title: Local delivery of minocycline from metal ion-assisted self-assembled complexes promotes neuroprotection and functional recovery after spinal cord injury.
abstract: Many mechanisms contribute to the secondary injury cascades following traumatic spinal cord injury (SCI). However, most current treatment strategies only target one or a few elements in the injury cascades, and have been largely unsuccessful in clinical trials. Minocycline hydrochloride (MH) is a clinically available antibiotic and anti-inflammatory drug that has been shown to target a broad range of secondary injury mechanisms via its anti-inflammatory, anti-oxidant, and anti-apoptotic properties. However, MH is only neuroprotective at high concentrations. The inability to translate the high doses of MH used in experimental animals to tolerable doses in human patients limits its clinical efficacy. In addition, the duration of MH treatment is limited because long-term systemic administration of high doses of MH has been shown to cause liver toxicity and even death. We have developed a drug delivery system in the form of hydrogel loaded with polysaccharide-MH complexes self-assembled by metal ions for controlled release of MH. This drug delivery system can be injected into the intrathecal space for local delivery of MH with sufficient dose and duration, without causing any additional tissue damage. We show that local delivery of MH at a dose that is lower than the standard human dose (3 mg/kg) was more effective in reducing secondary injury and promoting locomotor functional recovery than systemic injection of MH with the highest dose and duration reported in experimental animal SCI (90-135 mg/kg).
authors.affiliation: School of Biomedical Engineering, Science and Health Systems, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104, USA.
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: School of Biomedical Engineering, Science and Health Systems, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Nong
authors.affiliation: School of Biomedical Engineering, Science and Health Systems, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Shultz
authors.affiliation: School of Biomedical Engineering, Science and Health Systems, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104, USA.
authors.forename: Zhiling
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Spinal Cord Research Center, Department of Neurobiology & Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
authors.forename: Taegyo
authors.initials: T
authors.lastname: Kim
authors.affiliation: Spinal Cord Research Center, Department of Neurobiology & Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
authors.forename: Veronica J
authors.initials: VJ
authors.lastname: Tom
authors.affiliation: Department of Orthopaedic Surgery, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Ponnappan
authors.affiliation: School of Biomedical Engineering, Science and Health Systems, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104, USA. Electronic address: yz348@drexel.edu.
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Zhong
mesh_terms: D000818:Animals; D003460:Crystallization / Q000379:methods; D004343:Drug Implants / Q000008:administration & dosage* / Q000737:chemistry; D005260:Female; D020100:Hydrogels / Q000737:chemistry; D007477:Ions; D053768:Metal Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D008911:Minocycline / Q000008:administration & dosage* / Q000737:chemistry; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry / Q000648:ultrastructure; D009416:Nerve Regeneration / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects*; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D016896:Treatment Outcome
chemical_list: D004343:Drug Implants; D020100:Hydrogels; D007477:Ions; D053769:Nanocapsules; D018696:Neuroprotective Agents; D008911:Minocycline
keywords: Drug delivery; Inflammation; Minocycline; Neuroprotection; Secondary injury; Spinal cord injury