目的 合成4种顺铂前药并考察其自组装能力，制备聚乙二醇（PEG）化顺铂前药纳米粒，联合丁硫氨酸亚砜亚胺（BSO）用于肿瘤的共同治疗。方法 以顺铂为原料药，合成4种顺铂前药（C6-Pt、C10-Pt、C12-Pt、C18-Pt）；采用一步纳米沉淀法筛选出自组装能力较强的顺铂前药，制备纳米粒；完成纳米粒的外观形态、稳定性、粒径、Zeta电位及体外药物释放考察；CCK-8法考察顺铂、C12-Pt NPs对MCF-7、B16F10、LLC、4T1的细胞毒性，以B16F10为细胞模型测定BSO的无毒浓度及C12-Pt NPs和BSO联用的最佳摩尔比，考察顺铂、顺铂/BSO、C12-Pt NPs、C12-Pt NPs/BSO对B16F10细胞的生长抑制作用；试剂盒法测定顺铂、顺铂/BSO、C12-Pt NPs、C12-Pt NPs/BSO处理B16F10细胞24 h后的胞内GSH水平。结果 成功合成4种顺铂前药（C6-Pt、C10-Pt、C12-Pt、C18-Pt）；顺铂前药质量浓度为1 mg·mL^-1时，仅有C12-Pt能自组装成为纳米粒（C12-Pt NPs）；C12-Pt NPs粒径分布均匀，具有较好的长期稳定性和血浆稳定性；在含0、1 mmol·L-1 DTT的PBS（pH 7.4）缓冲液中纳米粒释药缓慢，在含10 mmol·L-1 DTT的PBS（pH 7.4）缓冲液中，72 h内药物释放率可达76%；C12-Pt NPs对4种肿瘤细胞的抑制作用强于顺铂；对于B16F10细胞，BSO未表现出明显毒性；当顺铂前药、BSO摩尔比为1∶40时对肿瘤细胞抑制作用最强，表明BSO对顺铂前药具有较好的化疗增敏作用；与顺铂相比，顺铂/BSO、C12-Pt NPs、C12-Pt NPs/BSO处理后B16F10细胞中GSH水平均显著下降（P＜0.001）。结论 C12-Pt NPs制剂学性质良好，C12-Pt NPs对多种肿瘤细胞均具有较强的生长抑制作用，BSO能够有效增强C12-Pt NPs对肿瘤的杀伤效果。

Objective To synthesize four cisplatin prodrugs and examine their self-assembly ability to prepare PEGylated cisplatin prodrug nanoparticles, combined BSO for co-treatment of tumors. Methods Four cisplatin prodrug (C6-Pt, C10-Pt, C12-Pt, C18-Pt) were synthesized using cisplatin as the raw material drug; a one-step nanoprecipitation method was used to screen the cisplatin precursors with better self-assembly ability; the appearance morphology, stability, particle size, Zeta potential and in vitro drug release of the nanoparticles were investigated; The cytotoxicity of cisplatin solution and C12-Pt NPs solution on MCF-7, B16F10, LLC, and 4T1 was examined; determination of the non-toxic concentration of BSO and the optimal molar ratio for the combination of C12-Pt NPs and BSO using B16F10 as a tumor cell model; the growth inhibitory effects of cisplatin solution, cisplatin/BSO mixed solution, C12-Pt NPs solution and C12-Pt NPs/BSO mixed solution on B16F10 cells were examined; the intracellular GSH contents of B16F10 cells after 24 h treatment with cisplatin solution, cisplatin/BSO mixed solution, C12-Pt NPs solution and C12-Pt NPs/BSO mixed solution were determined. Results Four cisplatin prodrugs (C6-Pt, C10-Pt, C12-Pt, C18-Pt) were successfully synthesized; only C12-Pt could self-assemble successfully at a cisplatin prodrug concentration of 1 mg·mL^-1; C12-Pt NPs had a uniform particle size distribution with good long-term stability and plasma stability; the drug release rate of nanoparticles was slow in PBS (pH 7.4) buffer containing 0 and 1 mM DTT, and up to 76% within 72 h in PBS (pH 7.4) buffer containing 10 mmol·L^-1 DTT; the inhibitory effect of C12-Pt NPs on four tumor cells was stronger than that of cisplatin solution; for B16F10 cells, BSO did not show significant toxicity; the strongest inhibitory effect on tumor cells was observed when the molar ratio of cisplatin prodrug:BSO was 1:40, indicating that BSO has a better chemotherapy sensitization effect on cisplatin prodrugs. Compared with cisplatin, the levels of GSH in B16F10 cells significantly decreased after treatment with cisplatin/BSO, C12-Pt NPs, and C12-Pt NPs/BSO (P＜0.001). Conclusion C12-Pt NPs have good formulation properties; C12-Pt NPs have strong growth inhibitory effects on a variety of tumor cells; BSO can effectively enhance the tumor-killing effect of C12-Pt NPs.

R944.2

国家自然科学基金资助项目（82003675）；高校优秀青年骨干教师国内访问研修项目（gxgnfx2022015）