七甲川菁染料介导的近红外荧光成像和对肝癌的靶向药物递送  

Heptamethine carbocyanine dye-mediated near-infrared fluorescence imaging and targeted drug delivery to liver cancer

作　　者：葛煦 张彩勤[1] 赵勇[1] 白冰[1] 谭邓旭 张贺 师长宏[1] GE Xu;ZHANG Caiqin;ZHAO Yong;BAI Bing;TAN Dengxu;ZHANG He;SHI Changhong(Lab Animal Center of the Fourth Military Medical University, Xi’an 710032, China)

机构地区：[1]第四军医大学实验动物中心,西安710032

出　　处：《中国实验动物学报》2018年第6期746-751,共6页Acta Laboratorium Animalis Scientia Sinica

基　　金：军队实验动物专项(SYDW2016-006)~~

摘　　要：目的初步评估七甲川菁染料衍生物(IR-783)和化疗药物吉西他滨(gemcitabine)的缀合物(NIRG)对肝癌模型荧光成像及靶向治疗效果。方法首先使用肝癌细胞系Hep3B验证肝癌细胞对NIRG的特异性吸收,并制备该细胞的裸鼠皮下移植瘤模型,观察NIRG在CDX模型中的近红外荧光成像效果;制备三例肝癌(C64003、C34566和B66873)裸鼠皮下PDX模型,研究NIRG在此模型中的肿瘤靶向荧光成像效果以及治疗效果,同时通过免疫组织化学法观察肝癌特异性抗原AFP在三例肝癌PDX模型的肿瘤组织中的表达,以及观察与NIRF染料特异性吸收相关的抗原HIF1α和OATP的表达。结果通过肝癌细胞系Hep3B观察到NIRG在肿瘤细胞内结合的部位分别为线粒体和溶酶体,在肝癌CDX皮下模型中发现NIRG特异性聚集肿瘤部位,随着肿瘤的生长NIRF信号增强,并与生物发光信号具有良好的相关性(R^2=0.99716);免疫组织化学检测显示在三例肝癌PDX模型中的AFP、 HIF1α和OATP均高表达;NIRG在三例肝癌PDX模型中荧光成像结果表明具有很好的肿瘤靶向性,同时能够抑制肿瘤的生长,显示了良好的治疗效果。结论化合物NIRG兼具荧光成像和肿瘤靶向转运化疗药物的能力,可作为人类肝肿瘤的新型影像探针和靶向制剂。Objective The goal here was to conduct a preliminary evaluation of the efficacy of a conjugate(NIRG)of heptamethine carbocyanine dye(IR-783)and the chemotherapeutic drug gemcitabine for tumor fluorescent imaging and targeted therapy.Methods First,the liver cancer cell line Hep3B was used to verify the specific absorption of NIRG,and nude mice as models of tumors from a subcutaneous xenograft of Hep3B cells were prepared to observe the effect of the NIRG fluorescence imaging in this CDX model.Three subcutaneous PDX models of liver cancer cases(C64003,C34566and B66873)were prepared to study the effect of NIRG tumor-targeted fluorescence imaging and targeted therapy.Simultaneously,the expression of the hepatoma-specific antigen AFP was observed by immunohistochemistry in tumor tissues of these models.In addition,the expression of the antigens HIF1αand OATP associated with the specific uptake of NIRF dye was observed.Results The results showed that the binding sites of NIRG in liver cancer cell line Hep3B cells were mitochondria and lysosomes.NIRG-specific tumor sites were found in the subcutaneous CDX model of liver cancer,and the NIRF signal was enhanced with the growth of the tumor.NIRF signal andthe luminescence signal had a good correlation(R2=0.99716).The IHC results showed that AFP was highly expressed inthe three PDX models,and HIF1αand OATP were also highly expressed.The fluorescence imaging results showed thatNIRG had good tumor targeting and could inhibit tumor growth,showing a good therapeutic effect.Conclusions Theconjugate NIRG has characteristics suitable for both fluorescence imaging and tumor targeting to deliver chemotherapeuticdrugs.It is potentially an effective novel imaging and targeting agent for treatment of human liver cancer.

关 键 词：七甲川菁染料 荧光成像 肝癌 靶向药物 

分 类 号：Q95-33[生物学—动物学]