Macrophage Delivery of Therapeutic Nanozymes in A Murine Model of Parkinson‘S Disease

Abstract

Background: Parkinson‘s disease is a common progressive neurodegenerative disorder associated with profound nigrostriatal degeneration. Regrettably, no therapies are currently available that can attenuate disease progression. To this end, we developed a cell-based nanoformulation delivery system using the antioxidant enzyme catalase to attenuate neuroinflammatory processes linked to neuronal death. Methods: Nanoformulated catalase was obtained by coupling catalase to a synthetic polyelectrolyte of opposite charge, leading to the formation of a polyion complex micelle. The nanozyme was loaded into bone marrow macrophages and its transport to the substantia nigra pars compacta was evaluated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice. Results: Therapeutic efficacy of bone marrow macrophages loaded with nanozyme was confirmed by twofold reductions in microgliosis as measured by CD11b expression. A twofold increase in tyrosine hydroxylase-expressing dopaminergic neurons was detected in nanozyme-treated compared with untreated MPTP-intoxicated mice. Neuronal survival was confirmed by magnetic resonance spectroscopic imaging. Bone marrow macrophage-loaded catalase showed sustained release of the enzyme in plasma. Conclusion: These data support the importance of macrophage-based nanozyme carriage for Parkinson‘s disease therapies.

Keywords::

• blood–brain barrier
• catalase
• cell-mediated drug delivery
• neuroinflammation
• Parkinson‘s disease

Supplementary Material

Financial & competing interests disclosure

This study was supported by the NIH grants 1RO1 NS057748 (EVB), 2R01 NS034239 (HEG), 2R37 NS36126 (HEG), P01 NS31492 (HEG), P20RR 15635 (HEG), P01 MH64570 (HEG), P01 NS43985 (HEG), and RR021937 (AVK). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Acknowledgements

We are grateful to Anita Jennings (Molecular Phenotyping Core Facility, UNMC) for her invaluable help and opinion with histochemical analysis; Janice A Taylor and James R Talaska (Confocal Laser Scanning Microscope Core Facility, UNMC) for providing assistance with confocal microscopy and the Nebraska Research Initiative and the Eppley Cancer Center for their support of the Core Facility; and Ashley Reynolds for her expert advices in data analysis. The authors would also like to thank Pfizer-Wyeth Pharmaceutical (Cambridge, MA), for their generous gift of macrophage colony-stimulating factor.

Additional information

Funding

This study was supported by the NIH grants 1RO1 NS057748 (EVB), 2R01 NS034239 (HEG), 2R37 NS36126 (HEG), P01 NS31492 (HEG), P20RR 15635 (HEG), P01 MH64570 (HEG), P01 NS43985 (HEG), and RR021937 (AVK). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.