Dynamic dual-isotope molecular imaging elucidates principles for optimizing intrathecal drug delivery
Daniel A. Wolf, Jacob Y. Hesterman, Jenna M. Sullivan, Kelly D. Orcutt, Matthew D. Silva, Merryl Lobo, Tyler Wellman, Jack Hoppin, Ajay Verma
Daniel A. Wolf, Jacob Y. Hesterman, Jenna M. Sullivan, Kelly D. Orcutt, Matthew D. Silva, Merryl Lobo, Tyler Wellman, Jack Hoppin, Ajay Verma
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Resource and Technical Advance Neuroscience Therapeutics

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

Abstract

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.

Authors

Daniel A. Wolf, Jacob Y. Hesterman, Jenna M. Sullivan, Kelly D. Orcutt, Matthew D. Silva, Merryl Lobo, Tyler Wellman, Jack Hoppin, Ajay Verma

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Figure 4

Effect of bolus volume on rostral drug distribution following intrathecal lumbar administration.

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Effect of bolus volume on rostral drug distribution following intratheca...
(A) Single-photon emission tomography with X-ray computed tomography images from representative animals demonstrating 123I-labeled human serum albumin (123I-HSA) distribution along the rostrocaudal neuraxis following either a 10-μl or 50-μl bolus injection of roughly equivalent amounts of tracer. Note that, due to radioactive decay of 123I over time, images are all scaled differently in order to allow for easier visual interpretation. (B) A graphical depiction of the distribution of 123I-HSA, within a region of interest (ROI) representative of the intrathecal space, spread along the rostrocaudal neuraxis over time. The graphs represent average values from multiple animals (n = 4 for 10 μl infusion, n = 5 for 50 μl infusion). (C) Time-activity curves demonstrating 123I-HSA uptake in the cervical, thoracic, and lumbar regions of the spinal column over time and a depiction of ROIs used for these analyses. Data points represent the mean ± SD. *P < 0.05, **P < 0.01, unpaired 2-tailed Student’s t test. 2-way repeated-measures ANOVA analyses revealed significant differences in overall uptake of 123I-HSA into the cervical (P < 0.001), thoracic (P < 0.01), and lumbar (P < 0.0001) regions of interest (ROIs) over the time course of the experiment attributable to the difference in the volume of bolus administered between the two groups. Mean AUC values: (lumbar: 10 μl = 273, 50 μl = 168), (thoracic: 10 μl = 48.1, 50 μl = 56.3), (cervical: 10 μl = 11.5, 50 μl = 19.3).