Localized drug delivery using pH and temperature-responsive nanoparticles to treat brain injury in newborns

INTRODUCTION The interruption of oxygen and blood supply to the newborn brain around the time of birth is a risk factor for hypoxic-ischemic damage, leading to death or lifelong neurological impairments. Currently, therapeutic hypothermia is the only treatment to curb the extent of brain damage, though the effectiveness is limited. Anti-inflammatory drugs, such as dexamethasone, may inhibit the biochemical pathways of brain injury, but the challenge is to deliver drugs to the brain to avoid the side effects of systemic administration. We developed a novel drug delivery system using polypeptides that reversibly self-assemble into drug-loaded nanoparticles (<300 nm). As the nanoparticles release drugs in a manner dependent on temperature and pH, we take advantage of external head cooling and the distinctively acidic site of brain injury as cues for targeting the brain damage. METHODS AND RESULTS We use a neonatal rat model of hypoxic-ischemic brain damage for testing our drug delivery system. To effectuate selective brain hypothermia, we designed a "focal brain cooling chamber" for each rat pup, where each chamber consists of a syringe in which cooled water at 18°C was circulated through a coil of tubing fitted onto the rat's head. Furthermore, we identified the conditions under which nanoparticle formation with drug encapsulation occurs under physiological pH 7.4 and temperature, 37°C. We further identified the conditions under which nanoparticle formation with drug encapsulation occurs under physiological pH 7.4 and temperature, 37°C. The encapsulation efficiency was determined to be 1.3%. Littermates at postnatal day 7, both male and female, will be subjected to hypoxic-ischemic brain damage and then injected with dexamethasone-loaded nanoparticles and placed in cooling chambers to assess the combinatorial therapeutic effect of hypothermia with pharmacology. The nanoparticles are expected to release the drug at the injury site in response to change in temperature due to hypothermia and an acidotic pH environment. In addition to quantification of the released dexamethasone in the brain tissue using high-performance liquid chromatography, its pharmacological effect will be assessed by immunohistochemical staining of coronal brain sections for markers of apoptosis and microglial activation. CONCLUSION We anticipate that the drug delivery system will limit the extent of brain damage in the rat model and will open the possibility for clinical translation to improve survival and quality of life in infants with brain injury.