α-Galactosidase-A-Loaded Nanoliposomes with Enhanced Enzymatic Activity and Intracellular Penetration
α-Galactosidase-A-Loaded Nanoliposomes with Enhanced Enzymatic Activity and Intracellular Penetration
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DOI：
10.1002/adhm.201500746
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发表时间：
2016-04-06
影响因子：
10
通讯作者：
Veciana, Jaume
中科院分区：
文献类型：
--
作者：
Cabrera, Ingrid;Abasolo, Ibane;Veciana, Jaume
溶酶体贮积症（LSD）是由溶酶体功能障碍引起的，通常是由于缺乏大分子（如脂质、糖蛋白和粘多糖）代谢所需的单一酶的结果。例如，法布里病患者中α-半乳糖苷酶A（GLA）活性的缺乏导致鞘糖脂在脉管系统中的积累，从而导致多器官病理学。酶替代疗法是LSD的最常见治疗，其表现出主要与外源施用的治疗酶的不稳定性和低功效相关的几个缺点。在这项工作中，前所未有的增加的酶活性和细胞内渗透实现的协会的人重组GLA与纳米脂质体功能化的精氨酸-甘氨酸-天冬氨酸（RGD）肽报道。此外，这些新的负载GLA的纳米脂质体在法布里病的细胞模型中导致名为globotriasylceramide的GLA底物的还原比通过相同浓度的游离酶实现的更高的功效。DELOS-SUSP基于CO2膨胀液体有机溶液的减压制备这些新的脂质体制剂，显示了这种基于CO2的方法一步生产蛋白质-纳米脂质体缀合物作为具有治疗意义的生物活性纳米材料的巨大潜力。
Lysosomal storage disorders (LSD) are caused by lysosomal dysfunction usually as a consequence of deficiency of a single enzyme required for the metabolism of macromolecules, such as lipids, glycoproteins, and mucopolysaccharides. For instance, the lack of a-galactosidase A (GLA) activity in Fabry disease patients causes the accumulation of glycosphingolipids in the vasculature leading to multiple organ pathology. Enzyme replacement therapy, which is the most common treatment of LSD, exhibits several drawbacks mainly related to the instability and low efficacy of the exogenously administered therapeutic enzyme. In this work, the unprecedented increased enzymatic activity and intracellular penetration achieved by the association of a human recombinant GLA to nanoliposomes functionalized with Arginine-Glycine-Aspartic acid (RGD) peptides is reported. Moreover, these new GLA loaded nanoliposomes lead to a higher efficacy in the reduction of the GLA substrate named globotriasylceramide in a cellular model of Fabry disease, than that achieved by the same concentration of the free enzyme. The preparation of these new liposomal formulations by DELOS-SUSP, based on the depressurization of a CO2-expanded liquid organic solution, shows the great potential of this CO2-based methodology for the one-step production of protein-nanoliposome conjugates as bioactive nanomaterials with therapeutic interest.