Evaluation of the biodistribution and preliminary safety profile of a novel brain-targeted manganese dioxide-based nanotheranostic system for Alzheimer’s disease

Abstract

A novel brain-targeted and reactive oxygen species-activatable manganese dioxide containing nanoparticle system functionalized with anti-amyloid-β antibody (named aAβ-BTRA-NC) developed by our group has shown great promise as a highly selective magnetic resonance imaging (MRI) contrast agent for early detection and multitargeted disease-modifying treatment of Alzheimer’s disease (AD). To further evaluate the suitability of the formulation for future clinical application, we investigated the safety, biodistribution, and pharmacokinetic profile of aAβ-BTRA-NC in a transgenic TgCRND8 mouse AD model, wild type (WT) littermate, and CD-1 mice. Dose-ascending studies demonstrated that aAβ-BTRA-NC was well-tolerated by the animals up to 300 μmol Mn/kg body weight [b.w.], 3 times the efficacious dose for early AD detection without apparent adverse effects; Histopathological, hematological, and biochemical analyses indicated that a single dose of aAβ-BTRA-NC did not cause any toxicity in major organs. Immunotoxicity data showed that aAβ-BTRA-NC was safer than commercially available gadolinium-based MRI contrast agents at an equivalent dose of 100 μmol/kg b.w. of metal ions. Intravenously administered aAβ-BTRA-NC was taken up by main organs with the order of liver, kidneys, intestines, spleen, followed by other organs, and cleared after one day to one week post injection. Pharmacokinetic analysis indicated that the plasma concentration profile of aAβ-BTRA-NC followed a 2-compartmental model with faster clearance in the AD mice than in the WT mice. The results suggest that aAβ-BTRA-NC exhibits a strong safety profile as a nanotheranostic agent which warrants more robust preclinical development for future clinical applications.

Keywords:

• biosafety
• hybrid manganese dioxide nanoparticles
• theragnostic
• Alzheimer’s disease
• mouse model

Acknowledgments

The authors also thank the Centre for Collaborative Drug Research Graduate Student Incentive Fund to P.E.F. and X.Y.W for L.Y.L. We thank Dr. Jack Uetrecht’s lab especially Tiffany Cho and Alison Jee for toxicology support, Dr. Meegan Larson for the pathological analysis, Michael Parson and Mount Sinai Hospital for flow cytometry services, and The Centre for Phenogenomics for hematology and clinical biochemistry services.

Author contributions

L.Y. Li, E. Park, and X.Y. Wu conceived the hypotheses, designed the experiments, performed the experiments, interpreted results, and wrote and edited the manuscript. C. He and A.Z. Abbassi conceived the hypotheses, performed the experiments, interpreted results and edited the manuscript. P.E. Fraser performed the experiments related to generating the TgCRND8 mouse model. J.P. Uetrecht, J.T. Henderson, P.E. Fraser, A.M. Rauth edited the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work is supported by the Weston Brain Institute Transformational Grant (TR170044) to X.Y.W, J.T.H, and P.E.F, Natural Sciences and Engineering Research Council of Canada Equipment Grants (EQPEQ 440689-13) and Canada Council for the Arts Killam Research Fellowship (#7025-18-0051) to X.Y.W.