Zhou Zhengyuan, Forbes Robert T, D'Emanuele Antony
School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, UK.
School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, UK.
Int J Pharm. 2017 May 15;523(1):260-269. doi: 10.1016/j.ijpharm.2017.03.032. Epub 2017 Mar 18.
In this study we explore the preparation of core-crosslinked micelles of linear-dendritic methoxy-poly(ethylene glycol) (MPEG)-co-poly(ester-sulfide) (PES) polymers to improve the stability of such polymeric micelle systems against premature disintegration and drug release. A series of MPEG-PES copolymers were synthesised via stepwise reactions of acetylation and thiol-ene photoreaction. Surface tension measurement showed that the copolymers with ethenyl surface groups could self-associate in dilute aqueous solutions to form micelles. Crosslinking within the micelle cores in the presence of dithioerythritol (DTT) linker was initiated under UV radiation. The formation of core-crosslinked micelles was confirmed by HPLC in combination with charged aerosol detection (CAD). The copolymers were found to readily hydrolyse under acidic conditions due to the ester-containing dendrons. Drug solubilisation capacities of the micellar solutions were determined using griseofulvin as a poorly water-soluble model drug. The solubility of griseofulvin showed a 10-fold enhancement in 1% w/v micelle solution and increased with the concentration of the copolymers. Drug release studies indicated that a more sustained release of griseofulvin was achieved for the core-crosslinked micelles compared to the non-crosslinked micelles, attributable to greater stability of the crosslinked core structure. The findings of this study present a new pathway towards developing biodegradable polymeric nanocarriers.
在本研究中，我们探索了线性-树枝状甲氧基聚（乙二醇）（MPEG）-共-聚（酯-硫醚）（PES）聚合物的核交联胶束的制备方法，以提高此类聚合物胶束系统对过早解体和药物释放的稳定性。通过乙酰化和硫醇-烯光反应的逐步反应合成了一系列MPEG-PES共聚物。表面张力测量表明，具有乙烯基表面基团的共聚物可在稀水溶液中自缔合形成胶束。在紫外辐射下，在二硫苏糖醇（DTT）连接剂存在的情况下引发胶束核心内的交联。通过高效液相色谱结合带电气溶胶检测（CAD）证实了核交联胶束的形成。由于含酯树枝状分子，发现共聚物在酸性条件下容易水解。使用灰黄霉素作为难溶性模型药物测定胶束溶液的药物增溶能力。在1%w/v胶束溶液中，灰黄霉素的溶解度提高了10倍，并且随着共聚物浓度的增加而增加。药物释放研究表明，与非交联胶束相比，核交联胶束实现了灰黄霉素更持续的释放，这归因于交联核心结构的更高稳定性。本研究的结果为开发可生物降解的聚合物纳米载体提供了一条新途径。
