Dynamic dual-isotope molecular imaging elucidates principles for optimizing intrathecal drug delivery

The intrathecal (IT) dosing route offers a seemingly obvious solution for delivering drugs directly to the central nervous system. However, gaps in understanding drug molecule behavior within the anatomically and kinetically unique environment of the mammalian IT space have impeded the establishment...

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Bibliographic Details
Published in:JCI insight 2016-02, Vol.1 (2), p.e85311-e85311
Main Authors: Wolf, Daniel A, Hesterman, Jacob Y, Sullivan, Jenna M, Orcutt, Kelly D, Silva, Matthew D, Lobo, Merryl, Wellman, Tyler, Hoppin, Jack, Verma, Ajay
Format: Article
Language:English
Subjects:
Animals
Central Nervous System - diagnostic imaging
Cerebrospinal Fluid
Drug Delivery Systems
Humans
Injections, Spinal
Isotopes
Magnetic Resonance Imaging
Molecular Imaging
Positron-Emission Tomography
Rats
Rats, Sprague-Dawley
Serum Albumin, Human
Technical Advance
Tomography, Emission-Computed, Single-Photon
Tomography, X-Ray Computed
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Summary:The intrathecal (IT) dosing route offers a seemingly obvious solution for delivering drugs directly to the central nervous system. However, gaps in understanding drug molecule behavior within the anatomically and kinetically unique environment of the mammalian IT space have impeded the establishment of pharmacokinetic principles for optimizing regional drug exposure along the neuraxis. Here, we have utilized high-resolution single-photon emission tomography with X-ray computed tomography to study the behavior of multiple molecular imaging tracers following an IT bolus injection, with supporting histology, autoradiography, block-face tomography, and MRI. Using simultaneous dual-isotope imaging, we demonstrate that the regional CNS tissue exposure of molecules with varying chemical properties is affected by IT space anatomy, cerebrospinal fluid (CSF) dynamics, CSF clearance routes, and the location and volume of the injected bolus. These imaging approaches can be used across species to optimize the safety and efficacy of IT drug therapy for neurological disorders.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.85311