Dipeptide-functionalized polyamidoamine dendrimer-mediated apoptin gene delivery facilitates apoptosis of human primary glioma cells

被引:31
|
作者
Bae, Yoonhee [2 ]
Green, Eric S. [8 ]
Kim, Goo-Young [9 ]
Song, Su Jeong [1 ]
Mun, Ji Young [7 ]
Lee, Sunray [6 ]
Park, Jong-Il [5 ]
Park, Jong-sang [4 ]
Ko, Kyung Soo [3 ]
Han, Jin [2 ]
Choi, Joon Sig [1 ]
机构
[1] Chungnam Natl Univ, Dept Biochem, Coll Nat Sci, Daejeon 305764, South Korea
[2] Inje Univ, Dept Physiol, Coll Med, Cardiovasc & Metab Dis Ctr, Busan 614735, South Korea
[3] Inje Univ, Sanggye Paik Hosp, Dept Internal Med, Cardiovasc & Metab Dis Ctr, Seoul 139707, South Korea
[4] Seoul Natl Univ, Sch Chem, Seoul 151742, South Korea
[5] Chungnam Natl Univ, Sch Med, Daejeon 301747, South Korea
[6] Cell Engn Origin Res Ctr, 46-21 Susong Dog, Seoul 110140, South Korea
[7] Eulji Univ, Dept Biomed Lab Sci, Coll Hlth Sci, Daejeon, South Korea
[8] Salt Lake Community Coll, Salt Lake City, UT USA
[9] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular Differentiat, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA
基金
新加坡国家研究基金会;
关键词
Apoptin; Gene therapy; PAMAM dendrimer; Human primary glioma cells; Apoptosis; TRANSFECTION EFFICIENCY; BIOLOGICAL APPLICATIONS; PAMAM DENDRIMER; BRAIN-TUMORS; PLASMID DNA; IN-VIVO; THERAPY; DEATH; CANCER; CYTOTOXICITY;
D O I
10.1016/j.ijpharm.2016.09.083
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Glioblastoma multiform (GBM) is the most frequent and aggressive form of brain tumors in adults. However, the development of more efficient and safe nonviral vector gene therapy represents a promising therapeutic approach, using a tumor-specific killer gene, named apoptin. In this study, we describe the efficacy of non-viral gene delivery vectors, the amino acid-conjugated PAMAM derivatives (PAMAM-H-R and PAMAM-H-K) in delivering a therapeutic gene, displaying affinity toward human primary glioma cells (GBL-14 cells) and dermal fibroblasts. We analyzed transfection efficiency, using luciferase (Luci) and a pDNA encoding for enhanced fluorescent protein (EGFP), and cytotoxicity in both cells. The results show that transfection efficiency of PAMAM-H-R improved compared to native PAMAM dendrimer, but cytotoxicity of PAMAM-H-R and PAMAM-H-K were very low. We treated both cells with a polyplex formation of PAMAM-H-R or PAMAM-H-K/apoptin, and analyzed their cellular uptake and localization by flow cytometry and confocal microscopy. Furthermore, we analyzed the endosomal escape effect using TEM images, and found that PAMAM-H-R showed very fast escape from endosome to the cytosol. Caspase 3 activity assay, cell cycle distribution, and JC-1 analysis showed apoptosis induced by apoptin in GBL-14 cells. This indicates that PAMAM-H-R can be a potential nonviral vector gene delivery carrier for brain tumor therapy. The present study demonstrates that PAMAM-H-R/apoptin gene polyplex can be used as an effective therapeutic candidate for GBM due to its selective induction of apoptosis in primary glioma cells as a potential nonviral gene delivery carrier for brain tumor therapy. (C) 2016 Elsevier B.V. All rights reserved.
引用
收藏
页码:186 / 200
页数:15
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