摘要
通过二硫键键合聚乙二醇(PEG;)和伊立替康活性代谢物SN38得到还原响应性的两亲性聚合物PEG-SS(O)-SN38,采用薄膜分散法将PEG-SS(O)-SN38制成自组装胶束。透射电镜(TEM)观察显示胶束呈球形或类球形。采用动态光散射法(DLS)测得其平均粒径为(106.3±0.5)nm、多分散系数为0.19±0.05。荧光法测得的临界胶束浓度为(0.070±0.008)mg/ml,提示形成的胶束能较好地维持结构完整性。在体外模拟的还原性环境中,测得该胶束2 h时释出的SN38含量增加至(66.55±0.53)%。在pH 7.4磷酸盐缓冲液(PBS)和胎牛血清(FBS)中,该胶束的48 h累积释放率分别为(50.24±4.53)%、(57.43±2.92)%,说明具有一定的缓释效果;并且,该胶束与PBS孵育24 h或与FBS孵育8 h,粒径几乎不变,表明PEG-SS(O)-SN38形成的胶束在模拟的生理条件下稳定性良好。体外细胞毒性试验结果显示,该胶束对人胰腺癌(Capan-1)细胞具有显著的生长抑制作用。裸小鼠体内药效试验结果显示,与相同剂量的盐酸伊立替康注射液相比,PEG-SS(O)-SN38自组装胶束对荷Capan-1瘤裸小鼠具有明显的肿瘤抑制作用,且裸小鼠体质量没有显著下降。
Reduction-responsive amphiphilic polymer PEG-SS(O)-SN38 was synthesized by conjugation of polyethylene glycol(PEG;) and the active metabolite SN-38 of irinotecan by disulphide bonds.Then,the self-assembled micelles were prepared by thin-film dispersion method.The transmission electron microscopy(TEM) observation revealed that the micelles were spherical in shape.The average particle size and polydispersion index measured by dynamic light scattering were (106.3±0.5)nm and 0.19±0.05.The critical micelle concentration(CMC) measured by fluorescence method was (0.070±0.008)mg/ml,suggesting that the formed micelles could maintain structural integrity.The content of SN38 released from the micelles increased to (66.55±0.53)% after incubation for 2 h in the simulated reductive tumor microenvironment in vitro.The cumulative release amounts at 48 h of the self-assembled micelles were (50.24±4.53)% in pH 7.4 phosphate buffer(PBS) and (57.43±2.92)% in fetal bovine serum(FBS),which proved that the self-assembled PEG-SS(O)-SN38 micelles had sustained-release effects.In addition,the particle sizes of the self-assembled PEG-SS(O)-SN38 micelles were almost unchanged in PBS for 24 h and in FBS for 8 h.The results showed that the self-assembled PEG-SS(O)-SN38 micelles had good stability in a simulated physiological environment.In vitro cytotoxicity showed that the self-assembled PEG-SS(O)-SN38 micelles had a significant growth inhibition effect on human pancreatic cancer(Capan-1) cells.Furthermore,compared with irinotecan hydrochloride injection at the same dose,the self-assembled PEG-SS(O)-SN38 micelles exhibited significant tumor inhibition in the Capan-1 tumor-bearing nude mice without a remarkable decrease in body weight.
作者
贾李瑛
陈伶俐
孙考祥
JIA Liying;CHEN Lingli;SUN Kaoxiang(School of Pharmaceutical Sciences,Yantai University,Yantai 264000;Pharmaceutical Preparation Research Center,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203)
出处
《中国医药工业杂志》
CAS
CSCD
北大核心
2022年第1期69-76,共8页
Chinese Journal of Pharmaceuticals
