共载索拉非尼与双硫仑靶向胶束的制备与表征

Preparation and Characterization of Targeted Micelles Co-Loaded with Sorafenib and Disulfiram

目的制备共载索拉非尼和双硫仑的普朗尼克P123-半乳糖(索拉非尼/双硫仑-半乳糖-P123)胶束。方法采用CCK-8法筛选索拉非尼和双硫仑最优药物协同比例。采用薄膜水化法制备索拉非尼/双硫仑-半乳糖-P123胶束,采用星点设计-响应面法优选最优工艺;采用高效液相色谱法测定包封率和载药率;采用马尔文粒度测定仪测定粒径、Zeta电位、多分散指数(PDI);通过透射电镜观察形态;采用透析法测定释放度。结果索拉非尼-双硫仑(1∶2,m/m)为最优药物协同比例。星点设计-响应面法优选最优工艺为总投药量20.67 mg,总材料量140.54 mg,水化体积8.22 mL。按此工艺制备,索拉非尼的包封率为(94.2±0.03)%,载药率为(5.38±0.32)%;双硫仑的包封率为(92.07±0.01)%,载药率为(7.89±0.32)%。所制得纳米胶束形态为球形,分散均匀,粒径为(61.36±0.74)nm,Zeta电位为(-9.38±1.5)mV,PDI为0.292±0.070。在pH 7.4环境中,索拉非尼和双硫仑在72 h时的释放率分别为58.70%,14.90%;在pH 5.0环境中,索拉非尼和双硫仑在72 h时的释放率分别为97.20%,28.60%。结论采用薄膜水化法制备的索拉非尼/双硫仑-半乳糖-P123胶束工艺优良、稳定性良好,具有较好的包封率、pH敏感性和缓释释放作用,可有效聚集在肿瘤部位。

Objective To prepare Pluronic P123-galactose(sorafenib/disulfiram-galactose-P123)micelles co-loaded with sorafenib and disulfiram.Methods CCK-8 method was used to select the optimal drug synergistic ratio of sorafenib and disulfiram.Sorafenib/disulfiram-galactose-P123 micelles were prepared by the thin film hydration method,and the optimal process was optimized by the central composite design-response surface methodology(CCD-RSM).The high-performance liquid chromatography(HPLC)method was used to determine encapsulation efficiency and drug loading rate.Malvern particle size analyzer was used to measure particle size,Zeta potential,and polydispersity index(PDI).The morphology was observed through transmission electron microscopy.The dialysis method was used to determine the release rate.Results Sorafenib-disulfiram(1∶2,m/m)was the optimal drug synergistic ratio.The optimal process of CCD-RSM was as follows:the total drug dosage was 20.67 mg,the total material dosage was 140.54 mg,and the hydration volume was 8.22 mL.According to this process,the encapsulation efficiency of sorafenib was(94.2±0.03)%,and the drug-loading rate of sorafenib was(5.38±0.32)%.The encapsulation efficiency of disulfiram was(92.07±0.01)%,and the drug-loading rate of disulfiram was(7.89±0.32)%.The prepared nano micelles were spherical,uniformly dispersed,with a particle size of(61.36±0.74)nm,a Zeta potential of(-9.38±1.5)mV,and a PDI of 0.292±0.070.Under the environment with pH of 7.4,the release rates of sorafenib and disulfiram at 72 h were 58.70%and 14.90%,respectively.Under the environment with the pH of 7.4,the release rates of sorafenib and disulfiram at 72 h were 58.70%and 14.90%,respectively.Under the environment with the pH of 5.0,the release rates of sorafenib and disulfiram at 72 h were 97.20%and 28.60%,respectively.Conclusion Sorafenib/disulfiram-galactose-P123 micelles prepared by the thin film hydration method have excellent process,good stability,good encapsulation efficiency,pH sensitivity,and sustained release effect,which can effectively aggregate at the tumor site.