近红外荧光染料在胃癌人源性肿瘤组织异种移植模型研究中的应用

摘要

目的：建立胃癌人源性肿瘤组织异种移植（ patient－derived tumor xenograft，PDX）裸鼠模型，探讨近红外荧光（ near infrared fluorescence，NIRF）染料IR－783在胃癌PDX模型活体成像研究中的应用。方法取临床胃癌新鲜手术切除标本，裸鼠肾包膜移植建立PDX模型， HE染色比较移植肿瘤组织与患者肿瘤组织形态结构的一致性。将移植肿瘤组织裸鼠皮下接种，20 d后，荷瘤小鼠腹腔注射NIRF染料IR－783（每只10 nmol／L），活体成像连续测定肿瘤部位近红外荧光强度并分析肿瘤体积与荧光强度的相关性；免疫组织化学检测移植肿瘤组织中HIF1α与OATP1B3的表达强度。结果成功建立了3个人胃癌PDX模型，移植肿瘤组织较好的保持了原发肿瘤的特征， NIRF活体成像早期检测到肾包膜部位荧光信号。 PDX模型中肿瘤体积与荧光强度的相关性均在98％以上。移植肿瘤组织中HIF1α与OATP1B3表达呈强阳性。结论 NIRF染料IR－783可在PDX模型肿瘤部位特异性聚集，用于PDX模型的早期检测，这种肿瘤靶向性可能与HIF1α和OATP1B3的表达相关。%Objective To establish a patient-derived gastric cancer xenograft( PDX) model in nude mice and to in-vestigate the application of near infrared fluorescent ( NIRF) dye IR-783 in in vivo imaging of gastric cancer xenograft mod-els.Methods Fresh human gastric cancer tissue was taken and transplanted into the subrenal capsule of nude mice to es-tablish the xenograft model.When the transplanted tumors grew,took part of the tumor tissue to do HE staining and compare the structural characteristics with the primary tumor.Another portion of the tumor was xenografted into nude mice subcutane-ously.Twenty days later,the tumor-bearing mice were injected intraperitoneally with IR-783 dye (10μM) in a dose of 100 mg/20 g.The intensity of the tumor image was monitored by optical NIRF imaging.The correction between tumor volume and fluorescence intensity was analyzed.Finally,the expression of OATP1B3 and HIF1αin the xenografted tumor tissue was detected by immunohistochemistry.Results We successfully established three patient-derived xenograft ( PDH) models of human gastric cancer.The transplanted tumor tissues maintained the histological characteristics of the primary tumor well.NIRF signal can be detec ted in subrenal capsule of the xenografted nude mice.The correlation between tumor size and fluorescence intensity in the PDX models reached higher than 98%.Strong positive expressions of HIF1αand OATP1B3 in the tumor tissues were detected.Conclusions NIRF dye IR-783 can be specifically accumulated at the tumor site,therefore, can be used to detect PDX in vivo early.The tumor targeting property may be related to the expression of OATP1B3 and HIF1α.