Traumatic spinal cord injury (SCI) causes partial or complete loss of sensory, motor, and autonomic functions below the injury site. Currently, there are no effective treatments for SCI. The overall goal of this study is to develop an effective therapeutic strategy to reduce secondary injury, and improve functional recovery after SCI. Many mechanisms and molecules contribute to secondary injury. However, current treatment strategies are highly specific, targeting only one or a few elements in the injury cascades, and have been largely unsuccessful in clinical trials. Minocycline is a highly promising therapeutic intervention for SCI because it has been shown to target a broad range of secondary injury mechanisms, and protect neural tissue from multiple neurotoxic insults after SCI, via its anti-inflammatory, anti-oxidant, and anti-apoptotic properties. A number of studies have shown that systemic administration of MH reduces secondary injury and improves functional recovery in various animal models of SCI. However, the inability to translate the high doses (45-90 mg/kg) of MH used in experimental animals to tolerable doses (3-6 mg/kg) in human patients limits the clinical application of this medication for SCI treatment. In addition, the duration of MH treatment is limited because long term systemic administration of high doses of MH has been shown to cause serious side effects and morbidity. Thus local drug delivery can potentially expose the injured spinal cord tissue to high concentrations of MH that systemic administration cannot achieve, while avoiding the deleterious side effects associated with systemic exposure. However, current drug delivery systems are not ideal for local delivery of bioactive MH with sufficient dose and duration because MH is a small molecule with high water solubility and unstable in aqueous solution. Based on a new drug delivery mechanism discovered in the PI's laboratory, novel MH-containing particles with high drug loading efficiency were developed for local delivery of high dose, bioactive MH for an extended period of time. Further, injectable hydrogels were used for particle encapsulation and local administration. The particle-loaded hydrogels can be injected into the intrathecal space of the injured spinal cord for local drug delivery at the injury site. The dose and duration of MH release can be controlled by initial loading and gel formulation. The drug delivery system is made from biocompatible, biodegradable polysaccharides ensuring the safety of clinical applications. Preliminary data shows that released minocycline retained neuroprotective and anti-inflammatory activities. In this study, we aim to 1) develop a drug delivery system with an in vivo release profile that matches the progression of secondary injury for optimum treatment effect;and 2) evaluate the efficacy of this drug delivery system to reduce secondary injury and improve functional recovery in a rat contusion SCI model. Successful completion of these Aims will facilitate future clinical application of MH treatment in spinal cord injury, as well as a variety of other debilitating neurological disorders and injuries where MH has demonstrated remarkable therapeutic potential.
Patients with spinal cord injury suffer lifelong disability and require continuous physical and medical care. The research described in this proposal utilizes a novel drug delivery system for local delivery minocycline with sufficient dose and duration to reduce secondary injury and promote functional recovery.