Endothelial targeting of semi-permeable polymer nanocarriers for enzyme therapies
Endothelial targeting of semi-permeable polymer nanocarriers for enzyme therapies
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DOI：
10.1016/j.biomaterials.2007.09.023
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发表时间：
2008-01-01
期刊：
影响因子：
14
通讯作者：
Muzykantov, Vladimir R.
中科院分区：
文献类型：
--
作者：
Dziubla, Thomas D.;Shuvaev, Vladimir V.;Muzykantov, Vladimir R.
蛋白质（例如治疗性酶）的医疗用途受到其不稳定性质和不充分递送的极大限制。大多数治疗性酶不会在其靶标中积累，并且会被蛋白酶灭活。将酶包封到可渗透底物的聚合物纳米载体（蛋白酶不可渗透的PNC）中可以克服这些限制。为了验证这一假设，我们设计了负载过氧化氢酶（一种H2 O2解毒酶）的内皮靶向PNC，并测试了这种方法是否能防止血管氧化应激，这是一种与缺血再灌注和其他疾病有关的病理过程。将过氧化氢酶（MW 247 kD）、过氧化物酶（MW 42 kD）和黄嘌呤氧化酶（XO，MW 300 kD）包封到由聚乙二醇和聚乳酸/聚乙醇酸的共聚物（PEG-PLGA）组成的类似于300 nm直径的PNC中对于所有酶来说在类似于10%的范围内。PNC/过氧化氢酶和PNC/过氧化物酶的保护，从外部蛋白水解，并发挥其PNC可扩散的底物，过氧化氢和邻苯二胺的酶活性，而封装XO的活动是可以忽略不计的，由于聚合物的不渗透性的基板。在细胞培养和动物研究中，靶向血小板-内皮细胞（EC）粘附分子-1的PNC向EC递送活性包封的过氧化氢酶，并保护内皮免受氧化应激。血管靶向的PNC负载的解毒酶可能会发现广泛的医疗应用，包括管理氧化应激和其他毒性。(C)2007爱思唯尔有限公司版权所有。
The medical utility of proteins, e.g. therapeutic enzymes, is greatly restricted by their labile nature and inadequate delivery. Most therapeutic enzymes do not accumulate in their targets and are inactivated by proteases. Targeting of enzymes encapsulated into substrate-permeable polymer nano-carriers (PNC impermeable for proteases might overcome these limitations. To test this hypothesis, we designed endothelial targeted PNC loaded with catalase, an H2O2-detoxifying enzyme, and tested if this approach protects against vascular oxidative stress, a pathological process implicated in ischemia-reperfusion and other disease conditions. Encapsulation of catalase (MW 247 kD), peroxidase (MW 42 kD) and xanthine oxidase (XO, MW 300kD) into similar to 300nm diameter PNC composed of co-polymers of polyethylene glycol and poly-lactic/poly-glycolic acid (PEG-PLGA) was in the range similar to 10% for all enzymes. PNC/catalase and PNC/peroxidase were protected from external proteolysis and exerted enzymatic activity on their PNC diffusible substrates, H2O2 and ortho-phenylendiamine, whereas activity of encapsulated XO was negligible due to polymer impermeability to the substrate. PNC targeted to platelet-endothelial cell (EC) adhesion molecule-1 delivered active encapsulated catalase to ECs and protected the endothelium against oxidative stress in cell culture and animal studies. Vascular targeting of PNC-loaded detoxifying enzymes may find wide medical applications including management of oxidative stress and other toxicities. (C) 2007 Elsevier Ltd. All rights reserved.