Hybrid polymer nanocapsules enhance in vitro delivery of azidothymidine-triphosphate to macrophages
Hybrid polymer nanocapsules enhance in vitro delivery of azidothymidine-triphosphate to macrophages
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DOI：
10.1016/j.jconrel.2006.09.016
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发表时间：
2006-12-01
影响因子：
10.8
通讯作者：
Couvreur, Patrick
中科院分区：
文献类型：
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作者：
Hillaireau, Herve;Le Doan, Trung;Couvreur, Patrick
核苷类逆转录酶抑制剂(NRTI)如叠氮胸苷(AZT)使用的主要限制之一在于它们在细胞内不能被激活为活性的三磷酸化形式。因此，直接给药三磷酸类NRTIs，如叠氮胸苷-三磷酸(AZT TP)，被认为可以绕过这一代谢瓶颈，但由于它们过于亲水的特性，这些分子不会在细胞内扩散。因此，聚氰基丙烯酸异丁酯(PIBCA)水核纳米胶囊被用作载体以克服AZT-TP的细胞递送。然而，AZT TP的包封性仍然具有挑战性，因为这种分子由于其相对低的分子质量，很快就从纳米胶囊中泄漏出来。在这项研究中，我们证明了AZT-TP与阳离子聚合物如聚乙烯亚胺(PEI)的结合可以使AZT-TP在PIBCA纳米胶囊中达到高的包封率(高达90%)，并在体外逐步释放。由此得到的PIBCA/PEI复合纳米胶囊在体外有效地将AZT-TP输送到巨噬细胞：与游离分子相比，细胞摄取增加了30倍，达到了用于治疗目的的相应细胞浓度。(C)2006爱思唯尔B.V.保留所有权利。
One of the main limitations in the use of nucleoside reverse transcriptase inhibitors (NRTIs) such as azidothymidine (AZT) lies in their poor intracellular activation by cellular kinases into their active tri-phosphorylated form. Thus, the direct administration of triphosphate NRTIs like azidothymidine-triphosphate (AZT TP), has been considered for bypassing this metabolic bottleneck, but these molecules do not diffuse intracellularly, due to their too hydrophilic character. Therefore, poly(iso-butylcyanoacrylate) (PIBCA) aqueous-cored nanocapsules have been tested as carriers to overcome the cellular delivery of AZT-TP. However, encapsulation of AZT TP remained challenging because this molecule, due to its relatively low molecular weight, rapidly leaked out of the nanocapsules. In this study, we show that association of AZT-TP to a cationic polymer such as poly(ethyleneimine) (PEI) allowed to reach high entrapment efficiency of AZT-TP in PIBCA nanocapsules (up to 90%) as well as gradual in vitro release. The resulting hybrid PIBCA/PEI nanocapsules efficiently delivered AZT-TP in vitro to macrophages: the cellular uptake was increased by 30-fold compared to the free molecule, reaching relevant cellular concentrations for therapeutic purposes. (c) 2006 Elsevier B.V All rights reserved.