阿霉素纳米胶束在大鼠体内的组织分布研究
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摘要
目的建立大鼠组织样品的预处理及液相色谱-串联质谱(LC-MS/MS)测定方法,测定阿霉素纳米胶束和阿霉素注射液在大鼠体内的组织分布。方法采用甲醇∶生理盐水(4∶1)作为组织匀浆介质;色谱柱:SunFire C_(18)(250 mm×4.6 mm,5μm);流动相:5 mmol·L~(-1)醋酸铵-乙腈-甲酸(70∶30∶0.5);流速:0.5 mL·min~(-1);对乙酰氨基酚作为内标。在此色谱条件下,以多反应监测(MRM)扫描方式进行检测,将大鼠随机分成2组,分别测定大鼠尾静脉注射阿霉素纳米胶束和阿霉素注射液后各组织中阿霉素的药物质量浓度,给药剂量均为1 mg·kg~(-1)。结果大鼠各组织中阿霉素的质量浓度在0.5～200 ng·mL~(-1)范围内线性关系良好,r=0.999 1,样品的日内精密度RSD值小于6.7%,日间精密度RSD值小于13.2%。结论该方法快速、准确,适用于阿霉素在大鼠体内组织分布的研究,阿霉素纳米胶束与阿霉素注射液在心、脾和肺中的分布差异无统计学意义,在肝和肾中的分布差异有统计学意义,2种制剂均不能透过血脑屏障。
Objective To establish a method for the determination of adriamycin nanomicelles and adriamycin injection in rat tissues by liquid chromatography-tandem mass spectrometry(LC-MS/MS).Methods Using methanol-physiological saline(4∶1) as the tissue sample homogenate medium,the separation was performed on a reversed-phase SunFire C_(18) column(250 mm×4.6 mm,5 μm).The mobile phase was consisted of 5 mmol·L~(-1)ammonium acetate-acetonitrile-formic acid(70∶30∶0.5),the flow rate:0.5 mL·min~(-1).The internal standard substance was paracetamol.Under the chromatographic conditions,the detection was carried out by multiple reaction monitoring(MRM).Rats were divided into 2 groups at random.Adriamycin nano micelles and adriamycin injection were used in rats by caudal vein injection with 1 mg·kg~(-1) respectively.Results The method had a linear calibration curve over the range of 0.5-200 ng·mL~(-1)(r=0.999 1).The intra-day precision RSD were within 6.7% and inter-day precision RSD were within 13.2% for the analyte.Conclusion The proposed analytic method is rapid,sensitive,and can be applied for the identification and quantification in tissue distribution studies of adriamycin in rats.The distribution of adriamycin nano micelles and adriamycin injection in heart,spleen and lung showed no significant difference,but showed significant differences in the liver and kidney.Both preparations could not penetrate the blood-brain barrier.
Objective To establish a method for the determination of adriamycin nanomicelles and adriamycin injection in rat tissues by liquid chromatography-tandem mass spectrometry(LC-MS/MS).Methods Using methanol-physiological saline(4∶1) as the tissue sample homogenate medium,the separation was performed on a reversed-phase SunFire C_(18) column(250 mm×4.6 mm,5 μm).The mobile phase was consisted of 5 mmol·L~(-1)ammonium acetate-acetonitrile-formic acid(70∶30∶0.5),the flow rate:0.5 mL·min~(-1).The internal standard substance was paracetamol.Under the chromatographic conditions,the detection was carried out by multiple reaction monitoring(MRM).Rats were divided into 2 groups at random.Adriamycin nano micelles and adriamycin injection were used in rats by caudal vein injection with 1 mg·kg~(-1) respectively.Results The method had a linear calibration curve over the range of 0.5-200 ng·mL~(-1)(r=0.999 1).The intra-day precision RSD were within 6.7% and inter-day precision RSD were within 13.2% for the analyte.Conclusion The proposed analytic method is rapid,sensitive,and can be applied for the identification and quantification in tissue distribution studies of adriamycin in rats.The distribution of adriamycin nano micelles and adriamycin injection in heart,spleen and lung showed no significant difference,but showed significant differences in the liver and kidney.Both preparations could not penetrate the blood-brain barrier.
