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使用转铁蛋白修饰的聚酰胺胺树枝状大分子靶向胶质瘤的质粒pORF-hTRAIL

Plasmid pORF-hTRAIL targeting to glioma using transferrin-modified polyamidoamine dendrimer.

作者信息

Gao Song, Li Jianfeng, Jiang Chen, Hong Bo, Hao Bing

机构信息

Department of Clinical Laboratory, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.

Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, People's Republic of China.

出版信息

Drug Des Devel Ther. 2015 Dec 17;10:1-11. doi: 10.2147/DDDT.S95843. eCollection 2016.

DOI:10.2147/DDDT.S95843
PMID:26719669
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4690643/
Abstract

A gene drug delivery system for glioma therapy based on transferrin (Tf)-modified polyamidoamine dendrimer (PAMAM) was prepared. Gene drug, tumor necrosis factor-related apoptosis-inducing ligand (hTRAIL)-encoding plasmid open reading frame (pORF-hTRAIL, Trail), was condensed by Tf-modified PAMAM to form nanoparticles (NPs). PAMAM-PEG-Tf/DNA NPs showed higher cellular uptake, in vitro gene expression, and cytotoxicity than PAMAM-PEG/DNA NPs in C6 cells. The in vivo targeting efficacy of NPs was visualized by ex vivo fluorescence imaging. Tf-modified NPs showed obvious glioma-targeting trend. Plasmid encoding green fluorescence protein (GFP) was also condensed by modified or unmodified PAMAM to evaluate the in vivo gene expression level. The PAMAM-PEG-Tf/plasmid encoding enhanced green fluorescence protein (pEGFP) NPs exhibited higher GFP expression level than PAMAM-PEG/pEGFP NPs. TUNEL assay revealed that Tf-modified NPs could induce much more tumor apoptosis. The median survival time of PAMAM-PEG-Tf/Trail-treated rats (28.5 days) was longer than that of rats treated with PAMAM-PEG/Trail (25.5 days), temozolomide (24.5 days), PAMAM-PEG-Tf/pEGFP (19 days), or saline (17 days). The therapeutic effect was further confirmed by magnetic resonance imaging. This study demonstrated that targeting gene delivery system had potential application for the treatment of glioma.

摘要

制备了一种基于转铁蛋白（Tf）修饰的聚酰胺胺树枝状大分子（PAMAM）的用于胶质瘤治疗的基因递送系统。基因药物，即编码肿瘤坏死因子相关凋亡诱导配体（hTRAIL）的质粒开放阅读框（pORF-hTRAIL，Trail），被Tf修饰的PAMAM浓缩以形成纳米颗粒（NPs）。在C6细胞中，PAMAM-PEG-Tf/DNA NPs比PAMAM-PEG/DNA NPs表现出更高的细胞摄取、体外基因表达和细胞毒性。通过离体荧光成像观察NPs的体内靶向效果。Tf修饰的NPs显示出明显的胶质瘤靶向趋势。编码绿色荧光蛋白（GFP）的质粒也被修饰或未修饰的PAMAM浓缩以评估体内基因表达水平。PAMAM-PEG-Tf/编码增强型绿色荧光蛋白（pEGFP）的质粒NPs比PAMAM-PEG/pEGFP NPs表现出更高的GFP表达水平。TUNEL检测显示Tf修饰的NPs可诱导更多的肿瘤细胞凋亡。PAMAM-PEG-Tf/Trail治疗的大鼠的中位生存时间（28.5天）长于用PAMAM-PEG/Trail（25.5天）、替莫唑胺（24.5天）、PAMAM-PEG-Tf/pEGFP（19天）或生理盐水（17天）治疗的大鼠。磁共振成像进一步证实了治疗效果。这项研究表明靶向基因递送系统在胶质瘤治疗中具有潜在应用价值。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c69a/4690643/b6d5c605b5a3/dddt-10-001Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c69a/4690643/b4aa202a49bf/dddt-10-001Fig1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c69a/4690643/3127aa5975ee/dddt-10-001Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c69a/4690643/b6d5c605b5a3/dddt-10-001Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c69a/4690643/b4aa202a49bf/dddt-10-001Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c69a/4690643/3927c0d08b34/dddt-10-001Fig2.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c69a/4690643/3127aa5975ee/dddt-10-001Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c69a/4690643/b6d5c605b5a3/dddt-10-001Fig8.jpg

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