Aniruddha Adhikari1, Vinod K Bhutani2, Susmita Mondal1, Monojit Das3,4, Soumendra Darbar5, Ria Ghosh6, Nabarun Polley7, Anjan Kumar Das8, Siddhartha Sankar Bhattacharya3, Debasish Pal3, Asim Kumar Mallick9, Samir Kumar Pal10,11,12. 1. Department of Chemical, Biological and Macromolecular Sciences, S. N. Bose National Centre for Basic Sciences, Block JD, Sector 3, Salt Lake, Kolkata, 700106, India. 2. Department of Neonatal and Developmental Medicine, Lucile Packard Children's Hospital, Stanford University, 750 Welch Road, Palo Alto, CA, 94304, USA. 3. Department of Zoology, Uluberia College, University of Calcutta, Uluberia, Howrah, 711315, India. 4. Department of Zoology, Vidyasagar University, Rangamati, Midnapore, 721102, India. 5. Research and Development Division, Dey's Medical Stores (Mfg.) Pvt. Ltd., 62 Bondel Road, Ballygunge, Kolkata, 700019, India. 6. Technical Research Centre, S. N. Bose National Centre for Basic Sciences, Block JD, Sector 3, Salt Lake, Kolkata, 700106, India. 7. Physical Chemistry - innoFSPEC, University of Potsdam, Am Mühlenberg 3, Golm, 14476, Potsdam, Germany. 8. Department of Pathology, Coochbehar Govt. Medical College and Hospital, Silver Jubilee Road, Coochbehar, 736101, India. 9. Department of Pediatric Medicine, Nil Ratan Sirkar Medical College and Hospital, 138 AJC Bose Road, Sealdah, Rajabazar, Kolkata, 700014, India. 10. Department of Chemical, Biological and Macromolecular Sciences, S. N. Bose National Centre for Basic Sciences, Block JD, Sector 3, Salt Lake, Kolkata, 700106, India. skpal@bose.res.in. 11. Department of Zoology, Uluberia College, University of Calcutta, Uluberia, Howrah, 711315, India. skpal@bose.res.in. 12. Technical Research Centre, S. N. Bose National Centre for Basic Sciences, Block JD, Sector 3, Salt Lake, Kolkata, 700106, India. skpal@bose.res.in.
Abstract
BACKGROUND: Targeted rapid degradation of bilirubin has the potential to thwart incipient bilirubin encephalopathy. We investigated a novel spinel-structured citrate-functionalized trimanganese tetroxide nanoparticle (C-Mn3O4 NP, the nanodrug) to degrade both systemic and neural bilirubin loads. METHOD: Severe neonatal unconjugated hyperbilirubinemia (SNH) was induced in neonatal C57BL/6j mice model with phenylhydrazine (PHz) intoxication. Efficiency of the nanodrug on both in vivo bilirubin degradation and amelioration of bilirubin encephalopathy and associated neurobehavioral sequelae were evaluated. RESULTS: Single oral dose (0.25 mg kg-1 bodyweight) of the nanodrug reduced both total serum bilirubin (TSB) and unconjugated bilirubin (UCB) in SNH rodents. Significant (p < 0.0001) UCB and TSB-degradation rates were reported within 4-8 h at 1.84 ± 0.26 and 2.19 ± 0.31 mg dL-1 h-1, respectively. Neural bilirubin load was decreased by 5.6 nmol g-1 (p = 0.0002) along with improved measures of neurobehavior, neuromotor movements, learning, and memory. Histopathological studies confirm that the nanodrug prevented neural cell reduction in Purkinje and substantia nigra regions, eosinophilic neurons, spongiosis, and cell shrinkage in SNH brain parenchyma. Brain oxidative status was maintained in nanodrug-treated SNH cohort. Pharmacokinetic data corroborated the bilirubin degradation rate with plasma nanodrug concentrations. CONCLUSION: This study demonstrates the in vivo capacity of this novel nanodrug to reduce systemic and neural bilirubin load and reverse bilirubin-induced neurotoxicity. Further compilation of a drug-safety-dossier is warranted to translate this novel therapeutic chemopreventive approach to clinical settings. IMPACT: None of the current pharmacotherapeutics treat severe neonatal hyperbilirubinemia (SNH) to prevent risks of neurotoxicity. In this preclinical study, a newly investigated nano-formulation, citrate-functionalized Mn3O4 nanoparticles (C-Mn3O4 NPs), exhibits bilirubin reduction properties in rodents. Chemopreventive properties of this nano-formulation demonstrate an efficacious, efficient agent that appears to be safe in these early studies. Translation of C-Mn3O4 NPs to prospective preclinical and clinical trials in appropriate in vivo models should be explored as a potential novel pharmacotherapy for SNH.
