(96a) Invited Talk: Nanotherapeutics for Neuroprotection in the Developing Brain

BACKGROUND: Neonatal brain injury is a major cause of morbidity and mortality in neonates. No therapy is currently curative. Therefore, more effective neuroprotective therapies are needed to improve neurological outcomes in newborns with brain injury. We aim to develop an effective neuroprotective treatment using enzyme or hydrophobic drug-loaded nanoparticles in the injured neonatal brain. We explore the therapeutic benefit of superoxide dismutase (SOD), catalase, and curcumin, broad-acting drugs that have antioxidant, anti-inflammatory, and anti-apoptotic effects, but low aqueous solubility, low stability, low bioavailability, and rapid first-pass hepatic metabolism. Polymeric nanoparticles are a useful tool to overcome these limitations, and can provide high drug encapsulation, sustained release, improved drug solubility and circulation kinetics.

METHODS: Protein or drug-loaded poly(lactic-co-glycolic acid) poly(ethylene glycol) (PLGA-PEG) nanoparticles were made, characterized, and evaluated for efficacy in the injured neonatal brain. SOD and catalase nanoparticles were applied to excitotoxic organotypic brain slices. Cell death and mRNA profiles following treatment were measured. Curcumin-PLGA-PEG particles (10 mg/kg curcumin) were administered intraperitoneally (i.p.) at 0.5h, 24h, and 48h after unilateral hypoxic ischemic injury in postnatal 7 (P7) rat pups. Control groups were saline, free curcumin (10 mg/kg dose), and blank nanoparticles. Brain, serum, and organs of interest were evaluated at 72h after HI for global pathology, histopathology, and neuropathology.

RESULTS: In neonatal brain injury models, PLGA-PEG nanoparticles uptake in the hippocampus, striatum, thalamus, and cortex, all regions of injury in the neonatal brain. SOD nanoparticles were able to halt excitotoxicity processes, decreasing oxidative stress and ongoing inflammation in injured brain slices compared to free drug controls. SOD outperformed catalase nanoparticles in this model. In HI pups, curcumin-PLGA-PEG nanoparticles reduce global and neuronal injury in the HI brain three days after systemic administration compared to all controls. We see no toxicity in the liver or kidney of curcumin-PLGA-PEG treated pups, and no particle uptake in healthy controls.

CONCLUSIONS: Strategies that provide better neuroprotection in the neonatal period can address the critical need for effective therapeutics for brain injury. We demonstrate the potential of nanotechnology-based neuroprotective therapies for neonatal brain injury, an area largely underserved by novel drug delivery technologies.