Pharmacokinetics and efficacy of a tunable curcumin-loaded polymeric nanoparticle for neonatal neuroprotection

Abstract

Newborns with neurological disorders are in particular need of therapeutic intervention, due to theimmaturity and rapid brain development in the perinatal period, which can increase risk of long-term neurodevelopmental disability. In many neurological disorders, including neonatal or perinatal brain injury, inflammation results in sustained activation of pro-inflammatory microglia that drives ongoing pathology and worse outcomes. This thesis research focused on using anti-inflammatory small molecules- loaded polymeric nanoparticles as potential neuroprotective agents for neonatal or perinatal brain disease and injury. Firstly, we quantified the pharmacokinetics (PK) and biodistribution of polymeric nanoparticles formulated using different surfactants as stabilizers, and investigated the effects of surfactants on PK profiles and biodistribution of polymeric nanoparticles in the term-equivalent rat. Our results show that the PK and biodistribution of polymeric nanoparticles can be adjusted by changing the surfactant. To increase the systemic half-life of polymeric nanoparticles and formulate nanoparticles with improved bioavailability, Pluronic F127 (F127) should be used as the stabilizer. Next, using F127 as the stabilizer, we investigated the effects of PLGA length, stabilizer concentration, polymer functionalization, and formulation method on curcumin loading. Upon successful optimization of a PLGA-PEG nanoparticle with high curcumin encapsulation efficiency and drug loading, we assessed particle PK and biodistribution in term pigs. To move into a clinical-trial ready model, we also assessed particle accumulation in the fetal growth restricted (FGR) piglet brain following different administration routes. We found curcumin-loaded nanoparticles were colocalized with microglia after intranasal administration, which demonstrated the potential of our polymeric nano-platform to be used as a microglia-targeting vehicle for hydrophobic molecules in perinatal brain injury. Finally, we used the curcumin-loaded nanoparticles with optimized curcumin loading and systemic circulation half-life to evaluate the neuroprotective effects in neonatal rats with brain injury at different developmental ages. The relationship between developmental age and neuroprotective effect of the nano-therapy was revealed: after a single dose of curcumin-loaded nanoparticles, neuroprotective effects were only observed in the acute period in late preterm-equivalent rats with hypoxic-ischemic (HI) brain injury, but not in term-equivalent or late- term equivalent rats with HI. Our results suggest that 1) neonatal dose determination should be based on developmental age, and 2) multiple doses of curcumin-loaded polymeric nanoparticles are needed for neonatal neuroprotection after HI.