Department of Molecular Science and Technology, Ajou University, San 5, Woncheon, Yeongtong, Suwon 443-749, Republic of Korea.
J Control Release. 2013 Dec 10;172(2):535-40. doi: 10.1016/j.jconrel.2013.05.003. Epub 2013 May 13.
We report a controlled dual drug delivery system using heparinized 4-arm poly(propylene oxide) (PPO)-poly(ethylene oxide) (PEO) micelles (cHTM) that are sterically stabilized by enzymatic shell cross-linking (SCL). Tyramine (TA) was chemically conjugated to 4-arm PPO-PEO (Tetronic) and heparin, resulting in Tetronic-TA (Tet-TA) and heparin-TA (Hep-TA), respectively. To prepare a series of cHTM, different amounts of Hep-TA were added to a micellar solution of Tet-TA, followed by addition of horseradish peroxidase (HRP) and hydrogen peroxide (H2O2) to trigger SCL between TA groups at the micellar surfaces. Increasing the feed amount of Hep-TA led to increased heparin content of cHTM, thereby resulting in increased micelle size with more negatively charged surfaces. All SCL micelles were found to be highly stable over 4weeks, showing negligible changes in their sizes and zeta potentials. Dual drug-loaded cHTM containing indomethacin (IMC) and basic fibroblast growth factor (bFGF) were prepared via a one-pot procedure. With favorable IMC loading, the loading efficiencies of bFGF into cHTM were much higher than those in the controls due to the presence of heparin on the micellar surface. After bFGF was added to IMC loaded cHTM the surface of HTM became less negative with an increase in size, suggesting successful binding of positively charged bFGF to heparinized micelle surfaces. In vitro release data clearly showed more sustained release of IMC and bFGF as compared with non-cross-linked micelles. Based on these results, we suggest that cHTM can be used as a new drug delivery platform for controlled dual drug release.
我们报告了一种使用肝素化 4 臂聚（丙烯氧化物）（PPO）-聚（乙氧化物）（PEO）胶束（cHTM）的控制双药物递送系统，该系统通过酶壳交联（SCL）进行空间稳定。通过化学共轭将酪胺（TA）连接到 4 臂 PPO-PEO（Tetronic）和肝素上，分别得到 Tetronic-TA（Tet-TA）和肝素-TA（Hep-TA）。为了制备一系列 cHTM，将不同量的 Hep-TA 加入到 Tet-TA 的胶束溶液中，然后加入辣根过氧化物酶（HRP）和过氧化氢（H2O2）以触发 TA 基团在胶束表面之间的 SCL。增加 Hep-TA 的进料量导致 cHTM 中的肝素含量增加，从而导致具有更多负电荷表面的胶束尺寸增加。所有 SCL 胶束在 4 周以上的时间内均表现出高度稳定性，其尺寸和 zeta 电位几乎没有变化。通过一锅法制备了包含吲哚美辛（IMC）和碱性成纤维细胞生长因子（bFGF）的双载药 cHTM。由于在胶束表面上存在肝素，因此 IMC 的 bFGF 负载效率比对照物高得多，达到了有利的 IMC 负载。在向 IMC 负载的 cHTM 中添加 bFGF 后，HTM 的表面变得不那么负电性，尺寸增大，表明带正电荷的 bFGF 成功结合到肝素化胶束表面。体外释放数据清楚地表明，与未交联的胶束相比，IMC 和 bFGF 的释放更持久。基于这些结果，我们认为 cHTM 可用作控制双药物释放的新型药物递送平台。
