Transport of epidermal growth factor in the stroke-injured brain

Stroke is a neurological disorder that currently has no cure. Intrathecal delivery of growth factors, specifically recombinant human epidermal growth factor (rhEGF), stimulates endogenous neural precursor cells in the subventricular zone (SVZ) and promotes tissue regeneration in animal models of stroke. In this model, rhEGF is delivered with an invasive minipump/catheter system, which causes trauma to the brain. A less invasive strategy is to deliver rhEGF from the brain cortex; however, this requires the protein to diffuse through the brain, from the site of injection to the SVZ. Although this method of delivery has great potential, diffusion is limited by rapid removal from the extracellular space and hence for successful translation into the clinic strategies are needed to increase the diffusion distance. Using integrative optical imaging we investigate diffusion of rhEGF vs. poly(ethylene glycol)-modified rhEGF (PEG-rhEGF) in brain slices of both uninjured and stroke-injured animals. For the first time, we quantitatively show that PEG modification reduces the rate of growth factor elimination by over an order of magnitude. For rhEGF this corresponds to a two to threefold increase in predicted brain penetration distance, which we confirm with in vivo data. [Display omitted]