School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, People's Republic of China.
Acta Biomater. 2012 Nov;8(11):3963-73. doi: 10.1016/j.actbio.2012.07.021. Epub 2012 Jul 24.
The convenient and precise fabrication of drug-hydrogel formulations with satisfactory degradability and a well-controlled drug release profile are crucial factors for injectable hydrogel formulations in clinical applications. Here a new injectable thermosensitive hydrogel formed from poly(ε-caprolactone) (PCL)-poly(ethylene glycol)-poly(ε-caprolactone) amphiphilicco-polymers with 1,4,8-trioxa[4.6]spiro-9-undecanone (TOSUO) moieties incorporated in the poly(ε-caprolactone) (PCL)block (PECT) was constructed to provide a route to tailor the degradation and drug release behavior. The effect of hydrophilic cyclic ether moieties on the degradation of and drug release by PECT hydrogels were evaluated in vitro and in vivo. The results indicated that a freeze-dried powder of paclitaxel-loaded PECT nanoparticles rapidly dissolved in water at ambient temperature with slightly shaking and formed a stable injectable in situ drug-hydrogel formulation at body temperature, which is convenient for clinical operations because it avoids the need for pre-quenching or long-term incubation. The paclitaxel distribution was also more quantitative and homogeneous on entrapping paclitaxel in PECT nanoparticles. Further, the small number of pendant cyclic ether groups in PCL could decrease the cystallinity and hydrophobicity and, as a result, the in vitro and in vivo retention time of PECT hydrogels and the release of entrapped paclitaxel could be tuned from a few weeks to months by varying the amount of PTOSUO in the hydrophobic block. Significantly, paclitaxel-loaded PECT nanoparticles and free paclitaxel could be simultaneously released during the in vitro paclitaxel release from PECT hydrogels. A histopathological evaluation indicated that in vivo injected PECT hydrogels produced only a modest inflammatory response. Thus pendant cyclic ether modification of PCL could be an effective way to achieve the desired degradation and drug release profiles of amphiphilicco-polymer thermosensitive hydrogels and PECT hydrogels may be suitable for local drug delivery.
具有令人满意的可降解性和药物释放性能的药物水凝胶制剂的便捷和精确制备，是可注射水凝胶制剂在临床应用中的关键因素。本文构建了一种新型的可注射温敏水凝胶，由聚（ε-己内酯）（PCL）-聚（乙二醇）-聚（ε-己内酯）两亲性共聚物组成，其中含有 1,4,8-三恶烷[4.6]螺-9-十一酮（TOSUO）部分并入聚（ε-己内酯）（PCL）嵌段（PECT）中，以提供一种定制降解和药物释放行为的途径。在体外和体内评价了亲水性环醚部分对 PECT 水凝胶降解和药物释放的影响。结果表明，载紫杉醇的 PECT 纳米粒子的冻干粉末在室温下在轻微摇晃下迅速溶解在水中，并在体温下形成稳定的可注射原位药物水凝胶制剂，这便于临床操作，因为它避免了预淬火或长期孵育的需要。紫杉醇的分布也更定量和均匀地包封在 PECT 纳米粒子中。此外，PCL 中少量的侧挂环醚基团可以降低结晶度和疏水性，因此通过改变疏水性嵌段中 PTOSUO 的量，可以调节 PECT 水凝胶的体外和体内保留时间以及包封的紫杉醇的释放，从数周到数月不等。显著的是，载紫杉醇的 PECT 纳米粒子和游离紫杉醇可以在 PECT 水凝胶的体外紫杉醇释放过程中同时释放。组织病理学评价表明，体内注射的 PECT 水凝胶仅产生适度的炎症反应。因此，PCL 的侧挂环醚修饰可以是实现两亲性共聚物温敏水凝胶所需的降解和药物释放性能的有效方法，PECT 水凝胶可能适用于局部药物递送。
