药学学报, 2014, 49(8): 1111-1116
引用本文:
王文喜, 代凯, 洪璐, 蔡婷, 唐岚. 基因胞内传递中的内体逃逸技术[J]. 药学学报, 2014, 49(8): 1111-1116.
WANG Wen-xi, DAI Kai, HONG Lu, CAI Ting, TANG Lan. The strategies of endosomal escape for intracellular gene delivery[J]. Acta Pharmaceutica Sinica, 2014, 49(8): 1111-1116.

基因胞内传递中的内体逃逸技术
王文喜, 代凯, 洪璐, 蔡婷, 唐岚
浙江工业大学药学院, 浙江 杭州 310032
摘要:
基因在细胞内的传递过程及胞内分布对其作用至关重要,成功的基因载体应能有效地克服内体膜 的屏障将基因送到特定的细胞器。传统的非病毒类载体由于不能有效地绕过内体途径,故具有较低的转染活性,从而限制了基因药物的应用。为了进一步提高外源基因的转染效率,已发现大量的促进内体逃逸的试剂。这些试剂可通过与内体膜融合、在内体膜内形成小孔、光激活的破膜作用或质子海绵效应等机制促进内体逃逸。本文总结了文献报道的各种内体逃逸技术,根据其作用机制的不同对其分类阐述,并说明其在基因胞内传递中的应用。
关键词:    基因传递      内体逃逸      致孔      质子海绵效应      膜融合      光化学内化     
The strategies of endosomal escape for intracellular gene delivery
WANG Wen-xi, DAI Kai, HONG Lu, CAI Ting, TANG Lan
College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310032, China
Abstract:
The intracellular trafficking and subcellular distribution of exogenous gene is very important for gene delivery. A successful gene vehicle should overcome various barriers including endosomal membrane bar-riers to delivery gene to the target organelle. Traditional nonviral vehicle is unable to avoid endosomal pathway efficiently, so the efficiency of gene delivery is low and the application of gene drugs is limited. In order to achieve efficient nonviral gene delivery, a lot of researches based on endosomal escape have been carried out and some agents with the function of endsomal escape have been found. These agents facilitate the endsomal escape via various mechanisms, such as fusion into the lipid bilayer of endosomes, pore formation in the endosomal membrane, proton sponge effect and photochemical methods to rupture the endosomal membrane. In this review, various reported strategies for endsomal escape are described according to the escape mechanisms, and their applications in intracellular gene delivery are also discussed.
Key words:    gene delivery    endosomal escape    pore formation    proton sponge effect    membrane fusion    photochemical internalization   
收稿日期: 2014-01-03
基金项目: 国家自然科学基金资助项目(81102396)
通讯作者: 王文喜 Tel:86-571-88320722,Fax:86-571-88320320,E-mail:yjw@zjut.edu.cn
Email: yjw@zjut.edu.cn
相关功能
PDF(263KB) Free
打印本文
0
作者相关文章
王文喜  在本刊中的所有文章
代凯  在本刊中的所有文章
洪璐  在本刊中的所有文章
蔡婷  在本刊中的所有文章
唐岚  在本刊中的所有文章

参考文献:
[1] Yang FF, Huang W, Li YF, et al. Current status of non-viral vectors for siRNA delivery [J]. Acta Pharm Sin (药学学报), 2011, 46: 1436-1443.
[2] Sun XY, Wei LL, Chen HL, et al. Advances in the study of organelles targeting nanocarriers [J]. Acta Pharm Sin (药学学报), 2009, 44: 838-844.
[3] Dominska M, Dykxhoorn DM. Breaking down the barriers: siRNA delivery and endosome escape [J]. J Cell Sci, 2010, 123: 1183-1189.
[4] Zasloff M. Antimicrobial peptides of multicellular organ-isms [J]. Nature, 2002, 415: 389-395.
[5] Bocchinfuso G, Palleschi A, Orioni B, et al. Different mechanisms of action of antimicrobial peptides: insights from fluorescence spectroscopy experiments and molecular dynamics simulations [J]. J Pept Sci, 2009, 15: 550-558.
[6] Mihajlovic M, Lazaridis T. Charge distribution and imper-fect amphipathicity affect pore formation by antimicrobial peptides [J]. Biochim Biophys Acta, 2012, 1818: 1274-1283.
[7] Mihajlovic M, Lazaridis T. Antimicrobial peptides in tor-oidal and cylindrical pores [J]. Biochim Biophys Acta, 2010, 1798: 1485-1493.
[8] Maher S, Feighery L, Brayden D, et al. Melittin as an epithelial permeability enhancer I: investigation of its mechanism of action in Caco-2 monolayers [J]. Pharm Res, 2007, 24: 1336-1345.
