【摘要】 目的 制备顺铂长循环脂质体，并对其进行工艺优化、质量评价和小鼠体内抗肿瘤效果研究。方法 采用氢化大豆磷脂酰胆碱（HSPC）、二棕榈酰磷脂酰甘油钠（DPPG-Na）、培化磷脂酰乙醇胺（MPEG-2000-DSPE）和胆固醇（CHOL）作为组成脂类，溶于体积分数90%乙醇作为脂相，顺铂溶于水解液三羟甲基氨基甲烷（Tris）溶液作为水相，将水相、脂相溶液混合孵育，挤出得到粒径均一的脂质体，透析置换外相溶液除去未包封的药物，得到顺铂长循环脂质体。以包封率和粒径作为指标，筛选影响产品工艺和质量的关键因素。用C57BL/6小鼠进行体内前列腺癌药效学和药动学研究。结果 通过单因素考察磷脂浓度、混合温度、孵育时间、挤出温度和透析倍数对工艺的影响，并通过正交试验以包封率为指标验证最优工艺。采用最佳工艺条件制备了三批样品，得到的产品粒径在（111.4±1.5） nm左右，透析后包封率在（98.22±0.45）%以上。与注射用顺铂普通制剂相比，顺铂长循环脂质体耐受剂量提高；相较于游离药物组，其肿瘤抑制效果也显著增强（P≤0.01）。结论 该方法可以制备出包封率高、稳定性好、疗效显著的顺铂长循环脂质体，为下一步临床研究奠定基础。更多还原

【Abstract】 Objective Cisplatin long-circulating liposomes were prepared, and their processes were optimized, quality was evaluated, and their anti-tumor effects in mice were studied. Methods Hydrogenated soybean phospholipids(HSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphorylglycerol sodium salt(DPPG-Na), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000](MPEG-2000-DSPE), and cholesterol(CHOL) were used as the lipid components and dissolved in 90% ethanol as the lipid phase. Cisplatin was dissolved in tris(hydroxymethyl) aminomethane(Tris) solution as the aqueous phase. The aqueous phase and lipid phase solutions were mixed and incubated, and extruded to obtain liposomes with uniform particle size. The external phase solution was replaced by dialysis to remove the unencapsulated drug to obtain cisplatin long-circulating liposomes. The key factors affecting the fabricating process and quality of the liposomes were screened according to its encapsulation efficiency and particle size. In vivo pharmacodynamic and pharmacokinetic studies were conducted on prostate cancer model using C57BL/6 mice. Results The effects of phospholipid concentration, mixing temperature, incubation time, extrusion temperature, and dialysis ratio were investigated via single-factor experiments. Orthogonal design was then conducted to verify the optimized process. Three batches of samples were prepared under the optimal process parameters, resulting a particle size of approximately(111.4 ± 1.5) nm and a post-dialysis encapsulation efficiency of over(98.22 ± 0.45)% of the obtained liposomes. Compared with the conventional cisplatin injection formulation, the cisplatin long-circulating liposomes indicated an improved tolerated dose. Moreover, their tumor-inhibiting effect was significantly enhanced compared with the free drug group(P ≤ 0.01). Conclusion In this study, a novel method was established to prepare cisplatin long-circulating liposomes with a high encapsulation efficiency, good stability and significant curative effect, laying a basis for further clinical practice.更多还原