Stabilization of the nitric oxide (NO) prodrugs and anticancer leads, PABA/NO and Double JS-K, through incorporation into PEG-protected nanoparticles.
Stabilization of the nitric oxide (NO) prodrugs and anticancer leads, PABA/NO and Double JS-K, through incorporation into PEG-protected nanoparticles.
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DOI：
10.1021/mp900245h
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发表时间：
2010-02-01
影响因子：
4.9
通讯作者：
Chakrapani H
中科院分区：
文献类型：
--
作者：
Kumar V;Hong SY;Maciag AE;Saavedra JE;Adamson DH;Prud'homme RK;Keefer LK;Chakrapani H
在这里，我们报告了一氧化氮 (NO) 前药和抗癌先导化合物 PABA/NO (O2-{2,4-二硝基-5-[4-(N-甲基氨基)苯甲酰氧基]苯基} 1-(N,N-二甲基氨基)diazen-1-ium-1,2-二醇) 和“Double JS-K”的稳定性(1,5-双{[1-[(4-乙氧基羰基)哌嗪-1-基]diazen-1-ium-1,2-diol-2-ato]-2,4-二硝基苯)，通过将其纳入聚合物保护的纳米颗粒中。通过新颖的快速沉淀工艺将前药配制为尺寸为 220 至 450 nm 的嵌段共聚物稳定的纳米颗粒。具有聚乙二醇 (PEG) 可溶性嵌段的嵌段共聚物提供了空间屏障，防止谷胱甘肽激活 NO 前药。过快的激活和 NO 释放一直是此类化合物有效给药的主要障碍。纳米颗粒稳定了 PABA/NO，使其免受谷胱甘肽的攻击，50% 分解所需的时间从 15 分钟（未配制）显着增加到 5 小时（配制）即可证明； Double JS-K 的 50% 分解时间从 4.5 分钟（未配制）延长至 40 分钟（配制）。与 Double JS-K 相比，疏水性更强的 PABA/NO 产生更稳定的纳米颗粒，相应地延长了释放时间。聚合物的疏水嵌段是聚苯乙烯或聚丙交酯。两个模块产生的纳米颗粒的尺寸和释放动力学大致相同。这种 PEG 保护纳米颗粒的组合，其尺寸适合通过增强渗透和保留 (EPR) 和 NO 延迟释放来靶向癌症，可能会带来增强的治疗效果。
Here we report the stabilization of the nitric oxide (NO) prodrugs and anti-cancer lead compounds, PABA/NO (O2-{2,4-dinitro-5-[4-(N-methylamino)benzoyloxy]phenyl} 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate) and “Double JS-K” (1,5-bis{[1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diol-2-ato]-2,4-dinitrobenzene), through their incorporation into polymer-protected nanoparticles. The prodrugs were formulated in block copolymer-stabilized nanoparticles with sizes from 220 to 450 nm by a novel rapid precipitation process. The block copolymers, with polyethylene glycol (PEG) soluble blocks, provide a steric barrier against NO prodrug activation by glutathione. Too rapid activation and NO release has been a major barrier to effective administration of this class of compounds. The nanoparticle stabilized PABA/NO from attack by glutathione as evidenced by a significant increase in time taken for 50% decomposition from 15 min (unformulated) to 5 h (formulated); in the case of Double JS-K, the 50% decomposition time was extended from 4.5 min (unformulated) to 40 min (formulated). The more hydrophobic PABA/NO produced more stable nanoparticles and correspondingly more extended release times in comparison with Double JS-K. The hydrophobic blocks of the polymer were either polystyrene or polylactide. Both blocks produced nanoparticles of approximately the same size and release kinetics. This combination of PEG-protected nanoparticles with sizes appropriate for cancer targeting by enhanced permeation and retention (EPR) and delayed release of NO may afford enhanced therapeutic benefit.
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