Choi Eunji, Han Jaesik, Tan Xiaonan, Oh Jungju, Lee Dahee, Rhim Taiyoun, Lee Minhyung
a Department of Bioengineering, College of Engineering , Hanyang University , Seongdong-Gu , Seoul , Korea.
J Drug Target. 2017 Feb;25(2):156-162. doi: 10.1080/1061186X.2016.1212202. Epub 2016 Jul 27.
Glioblastoma is the most malignant form of brain tumor. In this study, combination therapy with temozolomide (TMZ) and the herpes simplex virus thymidine kinase (HSVtk) gene was evaluated in glioblastoma models. The R7L10 peptide was used as a carrier of TMZ and the HSVtk gene. TMZ was loaded into R7L10 micelles using the oil-in-water emulsion/solvent evaporation method. The TMZ-loaded R7L10 (R7L10-TMZ) micelles formed a complex with the HSVtk gene, pHSVtk. The formation of the R7L10-TMZ/pHSVtk complex was confirmed by gel retardation and heparin competition assays. An in vitro transfection assay demonstrated that the transfection efficiency of R7L10-TMZ was similar to that of R7L10 in C6 glioblastoma cells. R7L10-TMZ had greater anti-tumor effects than TMZ alone in C6 cells in vitro, suggesting that R7L10 is an efficient carrier of TMZ. The in vivo efficacy of the R7L10-TMZ/pHSVtk complex was evaluated in the intracranial glioblastoma model. HSVtk expression in tumors was confirmed by immunohistochemistry. Furthermore, a greater anti-tumor effect was observed in the R7L10-TMZ/pHSVtk group compared with the TMZ or R7L10/pHSVtk single injection group. In conclusion, combined delivery of TMZ and the HSVtk gene using R7L10 peptides may be useful for the treatment of glioblastoma.
胶质母细胞瘤是脑肿瘤中最恶性的形式。在本研究中，对替莫唑胺（TMZ）与单纯疱疹病毒胸苷激酶（HSVtk）基因的联合疗法在胶质母细胞瘤模型中进行了评估。R7L10肽被用作TMZ和HSVtk基因的载体。采用水包油乳液/溶剂蒸发法将TMZ载入R7L10胶束中。载入TMZ的R7L10（R7L10-TMZ）胶束与HSVtk基因pHSVtk形成复合物。通过凝胶阻滞和肝素竞争试验证实了R7L10-TMZ/pHSVtk复合物的形成。体外转染试验表明，R7L10-TMZ在C6胶质母细胞瘤细胞中的转染效率与R7L10相似。在体外，R7L10-TMZ在C6细胞中比单独使用TMZ具有更强的抗肿瘤作用，这表明R7L10是TMZ的有效载体。在颅内胶质母细胞瘤模型中评估了R7L10-TMZ/pHSVtk复合物的体内疗效。通过免疫组织化学证实了肿瘤中HSVtk的表达。此外，与TMZ或R7L10/pHSVtk单次注射组相比，在R7L10-TMZ/pHSVtk组中观察到了更强的抗肿瘤作用。总之，使用R7L10肽联合递送TMZ和HSVtk基因可能对胶质母细胞瘤的治疗有用。
