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EBioMedicine. 2017 Dec;26:47-59. doi: 10.1016/j.ebiom.2017.11.017. Epub 2017 Nov 24.

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

Author information

1
Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA, United States; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States.
2
Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA, United States; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States.
3
McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States.
4
McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States; Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, United States.
5
Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, United States.
6
McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States; Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, United States.
7
McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States; Departments of Surgery, Ophthalmology and Bioengineering, Wake Forest School of Medicine, Wake Forest Institute of Regenerative Medicine, Winston Salem, NC, United States.
8
McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States; Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, United States; Department of Pathology, University of Pittsburgh, Pittsburgh, PA, United States.
9
McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States; Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA, United States; VA Pittsburgh Healthcare System, Pittsburgh, PA, United States.
10
McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States.
11
Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA, United States; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, United States; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States; Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, United States. Electronic address: SteketeeM@UPMC.edu.

Abstract

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 24h and 14days, 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.

KEYWORDS:

Axon regeneration; CNS; FK506; Optic nerve; Retinal ganglion cell; Tacrolimus

PMID:
29208469
PMCID:
PMC5832622
DOI:
10.1016/j.ebiom.2017.11.017
[Indexed for MEDLINE]
Free PMC Article

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