PI’s: Ravi Bellamkonda, Barunashish Brahma, Jack L. Arbiser
Spinal cord injury (SCI) is a debilitating condition, usually resulting in lifelong, irreversible paralysis. More than 1400 children afflicted with SCI are admitted to US hospitals annually. Damage to the spinal cord causes acute physical injury, which is followed by secondary inflammatory biochemical events. While the extent of the initial physical injury cannot be controlled, secondary injury can be attenuated by timely administration of anti-inflammatory agents. Systemic administration of high-dose anti-inflammatory drug, methylprednisolone (MP), has been the centerpiece of clinical therapy post-SCI; although, this treatment has been controversial due to its potent side effects. While site specific delivery is possible in transection injuries via local injection, in the clinically more common contusion injuries, local injections are not possible and it would be highly desirable to combine systemic injection with site specific localization if possible. Additionally, while MP is a potent anti-inflammatory agent, it has the deleterious effect of increasing pernicious reactive oxygen species (ROS) at the site of injury, potentially counter-productively exacerbating secondary injury after SCI .
Therefore the ability to develop therapies that would enhance local action after contusion injuries to the cord, and have a biological action superior to MP would have a significant impact on the management of SCI in children.
The blood-spinal cord barrier (BSB) usually serves as a major impediment to systemic delivery of anti-inflammatory agents to the contused cord. However, the BSB‟s permeability state following SCI is unknown although when open it provides a window of opportunity to successfully deliver drugs/nanocarriers across the BSB. The Bellamkonda laboratory has expertise in fabricating drug loaded nanocarriers that can take advantage of this increased permeability, specifically target inflammation sites and tumors, while additionally, enhancing contrast in magnetic resonance imaging (MRI). This allows for site specific, low dose drug delivery, coupled with non-invasive MRI tracking. Additionally, the Bellamkonda laboratory, in collaboration with Jack Arbiser at Emory University, has identified a novel anti-inflammatory agent, Imipramine Blue (IB), which may inhibit both inflammation as well as ROS exacerbated secondary injury after SCI, by virtue of being a NOX4 and nuclear factor kB (NFκB) inhibitor. (NFκB) and NOX-4 are pro-inflammatory factors, implicated in the upregulation of ROS in SCI.
Thus, the two goals of this study are to (1) accurately characterize the BSB permeability using contrast enhancing nanocarriers, in a rat model of contusion SCI; and (2) fabricate and characterize IB- and MP-nanocarriers and compare in vivo efficacy of IB- Vs. MP-nanocarriers. Successful culmination of this work could lead to a drastic improvement in SCI management clinically and the quality of life of children with SCI. Our team consists of Dr. Barun Brahma, a pediatric neurosurgeon with Children‟s Healthcare of Atlanta, Professor Ravi Bellamkonda, a Georgia Cancer Coalition Distinguished Scholar and Director of the Neurological Biomaterials and Cancer Therapeutics Laboratory in the Georgia Tech/Emory Department of Biomedical Engineering, Jack Arbiser a talented chemist and clinician at Emory (The Arbiser lab synthesized the novel compound imipramine blue) and Dr. Tarun Saxena, a postdoctoral fellow in the Bellamkonda laboratory with relevant surgery and nanocarrier fabrication experience.