肿瘤血管抑制剂XY-02与CA4P的组织分布比较研究

Comparisons of tissue distribution of tumor vascular inhibitors XY-02 and CA4P

建立HPLC对肿瘤血管抑制剂XY-02与CA4P在大鼠体内组织分布规律的研究方法,揭示两种药物靶组织的差异与潜在的治疗特征和安全性。SD大鼠分别静脉注射XY-02(80mg/kg)或CA4P(1mg/kg),于给药后15,40,90min采集大鼠心、肝、脾、肺、肾、胃、小肠、脑、子宫、睾丸等组织进行含量测定,以C18(250 mm×4.6 mm×5μm)为色谱柱,0.01%乙酸-甲醇(50∶50,ν/ν)为流动相,流量为1.0 m L/min,检测波长为325 nm。XY-02和CA4P分别在0.15~750μg/m L和0.03~60μg/m L范围内线性关系良好(r>0.999 5),检测限分别为17 ng/m L和4.93 ng/m L。两种肿瘤血管抑制剂均在大鼠组织中有广泛分布和快速消除的特点,预示二者可对各种组织肿瘤具有潜在的治疗作用且体内产生蓄积的可能性小。特别是XY-02在肾脏和肝脏中分布较多,提示XY-02可对临床上较难治疗的肾癌和肝癌有更好的治疗价值;XY-02在心脏和肠道的分布较CA4P低,表明XY-02的心脏毒性和肠道的不良反应比CA4P更小,安全性更好。

A HPLC method was developed for the comparative study of the tissue distribution of CA4P and XY-02 in rats. The test revealed the differences in target tissues as well as the potential treatment and safety features of the two tumor vascular targeting inhibitors. After intravenous administration of XY-02( 80 mg/kg) or CA4P( 1 mg/kg), samples like heart, liver,spleen, lung, stomach, intestine, brain, testis, uterus were taken at 15, 40, and 90 min after dosing. The separation was performed on a ODS column( 250 mm ×4.6 mm ×5 μm) with mobile phase methanol-0.01% acetic acid( 50:50, ν/ν). The wavelength was set at 325 nm and the flow rate was 1 ml/min. Calibration standards show that the excellent linearity range is 0.15-750 μg/m L for XY-02 and 0.03-60.0 μg/m L for CA4P( r>0.999 5). The lowest detectable concentration of XY-02 and CA4 P is 17 ng/m L and 4.93 ng/m L, respectively. The results indicate that both XY-02 and CA4 P are widely distributed and rapidly eliminated in tissues, suggesting that they may have potential treatment effect in vivo tumors in different tissues and the possibility of accumulation in vivo is little. The relatively high distribution of XY-02 in kidney and liver demonstrates that it may have a better value in treating kidney and liver cancers. Compared with CA4 P, XY-02 is lower in cardiotoxicity and gastrointestinal adverse reaction and much safer.