BACKGROUND: Targeted rapid degradation of bilirubin has the potential to thwart incipient bilirubin encephalopathy. We investigated a novel spinel-structured citrate-functionalized trimanganese tetroxide nanoparticle (C-Mn3O4 NP, the nanodrug) to degrade both systemic and neural bilirubin loads. METHOD: Severe neonatal unconjugated hyperbilirubinemia (SNH) was induced in neonatal C57BL/6j mice model with phenylhydrazine (PHz) intoxication. Efficiency of the nanodrug on both in vivo bilirubin degradation and amelioration of bilirubin encephalopathy and associated neurobehavioral sequelae were evaluated. RESULTS: Single oral dose (0.25 mg kg-1 bodyweight) of the nanodrug reduced both total serum bilirubin (TSB) and unconjugated bilirubin (UCB) in SNH rodents. Significant (p < 0.0001) UCB and TSB-degradation rates were reported within 4-8 h at 1.84 ± 0.26 and 2.19 ± 0.31 mg dL-1 h-1, respectively. Neural bilirubin load was decreased by 5.6 nmol g-1 (p = 0.0002) along with improved measures of neurobehavior, neuromotor movements, learning, and memory. Histopathological studies confirm that the nanodrug prevented neural cell reduction in Purkinje and substantia nigra regions, eosinophilic neurons, spongiosis, and cell shrinkage in SNH brain parenchyma. Brain oxidative status was maintained in nanodrug-treated SNH cohort. Pharmacokinetic data corroborated the bilirubin degradation rate with plasma nanodrug concentrations. CONCLUSION: This study demonstrates the in vivo capacity of this novel nanodrug to reduce systemic and neural bilirubin load and reverse bilirubin-induced neurotoxicity. Further compilation of a drug-safety-dossier is warranted to translate this novel therapeutic chemopreventive approach to clinical settings. IMPACT: None of the current pharmacotherapeutics treat severe neonatal hyperbilirubinemia (SNH) to prevent risks of neurotoxicity. In this preclinical study, a newly investigated nano-formulation, citrate-functionalized Mn3O4 nanoparticles (C-Mn3O4 NPs), exhibits bilirubin reduction properties in rodents. Chemopreventive properties of this nano-formulation demonstrate an efficacious, efficient agent that appears to be safe in these early studies. Translation of C-Mn3O4 NPs to prospective preclinical and clinical trials in appropriate in vivo models should be explored as a potential novel pharmacotherapy for SNH.
Authors: Calum Kinnear; Thomas L Moore; Laura Rodriguez-Lorenzo; Barbara Rothen-Rutishauser; Alke Petri-Fink Journal: Chem Rev Date: 2017-09-01 Impact factor: 60.622
Authors: Vinod K Bhutani; Alvin Zipursky; Hannah Blencowe; Rajesh Khanna; Michael Sgro; Finn Ebbesen; Jennifer Bell; Rintaro Mori; Tina M Slusher; Nahed Fahmy; Vinod K Paul; Lizhong Du; Angela A Okolo; Maria-Fernanda de Almeida; Bolajoko O Olusanya; Praveen Kumar; Simon Cousens; Joy E Lawn Journal: Pediatr Res Date: 2013-12 Impact factor: 3.756