Novel platform for MRI-guided convection-enhanced delivery of therapeutics: preclinical validation in nonhuman primate brain

Abstract

Background/aims: A skull-mounted aiming device and integrated software platform has been developed for MRI-guided neurological interventions. In anticipation of upcoming gene therapy clinical trials, we adapted this device for real-time convection-enhanced delivery of therapeutics via a custom-designed infusion cannula. The targeting accuracy of this delivery system and the performance of the infusion cannula were validated in nonhuman primates.

Methods: Infusions of gadoteridol were delivered to multiple brain targets and the targeting error was determined for each cannula placement. Cannula performance was assessed by analyzing gadoteridol distributions and by histological analysis of tissue damage.

Results: The average targeting error for all targets (n = 11) was 0.8 mm (95% CI = 0.14). For clinically relevant volumes, the distribution volume of gadoteridol increased as a linear function (R(2) = 0.97) of the infusion volume (average slope = 3.30, 95% CI = 0.2). No infusions in any target produced occlusion, cannula reflux or leakage from adjacent tracts, and no signs of unexpected tissue damage were observed.

Conclusions: This integrated delivery platform allows real-time convection-enhanced delivery to be performed with a high level of precision, predictability and safety. This approach may improve the success rate for clinical trials involving intracerebral drug delivery by direct infusion.

Fig. 1

Description of skull-mounted aiming device. a Basic components of the SmartFrame. b SmartFrame mounted on the left skull plug of a NHP, in a similar orientation to that depicted in a. The cannula (arrow) has been inserted through the fluid stem. A = Anterior; P = posterior; R = right; L = left.

Fig. 2

Sagittal screenshot of target trajectory alignment. The T1 MRI-visible fluid stem (arrowhead), which will hold the infusion cannula, has been aligned by translating the SmartFrame around a fixed pivot point (thick arrow) so that the trajectory (thin arrow) meets the target (red arrow, black in the printed version).

Fig. 3

Sequence for target trajectory alignment using ClearPoint software. a The selected target. b Pitch (orange/horizontal) and roll (blue/vertical) distances required for proper fluid stem alignment. Note that actual instructions for dialing-in these distances on the handheld controller are reported in a separate panel on the workstation. c The predicted error after pitch and roll adjustment, with the small distances remaining corrected by alignment in the X and Y planes. d Overlapping of the points indicated by arrows in b and c, indicating that the current trajectory matches the expected target trajectory. This trajectory is shown in the coronal plane in e and again following the infusion in f.

Fig. 4

Custom-designed infusion cannula. The distance between hash marks is 1 mm.

Fig. 5

Vd/Vi relationships. a Dependence of Vd on Vi for each individual infusion, with corresponding best-fit linear regression lines. b Variation of Vd/Vi with increasing infusion volumes, and corresponding best-fit thirdorder polynomial trend lines. • = Infusion 2; ▴ = infusion 5; ▪ = infusion 8; ♦ = infusion 11.

Fig. 6

Adjacent cannula trajectories in a single region. a An initial cannula trajectory (white arrows) and infusion in the subthalamic area. b The trajectory of the repositioned cannula (black arrows) and a large infusion in the thalamus that has encompassed the previous insertion tract (also visible in this plane, white arrows). No backflow through the initial insertion site is present.

Fig. 7

Lack of tissue damage in subcortical targets. Representative, alternating sections through a plane with 2 cannula tracts demonstrate minimal evidence for tissue damage in the thalamus or hippocampus, which were both targeted on the right side in this animal.