目的 合成4種順鉑前藥并考察其自組裝能力，制備聚乙二醇（PEG）化順鉑前藥納米粒，聯(lián)合丁硫氨酸亞砜亞胺（BSO）用于腫瘤的共同治療。方法 以順鉑為原料藥，合成4種順鉑前藥（C6-Pt、C10-Pt、C12-Pt、C18-Pt）；采用一步納米沉淀法篩選出自組裝能力較強(qiáng)的順鉑前藥，制備納米粒；完成納米粒的外觀形態(tài)、穩(wěn)定性、粒徑、Zeta電位及體外藥物釋放考察；CCK-8法考察順鉑、C12-Pt NPs對MCF-7、B16F10、LLC、4T1的細(xì)胞毒性，以B16F10為細(xì)胞模型測定BSO的無毒濃度及C12-Pt NPs和BSO聯(lián)用的最佳摩爾比，考察順鉑、順鉑/BSO、C12-Pt NPs、C12-Pt NPs/BSO對B16F10細(xì)胞的生長抑制作用；試劑盒法測定順鉑、順鉑/BSO、C12-Pt NPs、C12-Pt NPs/BSO處理B16F10細(xì)胞24 h后的胞內(nèi)GSH水平。結(jié)果 成功合成4種順鉑前藥（C6-Pt、C10-Pt、C12-Pt、C18-Pt）；順鉑前藥質(zhì)量濃度為1 mg·mL^-1時(shí)，僅有C12-Pt能自組裝成為納米粒（C12-Pt NPs）；C12-Pt NPs粒徑分布均勻，具有較好的長期穩(wěn)定性和血漿穩(wěn)定性；在含0、1 mmol·L-1 DTT的PBS（pH 7.4）緩沖液中納米粒釋藥緩慢，在含10 mmol·L-1 DTT的PBS（pH 7.4）緩沖液中，72 h內(nèi)藥物釋放率可達(dá)76%；C12-Pt NPs對4種腫瘤細(xì)胞的抑制作用強(qiáng)于順鉑；對于B16F10細(xì)胞，BSO未表現(xiàn)出明顯毒性；當(dāng)順鉑前藥、BSO摩爾比為1∶40時(shí)對腫瘤細(xì)胞抑制作用最強(qiáng)，表明BSO對順鉑前藥具有較好的化療增敏作用；與順鉑相比，順鉑/BSO、C12-Pt NPs、C12-Pt NPs/BSO處理后B16F10細(xì)胞中GSH水平均顯著下降（P＜0.001）。結(jié)論 C12-Pt NPs制劑學(xué)性質(zhì)良好，C12-Pt NPs對多種腫瘤細(xì)胞均具有較強(qiáng)的生長抑制作用，BSO能夠有效增強(qiáng)C12-Pt NPs對腫瘤的殺傷效果。

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

國家自然科學(xué)基金資助項(xiàng)目（82003675）；高校優(yōu)秀青年骨干教師國內(nèi)訪問研修項(xiàng)目（gxgnfx2022015）