目的 制备包载三苯基膦-阿霉素（TPP-DOX，TD）和槲皮素（Que）的还原敏感性抗肿瘤耐药纳米混合胶束，并对其进行制剂学评价。方法 以还原敏感性聚合物材料聚乙二醇-脱氧胆酸-二硫键-聚天冬氨酸苄酯（mPEG-DCA-SS-PBLA，PDSP）和非还原敏感性聚合物材料聚乙二醇-脱氧胆酸-碳碳键-聚天冬氨酸苄酯（PDCP）为载体，通过溶剂挥发法分别包载TD和Que，制备还原敏感性纳米胶束PDSP@TD、PDSP@Que和非还原敏感性纳米胶束PDCP@TD、PDCP@Que。应用激光粒度仪分析各胶束粒径、聚合物分散性指数（PDI），Zeta电位仪分析其 Zeta电位；HPLC法检测载药量、包封率；透射电镜法观察形态；进行各胶束储存稳定性、稀释稳定性、血浆稳定性、冻干粉复溶稳定性考察；考察 10 μmol·L^-1、10、20 mmol·L^-1谷胱甘肽（GSH）对胶束粒径的影响；考察在含0、10 μmol·L^-1、10 mmol·L^-1、20 mmol·L^-1 GSH的释放介质中各胶束体外释放行为。结果 制备的PDSP@TD、PDCP@TD胶束粒径约为 180 nm，PDSP@Que、PDCP@Que胶束的粒径约为230 nm；胶束的Zeta电位均在-17.4 mV以下；4种胶束的载药量和包封率分别在6.3%和65.3%以上；4种胶束的形态均呈类球形，物理稳定性良好；在浓度为 10、20 mmol·L^-1的 GSH存在下，PDSP@TD和 PDSP@Que粒径发生较为明显的变化；游离药物 TD和 Que在含有 20 mmol·L^-1 GSH的释放介质中 48 h 时的累积释放率均小于 30%，PDCP@TD 和PDCP@Que在所有介质中48 h内的累积释放率均在38%左右，PDSP@TD、PDSP@Que及混合胶束在20 mmol·L^-1 GSH释放介质中 48 h 内累积释放率均在 78% 左右。结论 制备的还原敏感性纳米胶束具有良好的稳定性、肿瘤细胞内还原敏感性，可以用于后续体内外抗肿瘤耐药研究。

Objective To prepare a reduction-responsive hybrid nano-micelles containing triphenylphosphine-doxorubicin (TPPDOX, TD) and quercetin (Que), and to evaluate its pharmacokinetics.Methods The redox-sensitive polymer material poly(ethylene glycol) -deoxycholic acid-disulfide-poly(aspartic acid benzyl ester), PDSP, and the non-redox-sensitive polymer material poly (ethylene glycol) -deoxycholic acid-carbon-carbon bond-poly(aspartic acid benzyl ester), PDCP, were used as the carrier. TD and Que were loaded onto the polymers by solvent evaporation, respectively, to prepare redox-sensitive nanovesicles PDSP@TD and PDSP@Que, and non-redox-sensitive nanovesicles PDCP@TD and PDCP@Que. The particle size, polydispersity index (PDI), and Zeta potential of the nanovesicles were analyzed using a laser particle size analyzer. The drug loading and encapsulation efficiency were determined by HPLC. The morphology of the nanovesicles was observed by transmission electron microscopy. The stability of the nanovesicles in storage, dilution, plasma, and freeze-dried powder reconstitution was evaluated. The effects of 10 μmol·L^-1, 10 mmol·L^-1, and 20 mmol·L^-1 GSH on the particle size of the nanovesicles were examined. The in vitro release behavior of the nanovesicles in release media containing 0, 10 μmol·L^-1, 10, and 20 mmol·L^-1 GSH was also investigated. Results The particle size of the prepared PDSP@TD and PDCP@TD micelles was approximately 180 nm, while the particle size of PDSP@Que and PDCP@Que micelles was around 230 nm, with a zeta potential below -17.4 mV. All of four micelles exhibited LC and EE values exceeding 6.3% and 65.3%, respectively. TEM imaging revealed that all of four micelles displayed spherical morphology and demonstrated excellent physical stability under various conditions. Under the condition of 10 and 20 mmol·L^-1 GSH, the particle size of PDSP@TD and PDSP@Que changes noticeably. The cumulative release rate of free drugs TD and Que in the release medium containing 20 mmol·L^-1 GSH is less than 30% within 48 h, while the cumulative release rate of PDCP@TD and PDCP@Que in all mediums was around 38% within 48 h, and the cumulative release rate of PDSP@TD, PDSP@Que, and the mixed vesicle in the release medium containing 20 mmol·L^-1 GSH was around 78% within 48 h.Conclusion The reduction-sensitive huydrid nano-micelles prepared exhibit excellent stability, and tumor cell-specific reduction sensitivity, rendering them suitable for subsequent investigations on in vitro and in vivo antitumor drug resistance.

R943

河南省科技攻关项目（232102311178）；河南应用技术职业学院名师工作室项目（2022-03）；河南应用技术职业学院教师创新团队项目（2022-02）