Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone, Lexington, KY 40536-0596, USA.
Pharm Res. 2011 Oct;28(10):2435-46. doi: 10.1007/s11095-011-0470-1. Epub 2011 May 26.
To develop polymer micelles for the tunable release of Dexamethasone (DEX) in tumors.
DEX was conjugated to poly(ethylene glycol)-poly(aspartate) block copolymers using hydrazone, ester, or hydrazone-ester dual linkers. Ketonic acids containing 3, 4, and 5 methylene groups were used as spacers to separate the dual linkers. Polymer micelles from the DEX-conjugated polymers were tested for drug release at different pH values and carboxylesterase activity levels.
DLS measurements and (1)H-NMR analysis confirmed all DEX-loaded micelles were <100 nm with core-shell structure. Single linker micelles appeared unsuitable to release DEX preferentially in acidic tumor tissues. Hydrazone linkages between DEX and polymers were non-degradable at both pH 7.4 and 5.0. Ester linkages stable at pH 5.0 were unstable at pH 7.4. Hydrazone-ester dual linkers suppressed DEX release at pH 7.4 while accelerating drug release at pH 5.0. DEX release decreased at pH 5.0 as the length of ketonic acid increased but was independent of spacer length at pH 7.4. Dual linker micelles were stable in the presence of carboxylesterases, suggesting DEX release was primarily due to pH-dependent hydrolysis.
Tunable release of DEX was achieved using pH-sensitive polymer micelles with hydrazone-ester dual linkers.
开发用于在肿瘤中可控释放地塞米松（DEX）的聚合物胶束。
使用腙键、酯键或腙-酯双连接键将 DEX 键接到聚乙二醇-聚天冬氨酸嵌段共聚物上。将含有 3、4 和 5 个亚甲基的酮酸用作间隔物以分离双连接键。对来自 DEX 缀合聚合物的聚合物胶束进行不同 pH 值和羧酸酯酶活性水平下的药物释放测试。
DLS 测量和（1）H-NMR 分析证实所有负载 DEX 的胶束均小于 100nm，具有核壳结构。单连接键胶束似乎不适合优先在酸性肿瘤组织中释放 DEX。DEX 和聚合物之间的腙键在 pH 7.4 和 5.0 下均不可降解。在 pH 5.0 下稳定的酯键在 pH 7.4 下不稳定。腙-酯双连接键在 pH 7.4 时抑制 DEX 释放，而在 pH 5.0 时加速药物释放。在 pH 5.0 下，DEX 释放随酮酸长度的增加而减少，但在 pH 7.4 下与间隔物长度无关。在羧酸酯酶存在下，双连接键胶束稳定，表明 DEX 释放主要是由于 pH 依赖性水解。
使用具有腙-酯双连接键的 pH 敏感聚合物胶束实现了 DEX 的可调释放。
