Reducible Poly(Oligo-d-Arginine) as an Efficient Carrier of the Thymidine Kinase Gene in the Intracranial Glioblastoma Animal Model

• Published in: Journal of pharmaceutical sciences 2015-11, Vol.104 (11), p.3743-3751
• Main Authors: Kim, Hyun Ah, Lee, Hyun-Lin, Choi, Eunji, Kim, Yong-Hee, Lee, Minhyung
• Format: Article
• Language: English
• Subjects: Animals; Arginine - analogs & derivatives; Brain - pathology; Brain Neoplasms - genetics; Brain Neoplasms - pathology; Brain Neoplasms - therapy; cancer; Cell Line, Tumor; gene delivery; gene therapy; Gene Transfer Techniques; Genes, Reporter; Genetic Therapy; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Genetic Vectors - therapeutic use; Glioblastoma - genetics; Glioblastoma - pathology; Glioblastoma - therapy; Humans; Oxidation-Reduction; polymeric drug carrier; polymeric drug delivery systems; Rats; Thymidine Kinase - genetics
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.24576

Gene therapy has been considered as an alternative treatment for glioblastoma therapy. In this study, a glioblastoma-specific suicide gene, pEpo–NI2–SV–TK, was delivered into the intracranial glioblastoma model using reducible poly(oligo-d-arginines) (rPOA). pEpo–NI2–SV–TK has the erythropoietin (Epo) enhancer and the nestin intron 2 (NI2) for glioblastoma specific gene expression. The in vitro studies showed that the rPOA formed stable complexes with pEpo–NI2–SV–TK. In the MTT and TUNEL assays, rPOA showed lower cytotoxicity than polyethylenimine (25kDa, PEI25k). In addition, the rPOA/pEpo–NI2–SV–TK complex induced higher glioblastoma cell death under hypoxic condition than normoxic condition, suggesting that pEpo–NI2–SV–TK induced gene expression in the hypoxic tumor tissue. For in vivo therapeutic efficacy evaluation, the rPOA/pEpo–NI2–SV–TK complex was injected into the brains of an intracranial glioblastoma rat model. The rPOA/pEpo–NI2–SV–TK injected group had a significantly reduced tumor size, compared with the control and the PEI25k/pEpo–NI2–SV–TK injected group. The TUNEL assay showed that the rPOA-pEpo–NI2–SV–TK complex had more apoptotic cells than the control and PEI25k/pEpo–NI2–SV–TK injected groups. These results suggest that the rPOA is an efficient carrier for pEpo–NI2–SV–TK and increased the therapeutic efficacy in the intracranial glioblastoma models. Therefore, the rPOA/pEpo–NI2–SV–TK complex may be useful for glioblastoma specific gene therapy. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association. J Pharm Sci 104:3743–3751, 2015.