引文
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[19] Tahover E,Patil Y P,Gabizon A A.Emerging delivery systems to reduce doxorubicin cardiotoxicity and improve therapeutic index:focus on liposomes[J].Anti-cancer Drugs,2015,26(3):241-258.
[2] Carter S K.Adriamycin-a review[J].J Natl Cancer Inst,1975,55(6):1265-1274.
[3] Park J H,Kwon S,Nam J O,et al.Self-assembled nanoparticles based on glycol chitosan bearing 5beta-cholanic acid for RGD peptide delivery[J].J Control Release,2004,95(3):579-588.
[4] Gao Z G,Lee D H,Kim D I,et al.Doxorubicin loaded pH-sensitive micelle targeting acidic extracellular pH of human ovarian A2780 tumor in mice[J].J Drug Target,2005,13(7):391-397.
[5] 刘哲,宋晓东,惠汝太.阿霉素心脏毒性的预防[J].中国分子心脏病学杂志,2007,7(6):379-380.
[6] 曲震理,王国贤,吴红芳,等.川芎嗪对阿霉素所致体外心肌细胞损伤的保护作用[J].中国组织工程研究与临床康复,2007,11(43):8683-8686.
[7] Bernstein D,Burridge P.Patient-specific pluripotent stem cells in doxorubicin cardiotoxicity:a new window into personalized medicine[J].Prog Pediatr Cardiol,2014,37(1/2):23-27.
[8] 余喆,周青,乔友备,等.聚苹果酸-阿霉素/多烯紫杉醇纳米共聚物的制备及性质研究[J].西北药学杂志,2018,33(3):369-373.
[9] 周佳莹,周立宏,张晓君,等.阿霉素-五味子乙素pH敏感聚合物胶束的制备与制剂学性质[J].沈阳药科大学学报,2016,33(9):686-695.
[10] 王雪莉,马红岩.阿霉素长循环热敏脂质体联合射频热疗的药效学研究[J].肿瘤防治研究,2016,43(5):350-354.
[11] Shi J,Wang L,Zhang J,et al.A tumor-targeting near-infrared laser-triggered drug delivery system based on GO@Ag nanoparticles for chemo-photothermal therapy and X-ray imaging[J].Biomaterials,2014,35(22):5847-5861.
[12] 王敏哲,贺欣,杨铁虹.基于当归多糖的酶敏肿瘤靶向纳米递药体系的研究[J].西北药学杂志,2018,33(2):211-216.
[13] 陈思明,金艺,乔明曦,等.大鼠血浆中阿霉素HPLC-MS/MS测定法及其在药动学中的应用[J].沈阳药科大学学报,2012,29(3):199-202,233.
[14] 贾莉,乔明曦,胡海洋,等.温度/pH双敏感嵌段共聚物胶束的体外性质研究[J].药学学报,2011,46(7):839-844.
[15] Tang L,Yang X,Yin Q,et al.Investigating the optimal size of anticancer nanomedicine[J].Proc Natl Acad Sci U S A,2014,111(43):15344-15349.
[16] Hoshyar N,Gray S,Han H,et al.The effect of nanoparticle size on in vivo pharmacokinetics and cellular interaction[J].Nanomedicinc (Lond),2016,11(6):673-692.
[17] 査如琴.基于SPSS的双总体(σ12,σ22未知,n≤30)配对样本t检验与独立样本t检验[J].读与写杂志,2016,13(7):44-45.
[18] 宋晓斌.键合表阿霉素纳米胶束肝动脉灌注靶向治疗大鼠移植性肝癌的实验研究[D].长春:吉林大学,2011.
[19] Tahover E,Patil Y P,Gabizon A A.Emerging delivery systems to reduce doxorubicin cardiotoxicity and improve therapeutic index:focus on liposomes[J].Anti-cancer Drugs,2015,26(3):241-258.