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化学进展 2019, Vol. 31 Issue (2/3): 300-310 DOI: 10.7536/PC180621 前一篇   后一篇

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多功能基因递送系统促进内皮细胞增殖

白凌闯1, 赵静1, 冯亚凯1,2,**()   

  1. 1. 天津大学化工学院 天津 300072
    2. 天津化学化工协同创新中心 天津 300072
  • 收稿日期:2018-06-19 出版日期:2019-02-15 发布日期:2018-12-20
  • 通讯作者: 冯亚凯
  • 基金资助:
    国家重点研发项目(2016YFC1100300); 国家自然科学基金项目(31370969); 国家自然科学基金项目(51673145); 国家自然科学基金项目(51873149)
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Multifunctional Gene Delivery Systems to Promote the Proliferation of Endothelial Cells

Lingchuang Bai1, Jing Zhao1, Yakai Feng1,2,**()   

  1. 1. School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China
    2. Collaborative Innovation Center of Chemical Science and Chemical Engineering(Tianjin), Tianjin University, Tianjin 300072, China
  • Received:2018-06-19 Online:2019-02-15 Published:2018-12-20
  • Contact: Yakai Feng
  • About author:
    ** E-mail:
  • Supported by:
    National Key R&D Program of China(2016YFC1100300); National Natural Science Foundation of China(31370969); National Natural Science Foundation of China(51673145); National Natural Science Foundation of China(51873149)

由于自体血管供应不足,人工血管在心血管疾病的临床治疗中发挥着非常重要的作用。人工血管由于表面缺乏活性内皮层,经常面临术后再狭窄等问题,严重限制了其在临床中的应用。人工血管内皮化能够提高其血液相容性并维持其长期通畅率。大量研究表明,多功能基因递送系统可以促进血管内皮细胞增殖,从而实现人工血管快速内皮化。近年来,功能多肽和阳离子聚合物为开发低毒且高效的多功能基因递送系统提供了有效途径。本文详细介绍了目前用于血管内皮细胞基因转染的功能多肽和聚阳离子基因载体,重点阐述了促进内皮细胞增殖的多功能逐级靶向基因递送系统的研究进展,对采用基因转染方式促进人工血管快速内皮化进行了分析和展望。

关键词： 人工血管, 内皮化, 基因递送系统, 功能多肽, 基因载体

Artificial vascular grafts play an important role in the clinical treatment of cardiovascular diseases due to the lack of autografts. Artificial vascular grafts, especially for small-diameter artificial vascular grafts, usually encounter the problems such as in-stent restenosis, thus limiting their application in clinical treatment. Endothelialization of artificial vascular grafts can improve their hemocompatibility and maintain their long-term patency. It has been confirmed that multifunctional gene delivery systems can promote the proliferation of vascular endothelial cells(ECs) and help achieve the rapid endothelialization of artificial vascular grafts. Recently, functional peptides and cationic polymers have provided an effective approach for the development of low-toxic and highly efficient multifunctional gene delivery systems. In this review, functional peptides, target genes and polycationic gene carriers used in the transfection of vascular ECs are detailedly introduced. Based on polycationic gene carriers, the current development of multifunctional step-by-step targeting gene delivery systems for promoting the proliferation of ECs and endothelialization are highlighted. Finally, some perspectives on achieving rapid endothelialization via gene transfection are also presented.

Key words: artificial vascular graft, endothelialization, gene delivery system, functional peptide, gene carrier
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图1 常见阳离子聚合物的化学结构
Fig. 1 Chemical structures of representative cationic polymers
图2 基于3(S)-甲基-吗啉-2,5-二酮共聚物修饰PEI基因载体的合成过程[71]
Fig. 2 Synthesis route of modified PEI gene carriers based on 3(S)-methyl-morpholine-2,5-dione copolymers[71]. Reproduced with permission from copyright(2014) Elsevier.
图3 mPEG-b-PLGA-g-PEI-CREDVW合成过程[79]
Fig. 3 Synthesis route of mPEG-b-PLGA-g-PEI-CREDVW[79]. Reproduced with permission from copyright(2015) American Chemical Society.
图4 CAG肽修饰的靶向性基因复合物的体外血管形成实验。(A) PEI-PLGA/pZNF580,(B) PEG-PEI-PLGA/pZNF580,(C) CAGW-PPP1/pZNF580,(D) CAGW-PPP2/pZNF580,(E) PEI(25 kDa)/pZNF580,(F)未处理HUVECs,(G) pZNF580[84]
Fig. 4 In vitro vessel formation assay of CAG modified targeting gene complexes.(A) PEI-PLGA/pZNF580,(B) PEG-PEI-PLGA/pZNF580,(C) CAGW-PPP1/pZNF580,(D) CAGW-PPP2/pZNF580,(E) PEI(25 kDa)/pZNF580,(F) non-treated HUVECs,(G) pZNF580[84]. Reproduced with permission from copyright(2017) American Chemical Society.
图5 CAG肽修饰的靶向性基因复合物的体内血管形成实验。(1)苏木精-伊红染色结果,(2)抗CD31组织免疫荧光染色结果。(A) PEI-PLGA/pZNF580,(B) PEG-PEI-PLGA/pZNF580,(C) CAGW-PPP1/pZNF580,(D) CAGW-PPP2/pZNF580,(E) PEI(25 kDa)/pZNF580,(F) pZNF580[84]
Fig. 5 In vivo neovascularization assay of CAG modified targeting gene complexes. The results of H&E(1) and immunohistochemical staining with anti-CD31(2).(A) PEI-PLGA/pZNF580,(B) PEG-PEI-PLGA/pZNF580,(C) CAGW-PPP1/pZNF580,(D) CAGW-PPP2/pZNF580,(E) PEI(25 kDa)/pZNF580,(F) pZNF580[84]. Reproduced with permission from copyright(2017) American Chemical Society.
图6 CAG肽修饰的星型基因复合物的体外转染。(A)未处理内皮细胞,(B)PLGA-g-PEI/pDNA,(C) PLGA-g-PEI-CAGW/pDNA,(D) PEI 10 kDa/pDNA,(E) PLGA-g-PEI-CAGW/pDNA处理的平滑肌细胞[85]
Fig. 6 In vitro transfection of CAG modified star-shaped targeting gene complexes. (A)Nontreated ECs,(B)PLGA-g-PEI/pDNA,(C) PLGA-g-PEI-CAGW/pDNA,(D) PEI 10 kDa/pDNA,(E) PLGA-g-PEI-CAGW/pDNA treated SMCs[85]. Reproduced from an open access journal from MDPI publication.
图7 多功能基因复合物形成及对内皮细胞转染过程[91]
Fig. 7 The formation of multifunctional gene complexes and the illustration of gene delivery to ECs[91]. Reproduced from an open access journal from BMC publication.
图8 三元基因复合物在细胞内运输行为的CLSM荧光图片[93]
Fig. 8 CLSM fluorescence images of the intracellular transport of ternary gene complexes[93]. Reproduced with permission from copyright(2016) John Wiley and Sons.
图9 八臂星型两亲性嵌段聚合物POSS-DP-CAG-TAT-NLS的合成过程[94]
Fig. 9 Synthesis route of eight-arm and star-shaped amphiphilic copolymer POSS-DP-CAG-TAT-NLS[94]. Reproduced with permission from copyright(2018) American Chemical Society.
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