[9] Bogaart G, Guzman JV, Mika JT. On the mechanism of pore formation by melittin [J]. J Biol Chem, 2008, 283: 33854-33857.
[10] Ogris M, Carlisle RC, Bettinger T, et al. Melittin enables efficient vesicular escape and enhanced nuclear access of nonviral gene delivery vectors [J]. J Biol Chem, 2001, 276: 47550-47555.
[11] Bavdek A, Kostanjsek R, Antonini V, et al. pH dependence of listeriolysin O aggregation and pore-forming ability [J]. FEBS J, 2012, 279: 126-141.
[12] Walls ZF, Goodell S, Andrews CD, et al. Mutants of listeriolysin O for enhanced liposomal delivery of macromolecules [J]. J Biotechnol, 2013, 164: 500-502.
[13] Mathew E, Hardee GE, Bennett CF, et al. Cytosolic deliv-ery of antisense oligonucleotides by listeriolysin O-containing liposomes [J]. Gene Ther, 2003, 10: 1105-1115.
[14] Andrews CD, Huh MS, Patton K, et al. Encapsulating immunostimulatory CpG oligonucleotides in listeriolysin O-liposomes promotes a Th1-type response and CTL activity [J]. Mol Pharm, 2012, 9: 1118-1125.
[15] Kauwe LK, Kasahara N, Kedes L. 3PO, a novel non-viral gene delivery system using engineered Ad5 penton proteins [J]. Gene Ther, 2001, 8: 795-803.
[16] Fender P, Ruigrok RW, Gout E, et al. Adenovirus dodecahedron, a new vector for human gene transfer [J]. Nat Biotechnol, 1997, 15: 52-56.
[17] Shayakhmetov DM, Eberly AM, Li ZY, et al. Deletion of penton RGD motifs affects the efficiency of both the internalization and the endosome escape of viral particles containing adenovirus serotype 5 or 35 fiber knobs [J]. J Virol, 2004, 79: 1053-1061.
[18] Nel AE, Madler L, Velegol D, et al. Understanding biophysicochemical interactions at the nano-bio interface [J]. Nat Mater, 2009, 8: 543-557.
[19] Benjaminsen RV, Mattebjerg MA, Henriksen JR, et al. The possible "proton sponge" effect of polyethylenimine (PEI) does not include change in lysosomal pH [J]. Mol Ther, 2013, 21: 149-157.
[20] Won YY, Sharma R, Konieczny SF. Missing pieces in understanding the intracellular trafficking of polycation/DNA complexes [J]. J Control Release, 2009, 139: 88-93.
[21] Sugiyama M, Matsuura M, Takeuehi Y, et al. Possible mechanism of polycation liposome (PCL)-mediated gene transfer [J]. Biochim Biophys Acta, 2004, 1660: 24-30.
[22] Nimesh S, Goyal A, Pawar V, et al. Polyethylenimine nano particle as efficient transfecting agents form ammalian cell [J]. J Control Release, 2006, 110: 457-468.
[23] Dean DA, Strong DD, Zimmer WE. Nuclear entry of non-viral vectors [J]. Gene Ther, 2005, 12:881-890.
[24] Lu Y, Yao J, Zhou JP, et al. Formation and aggregation behavior of polyethyleneimine-DNA complexes [J]. Acta Pharm Sin (药学学报), 2009, 44: 667-673.
[25] Lin C, Zhong Z, Lok MC, et al. Linear poly(amidoamine)s with secondary and tertiary amino groups and variable amounts of disulfide linkages: synthesis and in vitro gene transfer properties [J]. J Control Release, 2006, 116: 130-137.
[26] Kircheis R, Wightman L, Wangner E. Design and gene delivery activity of modified polyethylenimines [J]. Adv Drug Deliv Rev, 2001, 53: 341-358.
[27] Grzelinski M, Urban-Klein B, Martens T, et al. RNA interference-mediated gene silencing of pleiotrophin through polyethylenimine-complexed small interfering RNAs in vivo exerts antitumoral effects in glioblastoma xenografts [J]. Hum Gene Ther, 2006, 17: 751-766.
[28] Mateos-Timoneda MA, Lok MC, Hennink WE, et al. Poly (amidoamine)s as gene delivery vectors: effects of qua-ternary nicotinamide moieties in the side chains [J]. Chem Med Chem, 2008, 3: 478-486.
