Macrophages offer a paradigm switch for CNS delivery of therapeutic proteins.
Macrophages offer a paradigm switch for CNS delivery of therapeutic proteins.
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DOI：
10.2217/nnm.13.115
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发表时间：
2014-07
期刊：
影响因子：
--
通讯作者：
Batrakova EV
中科院分区：
文献类型：
--
作者：
Klyachko NL;Haney MJ;Zhao Y;Manickam DS;Mahajan V;Suresh P;Hingtgen SD;Mosley RL;Gendelman HE;Kabanov AV;Batrakova EV
在巨噬细胞中纳米配方氧化还原酶、过氧化氢酶的主动靶向转运减弱了氧化应激，并因此增加了帕金森病动物模型中多巴胺能神经元的存活。药物制剂的优化对于在活细胞中成功递送至关重要。我们先前证明，将过氧化氢酶包装到具有合成的嵌段共聚物的聚离子复合物胶束（“纳米酶”）中保护酶免受巨噬细胞中的降解并改善治疗结果。我们现在报道了具有上级结构和治疗指数的纳米酶的制造。最佳的基于细胞的纳米制剂的合成，表征和治疗效果进行了评估。药物载体的制剂设计通常用于避免在单核细胞和巨噬细胞中的包封，其集中于具有聚乙二醇冠的小尺寸纳米颗粒（以提供隐形效应）。相比之下，本研究中报道的用于巨噬细胞中递送的最佳纳米酶具有相对较大的尺寸（~200 nm），这导致负载能力和从巨噬细胞的释放得到改善。此外，纳米酶与过量的不可生物降解的接头的交联确保了它们的低细胞毒性和细胞载体中的有效过氧化氢酶保护。最后，在这些研究中使用的“替代活化”巨噬细胞表型（M2）没有促进脑中的进一步炎症，导致对体内神经元再生和修复的微妙但统计学显著的影响。装载到巨噬细胞中的优化的交联纳米酶减少了小鼠的神经炎症反应并增加了神经元存活。重要的是，用于细胞介导递送的纳米制剂设计的方法不同于可注射制剂的常见要求。
Active targeted transport of the nanoformulated redox enzyme, catalase, in macrophages attenuates oxidative stress and as such increases survival of dopaminergic neurons in animal models of Parkinson’s disease. Optimization of the drug formulation is crucial for the successful delivery in living cells. We demonstrated earlier that packaging of catalase into a polyion complex micelle (‘nanozyme’) with a synthetic polyelectrolyte block copolymer protected the enzyme against degradation in macrophages and improved therapeutic outcomes. We now report the manufacture of nanozymes with superior structure and therapeutic indices. Synthesis, characterization and therapeutic efficacy of optimal cell-based nanoformulations are evaluated. A formulation design for drug carriers typically works to avoid entrapment in monocytes and macrophages focusing on small-sized nanoparticles with a polyethylene glycol corona (to provide a stealth effect). By contrast, the best nanozymes for delivery in macrophages reported in this study have a relatively large size (~200 nm), which resulted in improved loading capacity and release from macrophages. Furthermore, the cross-linking of nanozymes with the excess of a nonbiodegradable linker ensured their low cytotoxicity, and efficient catalase protection in cell carriers. Finally, the ‘alternatively activated’ macrophage phenotype (M2) utilized in these studies did not promote further inflammation in the brain, resulting in a subtle but statistically significant effect on neuronal regeneration and repair in vivo. The optimized cross-linked nanozyme loaded into macrophages reduced neuroinflammatory responses and increased neuronal survival in mice. Importantly, the approach for nanoformulation design for cell-mediated delivery is different from the common requirements for injectable formulations.
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DOI：
10.2217/nnm.11.92
发表时间：
2011-09
期刊：
Nanomedicine (London, England)
影响因子：
--
作者：
Hood E;Simone E;Wattamwar P;Dziubla T;Muzykantov V
通讯作者：
Muzykantov V
影响因子：
3.7
作者：
Batrakova, EV;Han, HY;Kabanov, AV
通讯作者：
Kabanov, AV
DOI：
10.1523/jneurosci.3257-09.2009
发表时间：
2009-10-28
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Kigerl KA;Gensel JC;Ankeny DP;Alexander JK;Donnelly DJ;Popovich PG
通讯作者：
Popovich PG
影响因子：
5.4
作者：
Klyachko, Natalia L.;Manickam, Devika S.;Brynskikh, Anna M.;Uglanova, Svetlana V.;Li, Shu;Higginbotham, Sheila M.;Bronich, Tatiana K.;Batrakova, Elena V.;Kabanov, Alexander V.
通讯作者：
Kabanov, Alexander V.
影响因子：
4.7
作者：
Batrakova, Elena V.;Li, Shu;Gendelman, Howard E.
通讯作者：
Gendelman, Howard E.