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 BMMmediated 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 alphasynuclein 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.

Nanotechnology platforms in Parkinson’s Disease

“…Hence, it is possible to use macrophages as drug carriers for the delivery of various therapeutic payloads [96]. Batrakova et al delivered catalase using bone-marrow-derived macrophage (BMM) systems to PD-affected brain regions in an animal model [97]. The self-assembled catalase/polymer complexes referred to as nanozymes that were 60-100 nm in size were taken up by the BMMs and showed sustained release for about 24 hours as compared to immediate degradation of the free enzyme [97].…”

“…Batrakova et al delivered catalase using bone-marrow-derived macrophage (BMM) systems to PD-affected brain regions in an animal model [97]. The self-assembled catalase/polymer complexes referred to as nanozymes that were 60-100 nm in size were taken up by the BMMs and showed sustained release for about 24 hours as compared to immediate degradation of the free enzyme [97]. This had implications in decomposition of microglial hydrogen peroxide that could reduce oxidative stress in PD.…”

Cells As Delivery Vehicles for Cancer Therapeutics

“…[89] Peritoneal macrophages have also been used to deliver liposomal doxorubicin to both subcutaneous and metastatic models of lung carcinoma [90]. Batrakova and colleagues have reported that macrophages can be loaded ex vivo with a self-assembled catalase/PEI-PEG complex, penetrate the blood brain barrier, and deliver the catalase to diseased neurons in an Parkinson's disease model [91]. A similar approach could be potentially used to deliver a prodrug activating enzyme or other protein therapy to tumors without introducing a foreign gene into the homing cells.…”

Novel Nanomaterials for Clinical Neuroscience

“…Based on this, our laboratories developed cell mediated delivery of catalase nanozyme to the brain to mitigate production of ROS and induce neuroprotection (Batrakova et al 2007). To preclude BMM-mediated enzyme degradation, catalase was packaged into a block ionomer complex with a cationic block copolymer, PEI-PEG.…”