顺铂纳米脂质体的小鼠体内药代动力学研究

Pharmacokinetics of cisplatin packaged in a nanometer liposome

背景与目的:顺铂是临床常见的具有放疗增敏作用的抗肿瘤药物,但由于其进入体内迅速与血浆蛋白结合而限制了放疗增敏作用的发挥,顺铂的缓释制剂有望延长药物的作用时间,增加疗效,并降低毒性,因此本研究旨在探索长循环纳米脂质体包裹的顺铂在小鼠体内的药物动力学过程。方法:选用C57BL/6N近交系Lewis肺癌荷瘤小鼠80只(肿瘤生长5～7d),分成两组,普通顺铂组(CDDP)和顺铂脂质体组(LDDP),尾静脉分别注射顺铂注射液和顺铂长循环纳米脂质体,剂量均为6mg/kg,于注射后不同的时间取血并处死动物,取肿瘤、肾、肝和肺组织,每个时间点各5只小鼠。采用高效液相色谱法(HPLC)测定游离铂的含量。药动学软件3P97进行数据分析。结果:CDDP组小鼠在注射后游离铂立即达到最高血药浓度3.24μg/ml,并迅速降低,2h后在血液中已经无法检测出游离铂。LDDP组小鼠注射后1h,血浆游离铂达峰浓度13.79μg/ml,是CDDP组峰浓度的4倍多。72h后血药浓度为1.04μg/ml,血中顺铂浓度呈明显的两相性变化过程,初始相顺铂浓度快速下降,半衰期为1.27h,其后第二相顺铂浓度缓慢下降,半衰期为19.47h。结论:顺铂纳米脂质体新配方,使游离铂的血药浓度长时间维持在相对较高的水平。初步达到了长循环,缓释的要求。

Background and purpose：Cisplatin is one of the antitumor drugs with characteristics of radiosensitization.However,its application is limited because of its rapid bonding to protein in serum,thus,sustained-release preparation of cisplatin is expected to improve the therapeutic effect.In this study,the pharmacokinetics of cisplatin packaged in a nanometer polyethylene glycol（PEG）liposome was explored in mice.Methods：Eighty C57BL/6N mice bearing Lewis cancer were divided into two groups,CDDP group and LDDP group.5-7 days after tumor growth,the mice were given either cisplatin solution（CDDP）or cisplatin liposome（LDDP）respectively in two groups through their tail veins with dosage of 6 mg/kg.At different time points,five mice were sacrificed after their blood was collected,then their lungs,livers,kidneys and tumors were taken out.The content of free platinum in these plasmas and tissues was detected by HPLC.Results：In CDDP group,3.24 μg/ml of the peak concentration of free platinum in plasma was achieved soon after drug injection,but it decreased rapidly,and no free platinum could be detected after two hours.In LDDP group,13.79 μg/ml of the peak concentration was reached in 1 hour,4 times of that in CDDP group,and was documented.During the early hours after LDDP was injected,the free platinum concentration of LDDP group decreased very fast,after that,the intensity of the decline was very slow,and a concentration of 1.04 μg/ml could still be found after 72 hours.There were two-change phases of free platinum in LDDP group,in first phases,the concentration decreased very fast,t1/2 =1.27 hours,then the concentration declined very slowly,t1/2 =19.47 hours.Conclusions：The liposome of cisplatin made of a new preparation can keep the free platinum a higher level of concentration in plasma for a long time.