吉西他滨纳米衍生物在裸鼠体内的抗肿瘤作用

Anti-tumor effect of gemcitabine derivatives in nude mice

目的研究聚乙二醇(PEG)修饰后的新型吉西他滨药物抑制肿瘤生长的效果。方法将吉西他滨脂肪酸酰胺衍生物(Gem C18)与纳米粒(NPs)结合形成一种新型的吉西他滨纳米粒(Gem C18-NPs),并部分进行PEG修饰(PEG-Gem C18-NPs)。建立裸鼠TC-1或Bx PC-3肿瘤模型,观察PEG-Gem C18-NPs的抗肿瘤活性。结果在TC-1肿瘤模型中,Gem C18-NPs组和Gem C组从第1次给药后第11天起至第20天裸鼠肿瘤体积均小于对照组(P<0.05);Gem C18-NPs组与Gem C组从第17天至第20天裸鼠肿瘤体积比较差异有统计学意义(P<0.05)。对照组、Gem C组和Gem C18-NPs组的裸鼠肿瘤质量分别为(1.15±0.26)、(0.10±0.05)、(0.03±0.03)g,3组之间两两比较差异均有统计学意义(P<0.05)。在Bx PC-3肿瘤模型中,Gem C18-NPs组与Gem C组在第1次给药后第15天后2组裸鼠肿瘤体积比较差异有统计学意义(P<0.05);Gem C18-NPs组、Gem C组在第15天前与对照组肿瘤体积比较差异无统计学意义(P>0.05);Gem C组和Gem C18-NPs组裸鼠体质量比较差异无统计学意义(P>0.05),注射3周后,对照组裸鼠的体质量较Gem C18-NPs组和Gem C组减轻(P<0.05)。在NPs是否会对肿瘤生长产生影响的实验中,NPs组与对照组裸鼠各个时间点肿瘤体积比较差异均无统计学意义(P>0.05)。Gem C18-NPs组在第13、15、17、19天时肿瘤体积与对照组和NPs组比较差异均有统计学意义(P<0.05)。Gem C18-NPs组裸鼠肿瘤内血管数为60.9±16.0,对照组为85.4±26.5,2组比较差异有统计学意义(P<0.05)。Gem C18-NPs组裸鼠肿瘤内血管的平均长度为(12.6±18.9)μm,对照组为(27.9±45.4)μm,2组比较差异有统计学意义(P<0.05)。Gem C18-NPs组裸鼠体内Caspase-3阳性细胞数为13.9±5.3,对照组为5.9±2.3,2组比较差异有统计学意义(P<0.05)。PEG-Gem C18-NPs组和Gem C18-NPs组各时间点肿瘤体积比较差异均无统计学意义(P>0.05);PEG-Gem C18-NPs组和Gem C18-NPs组各时间点肿瘤体积与对照组比较差异有统计学意义(P<0.05)。结论新型的吉西他滨药物Gem C18-NPs与PEGGem C18-NPs均可明显提高吉西他滨抗肿瘤的疗效。

Objective To study the inhibition effect of chemically modified gemcitabine（ Gem C） on tumor in vivo.Methods A new Gem C nanoparticle formulation was developed by incorporating of a Gem C fatty acid amide derivative [4-（ N）-stearoyl-gemcitabine,Gem C18]and nanoparticles（ NPs）（ Gem C18-NPs）,then a part of Gem C18-NPs was modified by polyethylene glycol（ PEG）（ PEG-Gem C18-NPs）. The TC-1 or Bx PC-3 tumor model was stablished in nude mice,and the antitumor effect of PEG-Gem C18-NPs was observed. Results In TC-1 models,the tumor volumes of nude mice from the 11 th to 20 thafter the first administration in Gem C18-NPs group and Gem C group were significantly smaller than those in control group（ P〈0. 05）; there were statistic difference of tumor volumes between Gem C18-NPs group and Gem C group from the 17 th day to 20 thday after the first administration（ P〈0. 05）. The body weight of nude mice in control group,Gem C group and Gem C18-NPs group was（ 1. 15 ± 0. 26）,（ 0. 10 ± 0. 05） and（ 0. 03 ± 0. 03） g,there was statistic difference of the body weight of nude mice among the three groups（ P〈0. 05）. In Bx PC-3 models,there was statistic difference of tumor volumes between Gem C18-NPs group and Gem C group after the 15thday（ P〈0. 05）; there was no statistic difference of tumor volumes between Gem C18-NPs group,Gem C group and control group before the 15thday（ P〈0. 05）. There was no statistic difference of body weight of nude mice between Gem C group and Gem C18-NPs group; three weeks after administration,body weight of nude mice in control group was lighter than Gem C18-NPs group and Gem C group（ P〈0. 05）. In the experiment of whether NPs can affect the growth of tumor,there was no statistic difference of tumor volumes between NPs group and control group（ P〈0. 05）;there was statistic difference of tumor volumes between Gem C18-NPs group and NPs group,control group at the 13 th,15th,17 th and 19thday（ P〈0. 05）. The blood vessel number in tumor in Gem C18-NPs group and control group was 60. 9 ± 16. 0,85. 4 ± 26. 5 respectively; there was statistic difference of blood vessel number between the two groups（ P〈0. 05）. The average length of blood vessel in Gem C18-NPs group and control group was（ 12. 6 ± 18. 9） μm and（ 27. 9 ± 45. 4） μm respectively; there was statistic difference of the average length of blood vessel between the two groups（ P〈0. 05）. The positive cell number of Caspase-3 in Gem C18-NPs group and control group was 13. 9 ± 5. 3 and 5. 9 ± 2. 3 respectively; there was statistic difference of the positive cell number between the two groups（ P〉0. 05）. There were no statistic difference of tumor volumes between PEG-Gem C18-NPs group and Gem C18-NPs group at all time point（ P〈0. 05）; there were statistic difference of tumor volumes between PEG-Gem C18-NPs group,Gem C18-NPs group and control group at all time point（ P〈0. 05）. Conclusion The new Gem C formulation of Gem C18-NPs and PEG-Gem C18-NPs can potentially improve the curative effect of Gem C in the treatment of tumor.