目的 制備包載三苯基膦-阿霉素（TPP-DOX，TD）和槲皮素（Que）的還原敏感性抗腫瘤耐藥納米混合膠束，并對其進(jìn)行制劑學(xué)評價。方法 以還原敏感性聚合物材料聚乙二醇-脫氧膽酸-二硫鍵-聚天冬氨酸芐酯（mPEG-DCA-SS-PBLA，PDSP）和非還原敏感性聚合物材料聚乙二醇-脫氧膽酸-碳碳鍵-聚天冬氨酸芐酯（PDCP）為載體，通過溶劑揮發(fā)法分別包載TD和Que，制備還原敏感性納米膠束PDSP@TD、PDSP@Que和非還原敏感性納米膠束PDCP@TD、PDCP@Que。應(yīng)用激光粒度儀分析各膠束粒徑、聚合物分散性指數(shù)（PDI），Zeta電位儀分析其 Zeta電位；HPLC法檢測載藥量、包封率；透射電鏡法觀察形態(tài)；進(jìn)行各膠束儲存穩(wěn)定性、稀釋穩(wěn)定性、血漿穩(wěn)定性、凍干粉復(fù)溶穩(wěn)定性考察；考察 10 μmol·L^-1、10、20 mmol·L^-1谷胱甘肽（GSH）對膠束粒徑的影響；考察在含0、10 μmol·L^-1、10 mmol·L^-1、20 mmol·L^-1 GSH的釋放介質(zhì)中各膠束體外釋放行為。結(jié)果 制備的PDSP@TD、PDCP@TD膠束粒徑約為 180 nm，PDSP@Que、PDCP@Que膠束的粒徑約為230 nm；膠束的Zeta電位均在-17.4 mV以下；4種膠束的載藥量和包封率分別在6.3%和65.3%以上；4種膠束的形態(tài)均呈類球形，物理穩(wěn)定性良好；在濃度為 10、20 mmol·L^-1的 GSH存在下，PDSP@TD和 PDSP@Que粒徑發(fā)生較為明顯的變化；游離藥物 TD和 Que在含有 20 mmol·L^-1 GSH的釋放介質(zhì)中 48 h 時的累積釋放率均小于 30%，PDCP@TD 和PDCP@Que在所有介質(zhì)中48 h內(nèi)的累積釋放率均在38%左右，PDSP@TD、PDSP@Que及混合膠束在20 mmol·L^-1 GSH釋放介質(zhì)中 48 h 內(nèi)累積釋放率均在 78% 左右。結(jié)論 制備的還原敏感性納米膠束具有良好的穩(wěn)定性、腫瘤細(xì)胞內(nèi)還原敏感性，可以用于后續(xù)體內(nèi)外抗腫瘤耐藥研究。

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

河南省科技攻關(guān)項目（232102311178）；河南應(yīng)用技術(shù)職業(yè)學(xué)院名師工作室項目（2022-03）；河南應(yīng)用技術(shù)職業(yè)學(xué)院教師創(chuàng)新團(tuán)隊項目（2022-02）