Bhattacharya, S. S. | Search bioRxiv

bioRxiv2021

A Nanoceutical Agent for Chemoprevention of Bilirubin Encephalopathy

BackgroundTargeted 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-Mn3O4 NP) having the ability to degrade bilirubin without photo-activation. MethodThe efficiency of C-Mn3O4 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. ResultsOral 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. ConclusionThus, we report preliminary studies that explore an affordable chemoprevention mechanism to acutely prevent or minimize bilirubin neurotoxicity in newborn infants. IMPACT STATEMENTO_LIDespite several attempts, no pharmaco-therapeutics are available for the treatment of severe neonatal hyperbilirubinemia (SNH) and associated neurotoxicity. C_LIO_LIOur newly developed nanodrug, citrate functionalized Mn3O4 nanoparticles (C-Mn3O4 NPs), can efficiently ameliorate SNH and associated neurotoxicity as investigated in preclinical rodent model. C_LIO_LIChemoprevention effect of the nanodrug is found to be safe and sustainable. C_LIO_LIIf successfully translated into clinical trials, C-Mn3O4 NPs could become the first drug to treat SNH. C_LI

pharmacology and toxicology↗

bioRxiv2020

Incorporation of a Biocompatible Nanozyme in Cellular Antioxidant Enzyme Cascade Reverses Huntington's Like Disorder in Preclinical Model

The potentiality of nano-enzymes in therapeutic use has directed contemporary research to develop a substitute for natural enzymes, which are suffering from several disadvantages including low stability, high cost, and difficulty in storage. However, inherent toxicity, inefficiency in the physiological milieu, and incompatibility to function in cellular enzyme networks limit the therapeutic use of nanozymes in living systems. Here, we have shown that citrate functionalized manganese-based biocompatible nanoscale material (C-Mn3O4 NP) efficiently mimics glutathione peroxidase enzyme in the physiological milieu and easily incorporates into the cellular multienzyme cascade for H2O2 scavenging. A detailed computational study reveals the mechanism of the nanozyme action. We further established the in vivo therapeutic efficacy of C-Mn3O4 nanozyme in a preclinical animal model of Huntingtons disease, a prevalent progressive neurodegenerative disorder, which has no effective medication till date. SUMMARYAlthough, nano-enzymes have shown lots of promises in the management of several diseases, two major concerns limit their clinical translation. Apart from the inherent toxicity of the constituent materials (e.g., cerium, vanadium, gold, etc.), activities of contemporary nanozymes are often inhibited in physiological milieu. Furthermore, most of them are incapable of incorporation into the cellular metabolic networks for functioning in tandem and parallel with natural enzymes, a major criteria for potential therapeutics. Here, we have shown that citrate-functionalized spherical Mn3O4 nanoparticles can efficiently mimic glutathione peroxidase (GPX) enzyme without the limitations of contemporary nanozymes, and effectively manage neurodegenerative Huntingtons disease in preclinical animal model. The choice of the material in the nanozyme lies on the fact that Mn is an essential micronutrient for mammals, and the stabilizing ligand citrate helps the nanoparticles to cross the blood-brain-barrier to reach brain. We have shown that the nanozyme can easily be incorporated in cellular antioxidant enzyme cascade. The specificity and efficacy of the nanozyme in the cascade was significantly higher compared to other reported nanozymes. We have justified our experimental findings with a detailed computational study. Understanding the mode of operation and management of Huntingtons disease in preclinical animal trial using a biocompatible (non-toxic) nanozyme as a part of the metabolic network may uncover a new paradigm in nanozyme based therapeutic strategy.

pharmacology and toxicology↗