Direct interstitial infusion of NK1-targeted neurotoxin into the spinal cord: a computational model

Abstract

Convection-enhanced delivery of substance P (SP) nocitoxins to the spinal cord interstitium is under consideration for the treatment of chronic pain. To characterize treatment protocols, a three-dimensional finite-element model of infusion into the human dorsal column was developed to predict the distribution of SP-diphtheria toxin fusion protein (SP-DT′) within normal and target tissue. The model incorporated anisotropic convective and diffusive transport through the interstitial space, hydrolysis by peptidases, and intracellular trafficking. For constant SP-DT′ infusion (0.1 μl/min), the distribution of cytotoxicity in NK1receptor-expressing neurons was predicted to reach an asymptotic limit at 6–8 h in the transverse direction at the level of the infusion cannula tip (∼60% ablation of target neurons in lamina I/II). Computations revealed that SP-DT′ treatment was favored by a stable SP analog (half-life ∼60 min), high infusate concentration (385 nM), and careful catheter placement (adjacent to target lamina I/II). Sensitivity of cytotoxic regions to NK1receptor density and white matter protease activity was also established. These data suggest that intraparenchymal infusions can be useful for treatment of localized chronic pain.