卡铂碳包铁纳米笼壳聚糖微球在肝癌大鼠模型体内的分布和药动学研究

Pharmacokinetics and Tissue Distribution of Carboplatin-Fe@C-Loaded Chitosan Nanoparticles in Rat with Transplanted Liver Cancer

目的观察卡铂碳包铁纳米笼壳聚糖微球(carboplatin-Fe@C-loaded chitosan nanoparticles,C-Fe@C-CN)结合磁场在移植性肝癌大鼠模型体内的靶向分布情况和药动学过程。方法建立移植性肝癌大鼠模型40只为A组,正中开腹行肝动脉插管,按卡铂5mg·kg-1体重注入C-Fe@C-CN的生理盐水分散液,以肿瘤组织为靶区施加0.5T磁场30min。分别在给药后0.25,0.5,1,3,6,12,24和48h各时间点,每组取5只大鼠处死,采集血浆、靶区肿瘤、非靶区肝、肾、脾和肺组织标本,石墨炉原子分光光度计测定血浆和组织中卡铂浓度,药物浓度数据用3P87药动学程序分析处理,并组织学观察C-Fe@C-CN的在各脏器分布情况。另40只健康大鼠为B组,以左肝叶为靶区,给予相同的处理作为对照。结果A组靶区肿瘤组织cmax是65.21μg·g-1,为B组靶区肝组织(38.47μg·g-1)的1.7倍。48h时A组靶区肿瘤组织药物浓度是7.27μg·g-1,为B组靶区肝组织(3.11μg·g-1)的2.3倍。A组靶区肿瘤组织AUC是906mg·h·L-1,为B组靶区肝组织(421.34mg·h·L-1)的2.2倍。2组药动学参数值相近。病理学观察显示,C-Fe@C-CN在磁场作用下聚集于肿瘤细胞间隙中,并可栓塞于部分细小动脉。非靶区肝组织内少见C-Fe@C-CN的聚集和栓塞的血管。结论C-Fe@C-CN在体内具有长循环和缓释特性,在磁场的引导下对肿瘤组织具有更强的靶向性,成倍提高肿瘤组织中的药物浓度,延长维持时间。

OBJECTIVE To investigate the blood drug level and pharmacokinetic parameter and to detect the distribution performance of carboplatin-Fe@C-loaded chitosan nanoparticles（C-Fe@C-CN） injected by hepatic artery in rat with transplanted liver cancer. METHODS Forty rats with transplanted liver cancer were assigned to Group A. Abdominal exposure was carried out through a midline abdominal incision, and a cannula was inserted into the hepatic artery and fixed. C-Fe@C-CN was injected into hepatic artery and the liver tumor was under 0.5 T magnetic field as targeted region for 30 min. The doses of carboplatin were 5 mg.kg-1 body weight. The rats were sacrificed 15, 30 min, 1, 3, 6, 12, 24 and 48 h after the injection. The drug levels in plasma, liver tumor, non-targeted liver, kidney, spleen, and hmg were measured by flameless atomic absorption spectrophotometry. The data was analyzed by 3P87 computer program. The distribution of C-Fe@-C-CN in tumor, liver, kidney, spleen, lung tissue were observed. Another forty normal rats were assigned to Group B as control group. The left liver lobe was under magnetic field, and received the same treatment. RESULTS The Cmax of tumor in Group A （65.21 pg.g-l） was 1.7 times as that in targeted liver in Group B （38.47 μg.g-1）. The carboplatin concentration of tumor at 48 h in Group A （7.27 μg-1） was 2.3 times as that of targeted liver in Group B （3.11 μg.g-1）. The AUC of tumor in Group A （906 mg.h.L-1 ） was 2.2 times as a s that o f targeted liver in Group B （421.34 mg.h.L-1 ）. Both group displayed the similar pharmacokinetics performance in vivo. The histology examination demonstrated that a lot of C-Fe@C-CN was accumulated among tumor cell and some small arteries were embolismed due to the accumulation of C-Fe@C-CN in the magnetic field. On the contrast, there was no C-Fe@C-CN in non-targeted region.CONCLUSIONS C-Fe@C-CN with long-circulation and controlled release performance in vivo shows more rcmarkable magnetic target to tumor, increases the levels of drug, prolongs the active time, compared with normal liver tissue under magnetic field.