A Nanoceutical Agent for Chemoprevention of Bilirubin Encephalopathy

ABSTRACT Background Targeted degradation of bilirubin in vivo may enable safer and more effective approach to manage incipient bilirubin encephalopathy consequent to severe neonatal hyperbilirubinemia (SNH). This report builds on the use of a spinel structured mixed-valence transition metal oxide (trimanganese tetroxide) nanoparticle duly functionalized with biocompatible ligand citrate (C-Mn 3 O 4 NP) having the ability to degrade bilirubin without photo-activation. Method The efficiency of C-Mn 3 O 4 NP in in vivo degradation of serum bilirubin and amelioration of severe bilirubin encephalopathy and associated neurobehavioral changes was evaluated in C57BL/6j animal model of SNH. Results Oral single dose (0.25 mg kg -1 body weight) of the NPs efficiently reduced serum bilirubin levels (both conjugated and unconjugated) in study mice. It prevents bilirubin-induced neurotoxicity with reduction of SNH as observed by neurobehavioral and movement studies of SNH-mice. Pharmacokinetic data suggests intestinal reabsorption of the NPs and explain sustainable action. Biodistribution, pharmacokinetics, and biocompatibility of the NPs were tested during sub-chronic exposure. Conclusion Thus, we report preliminary studies that explore an affordable chemoprevention mechanism to acutely prevent or minimize bilirubin neurotoxicity in newborn infants. IMPACT STATEMENT Despite several attempts, no pharmaco-therapeutics are available for the treatment of severe neonatal hyperbilirubinemia (SNH) and associated neurotoxicity. Our newly developed nanodrug, citrate functionalized Mn 3 O 4 nanoparticles (C-Mn 3 O 4 NPs), can efficiently ameliorate SNH and associated neurotoxicity as investigated in preclinical rodent model. Chemoprevention effect of the nanodrug is found to be safe and sustainable. If successfully translated into clinical trials, C-Mn 3 O 4 NPs could become the first drug to treat SNH.