[29] Kim HJ, Ishii A, Miyata, K, et al. Introduction of stearoyl moieties into a biocompatible cationic polyaspartamide derivative, PAsp(DET), with endosomal escaping function for enhanced siRNA-mediated gene knockdown [J]. J Control Release, 2010, 145: 141-148.
[30] Ghosn B, Kasturi SP, Roy K. Enhancing polysaccharide-mediated delivery of nucleic acids through functionalization with secondary and tertiary amines [J]. Curr Top Med Chem, 2008, 8: 331-340.
[31] Yang Y, Zhang Z, Chen L, et al. Effect of multifold charge groups and imidazole-4-carboxaldehyde on physicochemical characteristics and transfection of cationic polyphosphazenes/DNA complexes [J]. Int J Pharm, 2010, 390: 191-197.
[32] Midoux P, Pichon C, Yaouanc JJ, et al. Chemical vectors for gene delivery: a current review on polymers, peptides and lipids containing histidine or imidazole as nucleic acids carriers [J]. Br J Pharm, 2009, 157: 166-178.
[33] Wen Y, Guo Z, Du Z, et al. Serum tolerance and en-dosomal escape capacity of histidine-modified pDNA-loaded complexes based on polyamidoamine dendrimer derivatives [J]. Biomaterials, 2012, 33: 8111-8121.
[34] Li Y, Han X, Lai AL, et al. Membrane structures of the hemifusion-inducing fusion peptide mutant G1S and the fusion-blocking mutant G1V of influenza virus hemagglutinin suggest a mechanism for pore opening in membrane fusion [J]. J Virol, 2005, 79: 12065-12076.
[35] Tara BW, Francüois N, Olivier Z, et al. Design, synthesis, and characterization of a cationic peptide that binds to nucleic acids and permeabilizes bilayers [J]. Biochemistry, 1997, 36: 3008-3017.
[36] Lee H, Jeong JH, Park TG. A new gene delivery formula-tion of polyethylenimine/DNA complexes coated with PEG conjugated fusogenic peptide [J]. J Control Release, 2001, 76: 183-192.
[37] Min SM, Lee DC, Lim MJ, et al. Composite gene delivery system consisting of polyethylenimine and amphipathic peptide KALA [J]. Gene Med, 2006, 8: 1425-1434.
[38] Simoes S, Slepushkin V, Pires P, et al. Mechanisms of gene transfer mediated by lipoplexes associated with targeting ligands or pH-sensitive peptides [J]. Gene Ther, 1999, 6: 1798-1807.
[39] Oliveira S, Rooy I, Kranenburg O, et al. Fusogenic pep-tides enhance endosomal escape improving siRNA-induced silencing of oncogenes [J]. Int J Pharm, 2007, 331: 211-214.
[40] Kakimoto S, Hamada T, Komatsu Y, et al. The conjugation of diphtheria toxin T domain to poly(ethylenimine) based vectors for enhanced endosomal escape during gene transfection [J]. Biomaterials, 2009, 30: 402-408.
[41] Pozo-Rodríguez A, Pujals S, Delgado D, et al. A proline-rich peptide improves cell transfection of solid lipid nanoparticle-based non-viral vectors [J]. J Control Release, 2009, 133: 52-59.
[42] Tu Y, Kim JS. A fusogenic segment of glycoprotein H from herpes simplex virus enhances transfection efficiency of cationic liposomes [J]. Gene Med, 2008, 10: 646-654.
[43] El-Sayed A, Masuda T, Akita H, et al. Stearylated INF7 peptide enhances endosomal escape and gene expression of PEGylated nanoparticles both in vitro and in vivo [J]. J Pharm Sci, 2011, 101: 879-882.
[44] Fernandaz-Carneado J, Kogan MJ, Castel S, et al. Potential peptide carriers: amphipathic proline-rich peptides derived from the N-terminal domain of γ-Zein [J]. Angew Chem Int Ed Eng, 2004, 43: 1811-1814.
[45] Berg K, Selbo PK, Prasmickaite L, et al. Photochemical internalization: a novel technology for delivery of macromolecules into cytosol [J]. Cancer Res, 1999, 59: 1180-1183.
[46] Ghosh A. First-principles quantum chemical studies of porphyrins [J]. Acc Chem Res, 1998, 31: 189-198.
[47] Andreas B, Parusel J, Ghosh A. Density functional theory based configuration interaction calculations on the electronic spectra of free-base porphyrin, chlorin, bacteriochlorin, and cis-and trans-isobacteriochlorin [J]. J Phys Chem A, 2000, 104: 2504-2507.
[48] Oliveira S, Fretz MM, Hogset A, et al. Photochemical internalization enhances silencing of epidermal growth factor receptor through improved endosomal escape of siRNA [J]. