目的 制备聚丙烯酸(PAA)修饰氨基改性介孔二氧化硅(MSNs)载三氧化二砷(ATO)纳米粒(PAA-ATO-MSNs), 并考察其理化性质、体外释药特性及大鼠体内药动学行为。方法 共沉淀法制备氨基改性MSNs, 静电吸附载入ATO, PAA酸碱共轭制备PAA-ATO-MSNs。采用透射电镜、小角粉末衍射仪、氮气吸脱附仪、红外光谱仪、热重分析仪、激光粒度仪等考察其理化性质;高速离心法结合电感耦合等离子发射光谱(ICP)测定其包封率及载药量;选用磷酸盐缓冲液(PBS)(pH 5.0、6.0和7.4)作为释放介质, 透析袋法考察其体外释药特性;大鼠尾iv给药后, 考察ATO体内药动学行为。结果 制备的PAA-ATO-MSNs透射电镜下外观呈圆形或类圆形, 平均粒径为(158.60±1.32)nm, Zeta电位为(-28.40±0.34)mV, 包封率和载药量分别为(40.95±3.21)%和(11.42±1.75)%。体外释药具有pH值响应性, 累积释药量随pH值减小而增大。药动学研究表明, 与ATO原料药和ATO-MSNs相比, PAA-ATO-MSNs给药后ATO的t_1/2β显著延长, AUC显著增大(P<0.01)。结论 PAA-ATO-MSNs体外释药具有明显的pH值响应性及缓释特性, 能明显改善ATO大鼠体内药动学行为, 该载体作为ATO肿瘤靶向递药系统具有较好的应用前景。

Objective To prepare polyacrylic acid grafted arsenic trioxide-loaded pH-responsive mesoporous silica nanoparticles (PAA-ATO-MSNs) and to investigate their physicochemical properties, in vitro release behavior, and pharmacokinetics in rats. Methods PAA was covalently attached to the exterior surface of amino group functionalized MSNs prepared by co-condensation method and ATO was loaded into them by electrostatic adsorption. Transmission electron microscope (TEM), small angle X-ray diffraction (SAXRD), nitrogen adsorption, thermogravimetric analysis (TGA), fourier transform infrared (FT-IR) spectra, and laser particle size analyzer were used to determine the physicochemical properties. The entrapment efficiency (EE) and drug loading (DL) of PAA-ATO-MSNs were investigated with the method of high speed centrifugation combined with inductively coupled plasma emission spectrum (ICP). The drug release behavior of PAA-ATO-MSNs was studied using dynamic dialysis method, PBS (pH 5.0, 6.0, and 7.4) chosen as release media. Pharmacokinetic behavior of PAA-ATO-MSNs after iv injection in rats was studied. Results Morphology of PAA-ATO-MSNs was spherical and the mean particle size, Zeta potential, EE, and DL of PAA-ATO-MSNs were (158.60 ± 1.32) nm, (-28.40 ± 0.34) mV, (40.95 ± 3.21)%, and (11.42 ± 1.75)%, respectively. In vitro release behavior of PAA-ATO-MSNs showed pH-responsive characteristic and the cumulative release amount was increased with the decrease of pH value. Compared with ATO-Sol and ATO-MSNs group, t_1/2β was significantly prolonged and AUC was significantly increased (P < 0.01). Conclusion Release of ATO from PAA-ATO-MSNs showed the obvious pH-responsive characteristic and sustained-release in vitro and PAA-ATO-MSNs could improve the pharmacokinetic behavior in rats. PAA-MSNs might be promising carrier to load ATO for cancer therapy.

国家自然科学基金资助项目(81274089/H2806, 81473361/H2806);浙江省自然科学基金资助项目(LZ13H280001)