; Institutes of Medical Science, University of Toronto, Toronto, ON, Canada.
⁷ Department of Psychology, Hospital for Sick Children, Toronto, ON, Canada.
⁸ Institutes of Medical Science, University of Toronto, Toronto, ON, Canada; Psychiatry Research, Hospital for Sick Children, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, ON, Canada.
⁹ Translational Medicine, Hospital for Sick Children Research Institute, Toronto, ON, Canada; Clinical Pharmacology and Toxicology, Hospital for Sick Children, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
¹⁰ Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada; Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada.
¹¹ Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada; Translational Medicine, Hospital for Sick Children Research Institute, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Ontario Institute for Cancer Research, ON, Canada.

PMID: 36572156
DOI: 10.1016/j.jneumeth.2022.109778

Abstract

Background: Intrathecal injections provide important access to the central nervous system for delivery of anesthetic, analgesic or chemotherapeutic drugs that do not otherwise cross the blood-brain barrier. The administration of drugs via this route in animal models is challenging due to an inability to visualize the small target space during injection. Successful drug delivery therefore requires expertise in indirectly assessing vertebral and spinal cord anatomy and gaining advanced procedural skills. These factors are especially compounded in small animals such as mice (the most common mammalian model) and in investigations modeling pediatric drug delivery, where the animal is even smaller.

New method: To address these issues, we have developed a method in which high-frequency ultrasound imaging is used to visualize and target the lumbar intrathecal space for injections. The technique is demonstrated in mice as young as postnatal day 16. To evaluate the method, a gadolinium-based magnetic resonance imaging (MRI) contrast agent was injected intrathecally, and subsequent brain delivery was verified post-injection by MRI.

Results: Successful intrathecal injections of the MRI contrast agent showed distribution to the brain. In this study, we achieved a targeting success rate of 80% in 20 animals.

Comparison with existing methods and conclusion: We expect that the new method will be convenient for drug delivery to the central nervous system in rodent research and provide higher reliability than unguided approaches, an essential contribution that will enable intrathecal delivery in pediatric mouse models.

Keywords: Central nervous system; Drug delivery; Intrathecal; Magnetic resonance imaging; Mouse; Ultrasound.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Central Nervous System* / diagnostic imaging
Contrast Media*
Injections, Spinal
Mammals
Mice
Reproducibility of Results
Ultrasonography
Ultrasonography, Interventional

Substances

Contrast Media

Grants and funding

168925/CIHR/Canada