Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin, 777 Highland Ave, Madison, WI 53705, USA.
Biomaterials. 2010 Mar;31(7):1765-72. doi: 10.1016/j.biomaterials.2009.11.038. Epub 2009 Dec 3.
Poly(ethylene glycol)-block-poly(aspartate-hydrazide) (PEG-p(Asp-Hyd)) was modified using either levulinic acid (LEV) or 4-acetyl benzoic acid (4AB) attached via hydrazone bonds. Paclitaxel (PTX) conjugated to the linkers formed PEG-p(Asp-Hyd-LEV-PTX) and PEG-p(Asp-Hyd-4AB-PTX). PEG-p(Asp-Hyd-LEV-PTX) and PEG-p(Asp-Hyd-4AB-PTX) assemble into unimodal polymeric micelles with diameters of 42 nm and 137 nm, respectively. PEG-p(Asp-Hyd-LEV-PTX) and PEG-p(Asp-Hyd-4AB-PTX) at a 1:1 and 1:5 molar ratio assemble into unimodal mixed polymeric micelles with diameters of 85 and 113 nm, respectively. PEG-p(Asp-Hyd-LEV-PTX) micelles release LEV-PTX faster at pH 5.0 than at pH 7.4 over 24 h. At pH 7.4 mixed polymeric micelles at 1:5 ratio show no difference in LEV-PTX release from PEG-p(Asp-Hyd-LEV-PTX) micelles. Mixed polymeric micelles at 1:5 molar ratio gradually release LEV-PTX at pH 5.0, with no release of 4AB-PTX. PEG-p(Asp-Hyd-LEV-PTX) micelles and mixed polymeric micelles exert comparable cytotoxicity against SK-OV-3 and MCF-7 cancer cell lines. In summary, mixed polymeric micelles based on PEG-p(Asp-Hyd-LEV-PTX) and PEG-p(Asp-Hyd-4AB-PTX) offer prospects for pH-dependent release of PTX, offering a novel prodrug strategy for adjusting its pharmacokinetic and pharmacodynamic properties for cancer therapy. If successful this delivery system offers an alternative new mode of delivery for paclitaxel with a new scope for its efficacy along with a minimal synthetic framework needed to accomplish this.
聚乙二醇-聚（天冬氨酸-酰腙）（PEG-p（Asp-Hyd））通过腙键连接用乙酰丙酸（LEV）或 4-乙酰苯甲酸（4AB）进行修饰。紫杉醇（PTX）与形成的连接物缀合得到 PEG-p（Asp-Hyd-LEV-PTX）和 PEG-p（Asp-Hyd-4AB-PTX）。PEG-p（Asp-Hyd-LEV-PTX）和 PEG-p（Asp-Hyd-4AB-PTX）分别自组装成粒径为 42nm 和 137nm 的单峰聚合物胶束。PEG-p（Asp-Hyd-LEV-PTX）和 PEG-p（Asp-Hyd-4AB-PTX）以 1:1 和 1:5 摩尔比组装成粒径分别为 85nm 和 113nm 的单峰混合聚合物胶束。PEG-p（Asp-Hyd-LEV-PTX）胶束在 pH5.0 下比在 pH7.4 下 24 小时内更快地释放 LEV-PTX。在 pH7.4 下，以 1:5 摩尔比混合的聚合物胶束在释放 LEV-PTX 方面没有表现出与 PEG-p（Asp-Hyd-LEV-PTX）胶束的差异。以 1:5 摩尔比混合的聚合物胶束在 pH5.0 下逐渐释放 LEV-PTX，没有 4AB-PTX 的释放。PEG-p（Asp-Hyd-LEV-PTX）胶束和混合聚合物胶束对 SK-OV-3 和 MCF-7 癌细胞系表现出相当的细胞毒性。总之，基于 PEG-p（Asp-Hyd-LEV-PTX）和 PEG-p（Asp-Hyd-4AB-PTX）的混合聚合物胶束为 PTX 的 pH 依赖性释放提供了前景，为调整其药代动力学和药效学特性用于癌症治疗提供了一种新的前药策略。如果成功，这种递药系统为紫杉醇提供了一种新的递药模式，为其疗效提供了新的范围，同时也为实现这一目标所需的最小合成框架提供了一种替代方案。
