Journal
BIOMATERIALS
Volume 31, Issue 19, Pages 5218-5226Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2010.03.026
Keywords
Brain; Superoxide dismutase; Nanotechnology; Drug delivery; Copolymer; Potassium current
Funding
- National Institutes of Health (NIH) COBRE (Nebraska Center for Nanomedicine) [RR021937]
- National Institutes of Health (NIH) COBRE [NS057748]
- Nebraska Research Initiative
- Eppley Cancer Center
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Adenoviral-mediated overexpression of the intracellular superoxide (O-2(center dot-)) scavenging enzyme copper/zinc superoxide dismutase (CuZnSOD) in the brain attenuates central angiotensin II (AngII)-induced cardiovascular responses. However, the therapeutic potential for adenoviral vectors is weakened by toxicity and the inability of adenoviral vectors to target the brain following peripheral administration. Therefore, we developed a non-viral delivery system in which CuZnSOD protein is electrostatically bound to a synthetic poly(ethyleneimine)-poly(ethyleneglycol) (PEI-PEG) polymer to form a polyion complex (CuZnSOD nanozyme). We hypothesized that PEI-PEG polymer increases transport of functional CuZnSOD to neurons, which inhibits AngII intra-neuronal signaling. The AngII-induced increase in O-2(center dot-) as measured by dihydroethidium fluorescence and electron paramagnetic resonance spectroscopy, was significantly inhibited in CuZnSOD nanozyme-treated neurons compared to free CuZnSOD- and non-treated neurons. CuZnSOD nanozyme also attenuated the AngII-induced inhibition of K+ current in neurons. Intracarotid injection of CuZnSOD nanozyme into rabbits significantly inhibited the pressor response of intracerebroventricular-delivered AngII; however, intracarotid injection of free CuZnSOD or PEI-PEG polymer alone failed to inhibit this response. Importantly, neither the PEI-PEG polymer alone nor the CuZnSOD nanozyme induced neuronal toxicity. These findings indicate that CuZnSOD nanozyme inhibits ArigII intra-neuronal signaling in vitro and in vivo. (C) 2010 Elsevier Ltd. All rights reserved.
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