Jo Yun Suk, van der Vlies André J, Gantz Jay, Thacher Tyler N, Antonijevic Sasa, Cavadini Simone, Demurtas Davide, Stergiopulos Nikolaos, Hubbell Jeffrey A
Institute of Bioengineering (IBI), Ecole Polytechnique Federale de Lausanne, Lausanne CH 1015, Switzerland.
J Am Chem Soc. 2009 Oct 14;131(40):14413-8. doi: 10.1021/ja905123t.
We designed block copolymer pro-amphiphiles and amphiphiles for providing very long-term release of nitric oxide (NO). A block copolymer of N-acryloylmorpholine (AM, as a hydrophile) and N-acryloyl-2,5-dimethylpiperazine (AZd, as a hydrophilic precursor) was synthesized. The poly(N-acryloyl-2,5-dimethylpiperazine) (PAZd) is water-soluble, but chemical reaction of the secondary amines with NO to form a N-diazeniumdiolate (NONOate) converts the hydrophilic PAZd into a hydrophobic poly(sodium-1-(N-acryloyl-2,5-dimethylpiperazin-1-yl)diazen-1-ium-1,2-diolate) (PAZd.NONOate), driving aggregation. The PAM block guides this process toward micellization, rather than precipitation, yielding ca. 50 nm spherical micelles. The hydrophobic core of the micelle shielded the NONOate from the presence of water, and thus protons, which are required for NO liberation, delaying release to a remarkable 7 d half-life. Release of the NO returned the original soluble polymer. The very small NO-loaded micelles were able to penetrate complex tissue structures, such as the arterial media, opening up a number of tissue targets to NO-based therapy.
我们设计了嵌段共聚物前体两亲物和两亲物，用于实现一氧化氮（NO）的超长效释放。合成了一种由N - 丙烯酰基吗啉（AM，作为亲水基团）和N - 丙烯酰基 - 2,5 - 二甲基哌嗪（AZd，作为亲水前体）组成的嵌段共聚物。聚（N - 丙烯酰基 - 2,5 - 二甲基哌嗪）（PAZd）是水溶性的，但仲胺与NO发生化学反应形成N - 二氮烯二醇盐（NONOate），会将亲水性的PAZd转变为疏水性的聚（1 - （N - 丙烯酰基 - 2,5 - 二甲基哌嗪 - 1 - 基）二氮烯 - 1,2 - 二醇酸钠）（PAZd.NONOate），从而促使聚集。PAM嵌段引导这一过程趋向于形成胶束，而非沉淀，得到约50 nm的球形胶束。胶束的疏水核心将NONOate与水隔离开来，因此也与NO释放所需的质子隔离开来，将释放延迟至显著的7天半衰期。NO的释放使聚合物恢复为原来的可溶状态。负载NO的非常小的胶束能够穿透复杂的组织结构，如动脉中膜，为基于NO的治疗开辟了许多组织靶点。
