A macrophage-nanozyme delivery system for Parkinson's disease
A macrophage-nanozyme delivery system for Parkinson's disease
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DOI：
10.1021/bc700184b
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发表时间：
2007-09-01
影响因子：
4.7
通讯作者：
Gendelman, Howard E.
中科院分区：
文献类型：
--
作者：
Batrakova, Elena V.;Li, Shu;Gendelman, Howard E.
在帕金森病（PD）期间选择性地将抗氧化剂递送至黑质丘脑部（SNpc）可以潜在地减弱氧化应激，并因此增加多巴胺能神经元的存活。为此，我们开发了一种骨髓源性巨噬细胞（BMM）系统，在人类疾病的动物模型中将过氧化氢酶递送到PD影响的脑区域。为了排除BM介导的酶降解，将过氧化氢酶包装成具有阳离子嵌段共聚物聚乙烯亚胺-聚（乙二醇）（PEIPEG）的嵌段离聚物复合物。自组装的过氧化氢酶/PEI-PEG复合物，“纳米酶”，是约。60至100 nm的大小，稳定的pH值和离子强度，并保留抗氧化活性。在生理纳米酶浓度范围内，细胞毒性可忽略不计。纳米酶颗粒被BMM迅速吸收，40-60分钟，保持催化活性，并以活性形式释放超过24小时。相反，“裸”过氧化氢酶迅速降解。在硝化α-突触核蛋白或肿瘤坏死因子α激活后，释放的酶分解小胶质细胞过氧化氢。在将纳米酶负载的BMM过继转移至1-甲基4-苯基1，2，3，6-四氢吡啶中毒小鼠后，约.脑组织中的含量占注射剂量的0.6%。我们的结论是，细胞介导的纳米酶的交付可以减少氧化应激在实验室和动物模型的PD。
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) (PEIPEG). 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 cellmediated delivery of nanozymes can reduce oxidative stress in laboratory and animal models of PD.