Acute low back pain is one of the most common conditions for which patients seek medical care. Herniation of the intervertebral disc can cause substantial pain and ;​ disability through mechanical compression and biochemical irritation of the apposed neural structures. The resulting inflammation and associated immune-activation are shown to involve the proinflammatory cytokine tumor necrosis factor alpha (TNFα) and can be attenuated by systemic delivery of therapeutics blocking the activity of this mediator. While such treatment can provide clinical improvement in symptoms of pain and self-reported disability, patients are are exposed to systemic toxicities of immunosuppression. This motivates research into the local delivery of such disease modifying therapeutics to treat inflammatory nerve pathology. The elastin-like polypeptide (ELP) biopolymers are hydrophobic polypentapeptides that can undergo a reversible environmentally-triggered phase transition. This dissertation explored the feasibility of using ELP as a carrier for a TNFα binding protein, soluble TNF receptor type II (STNFRII), by creating a fusion protein with the bivalent functionalities of thermally-triggered depot formation and high-affinity TNFα-binding and consequent antagonist activity.

The ELP-STNFRII fusion protein was expressed from Escherichia coli and characterized in vitro to demonstrate activity of each constituent domain. Supramolecular complex formation was observed at subphysiologic temperatures, with further demonstration of slow resolubilization from the formed in vitro depot. Specific receptor domain association with the TNFα ligand was observed, with consequent antagonism of TNFα-mediated effects of cytotoxicity in immortalized fibrosarcoma cells and inflammatory stimulation in immortalized glial cells and dorsal root ganglion explant cultures.

Pharmacokinetic modeling of protein biodistribution suggested that the depot forming behavior of ELP could sustain protein presence following perineural delivery, and that the kinetics of fusion protein association with TNFα could provide for prolonged therapeutic antagonism. Subsequent in vivo biodistribution studies reaffirmed the prediction of target compartment longevity, with a seven-fold increase in protein residence time in the perineural compartment and lower peak serum concentrations for the depot-forming ELP than for a soluble protein of similar molecular weight.

Taken together, the results of this dissertation support the application of ELP technology to develop anticytokine therapeutics for delivery to the perineural space, with the goal of prolonging therapeutic activity against local inflammatory stimulation.