pH响应型苯硼酸酯连接嵌段聚合物的合成及药物控释

Synthesis of pH-Responsive Phenylborat-Linked Block Polymers for Controlled Drug Delivery

以含苯硼酸酯(PBE)的聚乙二醇单甲醚(mPEG)大分子(mPEG-PBE-OH)为引发剂,引发ε-己内酯(ε-CL)开环聚合,制备了以硼酸酯结构连接的pH敏感两亲性聚合物(mPEG-PBEPCL)。然后,使该聚合物在水相环境中自组装形成"核-壳"结构纳米胶束,并将阿霉素(DOX)负载在胶束内核中,形成载药胶束(DOX@mPEG-PBE-PCL)。通过核磁共振氢谱(~1 H-NMR)、红外光谱(FT-IR)和凝胶渗透色谱(GPC)对聚合物结构进行了表征,通过透射电镜(TEM)和动态光散射(DLS)等对胶束的形貌和粒径进行了表征,通过紫外吸收光谱分析了胶束载药量和载药效率,并对胶束的pH敏感释药性能与体外细胞毒性进行了验证。结果表明:聚合物自组装形成粒径约127nm的球形胶束,对DOX具有较高的负载能力;聚合物具有良好的pH响应性和生物相容性,DOX@mPEG-PBE-PCL能在肿瘤细胞弱酸性环境中释放DOX,有效递送至细胞核;与游离的DOX·HCl相比,DOX@mPEG-PBE-PCL对鼠源黑色素瘤B16F10细胞具有相近的抗肿瘤活性。

A pH-sensitive amphiphilic polymer Poly(ethylene glycol)-phenylborate-poly(ε-caprolactone)(mPEG-PBE-PCL) linked by a borate structure was prepared by ring-opening polymerization of ε-caprolactone (ε-CL) initiated by a benzene-borate-containing polyethylene glycol macromolecule (mPEG-PBE-OH). The polymer was capable of self-assembling into a “core-shell” nanomicelles structure in aqueous environment, which can load doxorubicin (DOX) in their cores. The structure of polymer was characterized by 1H-NMR, IR spectra and gel permeation chromatography (GPC). The morphology and particle size of the prepared micelles were determined by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The drug loading and loading efficiency were analyzed by ultraviolet absorption detection. The investigations on pH-sensitive release properties of the micelles and the in vitro cytotoxicity were carried out as well. The results showed that the polymer micelles had a low critical micelle concentration, showed spherical micelles with a diameter of about 127 nm, and had a high loading capacity for DOX. Furthermore, the polymer presented good pH responsiveness and biocompatibility. The loaded DOX was released in weak acidic environment of tumor cells and was delivered effectively to nucleus. DOX@mPEG-PBE-PCL had a similar antitumor activity with free DOX ·HCl against murine melanoma B16F10 cells. Therefore, such smart micelles containing pH-responsive boronate bonds present great potential in efficient intracellular delivery of antitumor drugs.