Biocompatibility and efficacy of oligomaltose-grafted poly(ethylene imine)s (OM-PEIs) for in vivo gene delivery.
Biocompatibility and efficacy of oligomaltose-grafted poly(ethylene imine)s (OM-PEIs) for in vivo gene delivery.
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低聚麦芽糖接枝聚乙烯亚胺 (OM-PEI) 用于体内基因传递的生物相容性和功效
DOI：
10.1021/mp400479g
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发表时间：
2013
影响因子：
4.9
通讯作者：
Aigner A
中科院分区：
文献类型：
--
作者：
Gutsch D;Appelhans D;Hobel S;Voit B;Aigner A
聚阳离子聚合物如聚乙烯亚胺（PEIs）被广泛用于DNA或小rna （sirna）的非病毒转移。为了提高生物相容性和改变药代动力学性质，最近在一项系统研究中，超支化PEI与非配体低聚糖麦芽糖或麦芽糖三糖不同程度地接枝，以生产（低聚）麦芽糖PEIs （OM-PEIs）。在本文中，我们研究了整套（OM-） pei和相应的（OM-） pei DNA或siRNA复合物在小鼠全身（静脉注射，静脉注射）给药后的体内相容性和功效。我们确定了总体生存和动物福利、肝毒性、免疫刺激、红细胞聚集和DNA在体内传递的功效。根据血清肝酶水平测定，PEI的高程度低聚糖接枝可显著减少体重减轻，消除游离聚合物或配合物反复治疗时的致病性，并消除肝毒性。免疫刺激作用（TNF-α, IFN-γ）和红细胞聚集主要在部分麦芽糖移植PEI或PEI基复合物治疗时观察到，并且在更高程度的移植时基本消除。在携带皮下（s.c）肿瘤异种移植物的小鼠体内转染实验中，报告基因在特定器官中的表达强烈依赖于复杂给药模式（静脉注射或腹腔注射）和OM-PEI结构，其中高水平麦糖移植的PEI （PEI-(2-Mal)）最有效地传递DNA。我们得出结论，不同模式的麦芽糖或麦芽糖嫁接在生物相容性和体内功效方面存在明显差异，并确定了用于治疗应用的最佳低聚麦芽糖- peis。
Polycationic polymers like poly(ethylene imine)s (PEIs) are extensively explored for the nonviral transfer of DNA or small RNAs (siRNAs). To enhance biocompatibility and alter pharmacokinetic properties, hyperbranched PEI was recently grafted with the nonligand oligosaccharides maltose or maltotriose at various degrees in a systematic study to yield (oligo-)maltose PEIs (OM-PEIs). In this paper, we investigate thein vivobiocompatibility and efficacy of a whole set of (OM-)PEIs and the corresponding (OM-)PEI-based DNA or siRNA complexes upon systemic (intravenous, i.v.) administration in mice. We determine the overall survival and animal welfare, hepatotoxicity, immune stimulation, erythrocyte aggregation, and the efficacy of DNA deliveryin vivo. Higher-degree oligomaltose-grafting of PEI substantially decreases weight loss, abolishes lethality upon repeated treatment with the free polymers or with complexes, and abrogates hepatotoxicity, as determined by serum levels of liver enzymes. Immunostimulatory effects (TNF-α, IFN-γ) and erythrocyte aggregation are mainly observed upon treatment with partially maltotriose-grafted PEI or PEI-based complexes and are largely abolished upon higher-degree grafting.In vivotransfection experiments in mice bearing subcutaneous (s.c.) tumor xenografts reveal a strong dependence of reporter gene expression in a given organ on the mode of complex administration (i.v. vs intraperitoneal injection) and the OM-PEI architecture, with high-level maltose-grafted PEI (PEI-(2-Mal)) being most efficient for DNA delivery. We conclude that distinct differences between different patterns of maltose- or maltotriose-grafting are observed with regard to both biocompatibility andin vivoefficacy and identify optimal oligomaltose-PEIs for therapeutic applications.