靶向纳米胶粒PSMA-a10/TGX-221对人前列腺癌裸鼠移植瘤的抑制作用及安全性研究

Tumor-suppressing effect and safety of targeted nanomicellar PSMA-a10/TGX-221 in nude mice heterotransplanted models of human prostate

目的探讨靶向纳米胶粒PSMA-a10/TGX-221对人前列腺癌裸鼠移植瘤的生长抑制作用及其安全性。方法建立前列腺癌裸鼠移植瘤模型,将成瘤裸鼠随机分为PPG组(尾静脉注射PPG溶剂)、裸露TGX221组(尾静脉注射裸露TGX221)及纳米TGX221组(尾静脉注射PSMA-a10/TGX-221纳米胶粒),观察各组裸鼠移植瘤生长情况并绘制肿瘤生长曲线;检测药物对各组荷瘤裸鼠血常规、肝肾功能、心、肝及肾组织学的影响;Western blot检测各组肿瘤组织中p110β和bcl-2蛋白的表达。结果治疗后第13天,纳米TGX221组和裸露TGX221组肿瘤生长速度明显慢于PPG组(P<0.05)。第17天,纳米TGX221组肿瘤大小和裸露TGX221组肿瘤大小出现差异(P<0.05)。治疗结束后纳米TGX221组肿瘤大小均小于其他两组(P<0.05),裸露TGX221组对肿瘤生长的抑制率低于纳米TGX221组(P<0.05)。与PPG组和裸露TGX221组相比,纳米TGX221组p110β和bcl-2蛋白表达均下降(P<0.05)。不同给药组荷瘤裸鼠的白细胞数、血红蛋白、丙氨酸氨基转移酶和肌酐差异均无统计学意义(均P>0.05)。PPG组和裸露TGX221组可见心肌细胞轻度水肿,各组肝、肾组织形态正常,无镜下可见的炎细胞浸润和损伤。结论PSMA-a10/TGX-221纳米胶粒具有良好的肿瘤靶向特异性和生物相容性,可以通过抑制p110β的活性,降低bcl-2的表达来抑制前列腺癌的生长。

Objective To investigate the treatment efficiency and safety of targeted nanomicellar PSMA-a10/TGX-221 in nude mice heterotransplanted models of human prostate cancer.Methods Heterotransplanted models of human prostate cancer cell line LNCaP cells in nude mice were established.The mice were randomly divided into three groups during the experiment:PPG group(tail vein injection of PPG solvent),naked TGX221 group(tail vein injection of naked TGX221),nanomicellar TGX221 group(tail vein injection of PSMA-a10/TGX-221 nanomicellar).The growth of tumors was observed and the growth curve was mapped.The expression ofp110β and bcl-2 were examined by Western blot The pathological changes of heart,liver and kidney tissue,routine blood test and biochemical test were used to evaluate the biosafety of nanomicellar TGX221.Results The tumor growth rate was significantly slower in the nanomicellar TGX221 group and naked TGX221 group than that in the PPG group(all P<0.05)on the 13th day after treatment.On the 17th day,there was a difference in the tumor size between the nanomicellar TGX221 group and the naked TGX221 group(all P<0.05).The tumor quality in the nanomicellar TGX221 group was lighter than that in the other two groups,and the difference was statistically significant(p<0.05).The inhibition rate of tumor growth by naked TGX221 was lower than that of nanomicellar TGX221 group(P<0.05).Compared with the PPG group and naked TGX221 group,the protein expressions of p 110β and bcl-2 in the nanomicellar TGX221 group were decreased,and the differences were significant(p<0.05).There were no significant differences in the number of white blood cells,hemoglobin,alanine aminotransferase,and creatinine in tumor-bearing nude mice in different administration groups(all P>0.05).Slight edema of myocardial cells was seen in the PPG group and naked TGX221 group,suggesting that the myocardium was damaged,while the myocardial cells in the nano-TGX221 group were normal.The morphology of liver and kidney tissues of nude mice in each group was normal,and no inflammatory cell infiltration and damage were visible under the microscope.Conclusions The PSMA-a10/TGX-221 nanomicellar was an effective anti-cancer agent for prostate cancer with high tumor targeting specificity and biocompatibility,which can inhibit the growth of prostate cancer by inhibiting the activity ofp110β and reducing the expression of bcl-2.