Implementation of a chronic unilateral intraparenchymal drug delivery system in a swine model

Abstract

Background Systemic delivery of pharmacologic agents has led to many significant advances in the treatment of neurologic and psychiatric conditions. However, this approach has several limitations, including difficulty penetrating the blood-brain barrier and enzymatic degradation prior to reaching its intended target. Here, we describe the testing of a system allowing intraparenchymal (IPa) infusion of therapeutic agents directly to the appropriate anatomical targets, in a swine model. New Method Five male pigs underwent 3.0 T magnetic resonance (MR) guided placement of an IPa catheter into the dorso-medial putamen, using a combined system of the Leksell Stereotactic Arc, a Mayo-developed MRI-compatible pig head frame, and a custom-designed Fred Haer Company (FHC) delivery system. Results Our results show hemi-lateral coverage of the pig putamen is achievable from a single infusion point and that the volume of the bolus detected in each animal is uniform (1544±420mm3). Comparison with Existing Method The IPa infusion system is designed to isolate the intracranial catheter from bodily-induced forces while delivering drugs and molecules into the brain tissue by convection-enhanced delivery, with minimal-to-no catheter track backflow. Conclusion This study presents an innovative IPa drug delivery system, which includes a sophisticated catheter and implantable pump designed to deliver drugs and various molecules in a precise and controlled manner with limited backflow. It also demonstrates the efficacy of the delivery system, which has the potential to radically impact the treatment of a wide range of neurologic conditions. Lastly, the swine model used here has certain advantages for translation into clinical applications.

The Relationship Between Dopamine Neurotransmitter Dynamics and the Blood-Oxygen-Level-Dependent (BOLD) Signal: A Review of Pharmacological Functional Magnetic Resonance Imaging

“…Administering receptor antagonists along the stimulated pathway enables the evaluation of receptor-specific effects on BOLD (Ross et al, 2016 ); (C) Circuit-specific drug effect. Popular in animal studies, brain circuit-specific intracranial drug injection (Wise and Hoffman, 1992 ; Kim et al, 2014 ) combined with fMRI, could open new possibilities for studying circuit-specific neurotransmitter (agonist) effects on BOLD by limiting the involvement of presynaptic dynamics.…”

“…Borland and Michael ( 2004 ) also showed a decrease of tonic DA release in the rat striatum by intrastriatal infusion of kynurenic acid, a broad-spectrum antagonist of the ionotropic glutamate receptors (Borland and Michael, 2004 ). There is also a recent report of chronic adaptation to an intracranial micro-infusion drug system that could be implanted through stereotactic surgery in the large animal brain (swine) (Kim et al, 2014 ). Micro-infusion-induced DA changes (i.e., through DA agonist) and related changes in the BOLD signal can be used together to identify brain site- and neurotransmitter-specific neuronal activity (see Figure 2C ).…”

“…The use of nanoparticles to more directly detect DA is a new approach on the horizon (Lee et al, 2014 ). Nanoparticle contrast agents that generate signals based on interactions with endogenously released DA have been introduced for MRI (Kim et al, 2014 ). The MRI intensity can be modulated based on magnetic field strength or certain properties of the reporter agent such as proton relaxivity and the chemical exchange saturation transfer effect.…”

Acute pressure changes in the brain are correlated with MR elastography stiffness measurements: initial feasibility in an in vivo large animal model

“…To simultaneously monitor and be able to intermittently increase ICP, silicon 1.5‐mm lumen pediatric catheters (BACTISEAL EVD, Codman, Raynham, Massachusetts, USA) were implanted in the left and right lateral ventricles of the animals using a procedure similar to that previously described for an intraparenchymal drug‐delivery system technique by MR image‐guided stereotactic targeting . Briefly, this technique involves three steps: 1) an MRI‐compatible stereotactic frame with a nine fiducial marker localizer box was mechanically attached with screws to the porcine skull; 2) a high‐resolution T 1 ‐weighted anatomical MRI of the pig brain with the stereotactic frame was acquired; 3) the DICOM image data was then transferred to a stereotactic planning computer for catheter projection planning.…”

The Challenge of Gene Therapy for Neurological Diseases: Strategies and Tools to Achieve Efficient Delivery to the Central Nervous System

“…However, this method still has constraints and limitations. For >10 years, considerable research has focused on developing methods to enhance drug delivery, 102 through dedicated intraparenchymal devices.…”