还原响应性卡巴他赛交联前药胶束的制备及评价

Preparation and Evaluation of Redox-Sensitive Cabazitaxel Cross-Linked Prodrug Micelles

通过在卡巴他赛(CTX)的C-2位接枝可交联硫辛酸(LA)制备改构药物CTX-LA,以硫辛酸接枝的两亲性嵌段共聚物聚乙二醇-聚乳酸-硫辛酸(mPEG-PLA-(LA)4)为辅料,采用固体分散-薄膜水化法制备了包载CTX的载药胶束(CTX-loaded CCMs)。通过纳米粒度分析仪、紫外-可见分光光度计、透射电子显微镜(TEM)、傅里叶变换红外光谱(FT-IR)、核磁共振氢谱(1HNMR)、X射线衍射(XRD)等对载药胶束的粒径分布、包封率、载药量、稳定性进行测试,并对体外药物释放行为、体外细胞毒性、急性毒性和抗肿瘤效果进行考察。结果表明:载药胶束平均粒径为(26.09±0.18)nm,包封率为(97.43±2.34)%,载药量为8.94%。该胶束稳定性极好,具有明显的缓释效果和还原响应性,可显著降低CTX的急性毒性,药物耐受剂量较CTX市售制剂(Jevtana)提高2倍以上,且抗肿瘤效果显著提升,对A549肺腺癌生长抑制率高达99.06%。

By grafting lipoic acid(LA)onto the C-2 position of cabazitaxel(CTX),a modified cross-linked cabazitaxel(CTX-LA)was successfully synthesized.Disulfide core-crosslinked CTX prodrug micelles(CTX-loaded CCMs)were prepared by a solid dispersion-thin film hydration method using a telodendrimer methoxy-poly(ethylene glycol)-poly(D,Llactic acid)-end-capped with lipoic acid(mPEG-PLA-(LA)4)as the carrier.The particle size distribution,encapsulation efficiency,drug loading and stability of the drug-loaded micelles were investigated by nano particle size analyzer,ultravioletvisible spectrophotometer,transmission electron microscope(TEM),Fourier transform infrared spectroscopy(FT-IR),nuclear magnetic resonance hydrogen spectroscopy(1H-NMR)and X-ray diffraction(XRD).The normal physiological environment was simulated to induce drug release in vitro.The acute toxicity was investigated with BALB/c Nude mice as a model,and the cytotoxicity and anti-tumor activity were investigated with A549 lung adenocarcinoma cells as a cell model.Results showed that the mean particle size of the prepared micelles was(26.09±0.18)nm,the encapsulation rate was(97.43±2.34)%,and the drug loading capacity was 8.94%.Meanwhile,the micelles had excellent colloidal stability,and had obvious sustained release effect and reduction responsiveness. In addition, the micelles significantly reduced the acute toxicity of CTX without significant cytotoxicity, and the drug tolerance dose was more than 2 times higher than that of the commercial available cabazitaxel formulation (Jevtana). The anti-tumor efficacy was significantly improved with a tumor growth inhibition rate of 99.06% in an A549 lung cancer xenograft model.