Back to 2017 Annual Meeting Program
In Vivo FK506 Transport from a Novel Local Delivery System in Rats
Kasra Tajdaran, MASc; Molly Shoichet, PhD; Tessa Gordon, PhD; Gregory H Borschel, MD
The Hospital for Sick Children, Toronto, ON, Canada
Purpose: Administration of FK506, an FDA approved immunosuppressant, has shown to enhance nerve regeneration following peripheral nerve injuries. However, the severe side effects of the systemically delivered FK506 has prevented clinicians from using this drug routinely. Therefore, we have developed a novel fibrin gel based local delivery system for FK506. In this study, for the first time, we analyzed FK506 transport to the surrounding tissues and the nervous system, in vivo, from the local delivery system placed at the nerve injury site.
Methods: FK506 was incorporated into fibrin gel in solubilized, particulated and poly(lactic-co-glycolic) acid (PLGA) microspheres-encapsulated forms. A nerve transection model was used in which the rat common peroneal nerve was immediately coapted after transection. Three experimental groups received the three forms of the FK506 delivery system. Rats in a negative control group did not receive any delivery system. Using mass spectrometry, FK506 tissue concentrations were analyzed at the site of the injury, in sciatic nerve, dorsal root ganglia (DRGs), spinal cord, brain, heart, liver, kidney, and plasma at 7, 14, and 28 days post repair.
Results: The duration of FK506 release was the shortest in the solubilized form for 7-days, then the particulate form for 14-days. The most prolonged release period was seen with the PLGA microsphere-encapsulated form for 28-days. FK506 was detectable within the injured sciatic nerve, DRGs (L4, L5), the entire spinal cord, and the muscles surrounding the nerve repair site, decreasing in concentration over time. The highest FK506 tissue concentration was detected within the entire spinal cord at day 7 regardless of the delivery system formulation. Kidney tissues had low FK506 levels only during the first week in the solubilized FK506 treated rats. No FK506 was detected in plasma, brain, liver, and heart during the study period in all rats. Twenty-eight days post repair, all rats had below the detectable level of FK506 in the examined tissues, except at the site of nerve injury and the surrounding muscles. Most importantly, the treated rats did not show any side effects during the entire study.
Conclusions: We have demonstrated effective release of FK506 from the novel fibrin gel based delivery system in vivo. For the first time, this study shows the in vivo transport of the locally released FK506. The findings from this study are necessary to engineer a local FK506 delivery system that provides the optimal concentration of the drug within the targeted tissues.
Back to 2017 Annual Meeting Program