目的 制备共载吉西他滨单磷酸盐（gemcitabine monophosphate，GMP）/紫杉醇（paclitaxel，PTX）的靶向纳米粒并对其大鼠体内药动学行为进行研究。方法 采用金正均Q值法筛选GMP/紫杉醇协同比例；采用钙磷沉淀-微乳法、薄膜分散法制备1，2-二硬酯酰-sn-甘油-3-磷酰乙醇胺-聚乙二醇-cRGD修饰的非对称脂质双层紫杉醇/GMP纳米粒（P/G-NPs）；采用透射电子显微镜、马尔文激光粒度仪、超滤离心法、LC-MS/MS、流通池法测定P/G-NPs的形态、平均粒径、Zeta电位、包封率及载药量、体外释放行为，并对P/G-NPs iv后在大鼠体内药动学行为进行研究。结果 GMP/紫杉醇联用最佳物质的量比为17：1，按照该配比制备得到P/G-NPs外观呈乳白色光，粒子形态呈球型，平均粒径为（85.7±10.5）nm，多分散指数（PDI）为0.14±0.06，Zeta电位为（18.30±0.63）mV。GMP和紫杉醇的包封率分别为（93.60±1.20）%和（98.70±0.50）%，载药量分别为（6.300±0.100）%和（0.800±0.004）%。体外释放行为显示P/G-NPs可实现药物的pH值敏感性缓释。药动学参数显示，P/G-NPs药-时曲线下面积是紫杉醇和吉西他滨单磷酸盐混合溶液的6倍。结论 钙磷沉淀-微乳法、薄膜分散法联用可实现溶解度相异的GMP、紫杉醇的按比例协同包载，得到稳定性良好的pH值敏感性靶向纳米粒，为更好发挥其临床应用提供了支持。

Objective To prepare targeting nanoparticles co-loaded with gemcitabine monophosphate (GMP) and paclitaxel (PTX) and investigate its in vivo pharmacokinetics behaviors in rats. Methods The optimal molar ratio of GMP to PTX was screened by the Q value method. Calcium-phosphate precipitation-microemulsion and thin film dispersion methods were used to prepare the 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]-cRGD modified nanoparticles with asymmetric lipid bilayers containing PTX and GMP (P/G-NPs). Transmission electron microscope, Malvern Nano ZS, ultrafiltration combined with LC-MS/MS, and flow-through cell method were employed to study the physicochemical properties and drug concentrations of P/G-NPs after iv injection. Results P/G-NPs were prepared by the optimal molar ratio of GMP to PTX of 17:1. P/G-NPs was milky white with spherical shape. The mean particle size was (85.7±10.5) nm, PDI was 0.14±0.06, and the Zeta potential was (18.30±0.63) mV. The entrapment efficiency of GMP and PTX in P/G-NPs were (93.60 ±1.20)% and (98.70 ±0.50)%, respectively, and the drug loading was (6.300 ±0.100)% and (0.800 ±0.004)%, respectively. In vitro release of P/G-NPs showed a sustained-release behavior with certain pH sensitivity. The AUC of P/G-NPs was six folds higher than that of mixed solution containing free PTX and GMP. Conclusion The targeting synergistic nanoparticles co-loaded with GMP and PTX, two drugs with different solubility, can be obtained by calcium-phosphate precipitation-microemulsion and thin film dispersion methods, with good stability and pH-sensitive release profile, which provides support for better clinical application in future.

R283.6

国家自然科学基金资助项目（81760639）；国家自然科学基金资助项目（81603054）；江西省自然科学基金资助项目（20171BAB215066）；江西省自然科学基金资助项目（20202ACBL216015）；江西省自然科学基金资助项目（20202BABL206157）；江西省教育厅科研项目（GJJ190666）；江西省教育厅科研项目（GJJ190663）；江西省青年井冈学者（赣教党字[2018]41号，张婧）；江西省新世纪百千万人才（2017082李翔）；江西省新世纪百千万人才（2020028张婧）；江西中医药大学“1050”青年人才（李翔，张婧）