title: A macrophage-nanozyme delivery system for Parkinson's disease.
abstract: Selective delivery of antioxidants to the substantia nigra pars compacta (SNpc) during Parkinson's disease (PD) can potentially attenuate oxidative stress and as such increase survival of dopaminergic neurons. To this end, we developed a bone-marrow-derived macrophage (BMM) system to deliver catalase to PD-affected brain regions in an animal model of human disease. To preclude BMM-mediated enzyme degradation, catalase was packaged into a block ionomer complex with a cationic block copolymer, polyethyleneimine-poly(ethylene glycol) (PEI-PEG). The self-assembled catalase/PEI-PEG complexes, "nanozymes", were ca. 60 to 100 nm in size, stable in pH and ionic strength, and retained antioxidant activities. Cytotoxicity was negligible over a range of physiologic nanozyme concentrations. Nanozyme particles were rapidly, 40-60 min, taken up by BMM, retained catalytic activity, and released in active form for greater than 24 h. In contrast, "naked" catalase was rapidly degraded. The released enzyme decomposed microglial hydrogen peroxide following nitrated alpha-synuclein or tumor necrosis factor alpha activation. Following adoptive transfer of nanozyme-loaded BMM to 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine-intoxicated mice, ca. 0.6% of the injected dose were found in brain. We conclude that cell-mediated delivery of nanozymes can reduce oxidative stress in laboratory and animal models of PD.
authors.affiliation: Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, Omaha, Nebraska, USA. ebatrako@unmc.edu
authors.forename: Elena V
authors.initials: EV
authors.lastname: Batrakova
authors.forename: Shu
authors.initials: S
authors.lastname: Li
authors.forename: Ashley D
authors.initials: AD
authors.lastname: Reynolds
authors.forename: R Lee
authors.initials: RL
authors.lastname: Mosley
authors.forename: Tatiana K
authors.initials: TK
authors.lastname: Bronich
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Kabanov
authors.forename: Howard E
authors.initials: HE
authors.lastname: Gendelman
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000032:analysis / Q000378:metabolism; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism*; D002374:Catalase / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods*; D006861:Hydrogen Peroxide / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000201:enzymology; D049329:Nanostructures / Q000737:chemistry*; D009474:Neurons / Q000378:metabolism*; D009994:Osmolar Concentration; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D011092:Polyethylene Glycols / Q000737:chemistry; D011094:Polyethyleneimine / Q000737:chemistry; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D000975:Antioxidants; D014409:Tumor Necrosis Factor-alpha; D051844:alpha-Synuclein; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D006861:Hydrogen Peroxide; D002374:Catalase