紫杉醇纳米晶的细胞毒作用及药代动力学研究

目的 考察紫杉醇纳米晶对乳腺癌细胞的细胞毒作用,并考察其在小鼠体内的药动学及组织分布特征.方法 采用沉淀法制备紫杉醇纳米晶,采用动态光散射法和透射电镜对纳米晶粒径、Zeta电位及粒子形态进行测量;MTT法评价纳米晶对乳腺癌细胞的细胞毒作用;采用液相色谱-串联质谱（LC-MS/MS）法检测小鼠体内紫杉醇的浓度.结果 所制备的紫杉醇纳米晶平均粒径为194.9 nm,Zeta电位值为-29.6 mV;紫杉醇纳米晶与市售紫杉醇注射液对MCF-7细胞的细胞毒性没有显著性差异（P＞0.05）;紫杉醇纳米晶和紫杉醇注射液在小鼠体内的药-时曲线符合二房室模型,t1/2,α分别为（2.91±0.067）和（3.70±0.063） min,t1/2.β分别为（69.41±0.73）和（53.94 ±0.62） min,AUC（o-∞）分别为（276 700±960）和（464 160±710）μg·min/L,CL分别为（0.036±0.011）和（0.022 ±0.010） L/（min·kg）;与紫杉醇注射液相比,紫杉醇纳米晶在小鼠肝、脾中药物浓度显著增加（P＜0.01）,而在心、肾中药物浓度减少（P＜0.01）.结论 紫杉醇纳米晶与市售紫杉醇注射液细胞毒作用相当,且紫杉醇纳米晶能够快速地分布于周围组织中,主要被肝、脾吸收,能降低心、肾毒性,对减轻药物毒副作用具有一定临床意义.

Cytotoxicity and pharmacokinetics study of paclitaxel nanocrystals

Objective To investigate the cytotoxicity of paclitaxel nanocrystals on breast cancer cells and the characteristics of pharmacokinetics and tissue distribution in mice. Methods Precipitation method was used to prepare paclitaxel nanocrystais. Particle size, Zeta potential and particle morphology of nanocrystals were determined by dynamic light scattering and the transmission electron microscopy. MTT assay was performed to evaluate the cytotoxicity of nanocrystals on breast cancer ceils. Paclitaxel concentration in vivo was detected by LC-MS/MS. Results The average particle size of paclitaxel nanocrystals was 194. 9 nm and the Zeta potential value was -29. 6 mV. There was no significant difference（P 〉 0.05 ）between paclitaxel nanocrystals and commercial Taxol on the cy- totoxicity against MCF-7 cells. The plasma concentration-time profiles of paclitaxel nanocrystals and Taxol in mice were described by a two-compartment model. The t1/2,αwere （2. 91 ± 0. 067 ） and （3.70 ± 0. 063 ） min, t 1/2,βwere （69.41 ± 0. 73 ） and （53.94 ± 0. 62 ） min,AUC（0-∞）were （276 700 ±960） and （464 160 ±710） μg· min/L,CL were （0. 036 ±0. 011 ） and （0. 022 ±0. 010） L/（ min· kg） , respectively. The drug concentration in liver and spleen was significantly increased for paclitaxel nanoerystals compared with Tax- ol（P 〈0. 01 ）, but lower in heart and kidneys （P 〈 0. O1 ）. Conclusion Paclitaxel nanocrystals have the same cytoxicity as Taxol. Paclitaxel nanocrystals, mainly absorbed by the liver and spleen, could rapidly distribute into the surrounding tissue and reduce the toxicity in heart and kidneys, which have clinical significance to decrease the side effects.