Intervertebral disc herniation involves both inflammatory cytokine expression and compression of the nerve roots that may contribute to a painful lumbar radiculopathy (sciatica). Much recent work has focused on use of tumor necrosis factor (TNF) antagonists to attenuate radiculopathy in animal models. A recent clinical trial of systemically administered TNF blocking antibody (infliximab) revealed no benefit, however, in reducing patient symptoms or restoring function in lumbar radiculopathy. Instead, epidural administration of a TNF receptor (etanercept) showed some therapeutic benefits in a limited cohort. This suggests potential for local delivery of antagonists of inflammatory mediators to attenuate the symptoms and neuropathology of radiculopathy. We have experience with injectable and in situ forming elastin-like polypeptide (ELP) depots that provide for sustained local drug release. Our studies show that injectable ELP depots persist in the perineural space ~8-fold longer than soluble proteins and decrease peak serum drug exposure by 14- fold. Here we propose to synthesize novel ELP-based depots to provide for sustained release of a safe, small molecule inhibitor of inflammation - curcumin. We propose that an injectable, in situ forming curcumin drug depot will provide for rapid reversal of symptoms and neuropathology associated with radiculopathy in a rat model, while providing for important benefits of reducing peak serum drug levels and total drug use.
In Aim 1, we will synthesize a depot-forming curcumin-ELP conjugate. Curcumin will be modified to include chemically reactive amines for reversible coupling to ELP. Depots formed from curcumin-ELP conjugates will be evaluated for release kinetics and bioactivity against TNF-induced neuroinflammation in cell systems and dorsal root ganglia in vitro.
In Aim 2, we will design an ELP depot optimized for entrapping curcumin, and evaluate curcumin-ELP depots as in Aim 1. In vitro tests of curcumin release from ELP depots and bioactivity will be performed as in Aim 1, and also compared against corresponding values for corticosteroid (triamcinolone acetonide) to test for therapeutic potential against the current standard-of-care.
In Aim 3, we will evaluate top curcumin-depot candidates for an ability to modify sensitivity and functional deficits in a rat model of radiculopathy. Shortly after placement of autologous nucleus pulposus at the lumbar dorsal root ganglion, rats develop mechanical allodynia and abnormal gait. Here, rats will be evaluated for parameters of gait, allodynia, and thermal hyperalgesia prior to and after transforaminal delivery of in situ forming curcumin-ELP depots;all data will be compared against values for curcumin or corticosteroid alone. These longitudinal gait and sensitivity measures, as well as spinal cord and ganglion markers of neuropathology, will be compared between no treatment, drug depot and bolus drug-treated rats to test for an ability for curcumin to modify radiculopathy and associated neuropathology.
This project will synthesize injectable and in situ-forming perineural depots that provide for sustained release of small molecule antagonists of inflammation in radiculopathy. Sustained release of a model small molecule, curcumin, will be studied and compared against findings for a bolus delivery of a standard-of-care corticosteroid, triamcinolone acetonide, to test for an ability of the drug depot to modify pain sensitivity and gait characteristics in a rat model of lumbar radiculopathy.
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