Drug delivery system for poorly water-soluble compounds using lipocalin-type prostaglandin D synthase
Drug delivery system for poorly water-soluble compounds using lipocalin-type prostaglandin D synthase
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DOI：
10.1016/j.jconrel.2011.12.020
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发表时间：
2012-04-10
影响因子：
10.8
通讯作者：
Inui, Takashi
中科院分区：
文献类型：
--
作者：
Fukuhara, Ayano;Nakajima, Hidemitsu;Inui, Takashi
脂载蛋白型前列腺素D合成酶（L-PGDS）是脂载蛋白超家族的一员，是一种分泌性脂质转运蛋白，与多种疏水小分子结合。在这里，我们展示了一种新的药物传递系统（DDS）的可行性，利用L-PGDS，用于低水溶性化合物，如地西泮（DZP），一种主要的苯二氮卓类抗焦虑药物，以及6-硝基-7-磺胺酰基苯并[f]喹啉-2,3-二酮（NBQX），一种a-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体拮抗剂和抗惊厥药。量热实验表明，这两种化合物每个L-PGDS含有三个高结合亲和力的分子。质谱法检测到L-PGDS与NBQX的复合物为1:3。500 μ M的L-PGDS与单独PBS相比，分别使DZP和NBQX的溶解度提高了7倍和2倍。为了验证L-PGDS作为体内药物递送载体的潜力，我们通过两种不同的递送策略证明了这些化合物的预期效果。首先，在小鼠中口服DZP/L-PGDS复合物显示戊巴比妥诱导的翻正反射丧失持续时间增加。其次，静脉注射NBQX/L-PGDS复合物对缺血沙鼠海马CA1区延迟神经元细胞死亡具有保护作用。我们认为我们的新型DDS可以促进各种水不溶性化合物的药物开发和临床应用。(C) 2011 Elsevier B.V.版权所有
Lipocalin-type prostaglandin D synthase (L-PGDS) is a member of the lipocalin superfamily and a secretory lipid-transporter protein, which binds a wide variety of hydrophobic small molecules. Here we show the feasibility of a novel drug delivery system (DDS), utilizing L-PGDS, for poorly water-soluble compounds such as diazepam (DZP), a major benzodiazepine anxiolytic drug, and 6-nitro-7-sulfamoylbenzo[f] quinoxaline-2,3-dione (NBQX), an a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist and anticonvulsant. Calorimetric experiments revealed for both compounds that each L-PGDS held three molecules with high binding affinities. By mass spectrometry, the 1:3 complex of L-PGDS and NBQX was observed. L-PGDS of 500 mu M increased the solubility of DZP and NBQX 7- and 2-fold, respectively, compared to PBS alone. To validate the potential of L-PGDS as a drug delivery vehicle in vivo, we have proved the prospective effects of these compounds via two separate delivery strategies. First, the oral administration of a DZP/L-PGDS complex in mice revealed an increased duration of pentobarbital-induced loss of righting reflex. Second, the intravenous treatment of ischemic gerbils with NBQX/L-PGDS complex showed a protective effect on delayed neuronal cell death at the hippocampal CA1 region. We propose that our novel DDS could facilitate pharmaceutical development and clinical usage of various water-insoluble compounds. (C) 2011 Elsevier B.V. All rights reserved.