An Elastomeric Polymer Matrix, PEUU-Tac, Delivers Bioactive Tacrolimus Transdurally to the CNS in Rat

Central nervous system (CNS) neurons fail to regrow injured axons, often resulting in permanently lost neurologic function. Tacrolimus is an FDA-approved immunosuppressive drug with known neuroprotective and neuroregenerative properties in the CNS. However, tacrolimus is typically administered systemically and blood levels required to effectively treat CNS injuries can lead to lethal, off-target organ toxicity. Thus, delivering tacrolimus locally to CNS tissues may provide therapeutic control over tacrolimus levels in CNS tissues while minimizing off-target toxicity. Herein we show an electrospun poly(ester urethane) urea and tacrolimus elastomeric matrix (PEUU-Tac) can deliver tacrolimus trans-durally to CNS tissues. In an acute CNS ischemia model in rat, the optic nerve (ON) was clamped for 10s and then PEUU-Tac was used as an ON wrap and sutured around the injury site. Tacrolimus was detected in PEUU-Tac wrapped ONs at 24 h and 14 days, without significant increases in tacrolimus blood levels. Similar to systemically administered tacrolimus, PEUU-Tac locally decreased glial fibrillary acidic protein (GFAP) at the injury site and increased growth associated protein-43 (GAP-43) expression in ischemic ONs from the globe to the chiasm, consistent with decreased astrogliosis and increased retinal ganglion cell (RGC) axon growth signaling pathways. These initial results suggest PEUU-Tac is a biocompatible elastic matrix that delivers bioactive tacrolimus trans-durally to CNS tissues without significantly increasing tacrolimus blood levels and off-target toxicity.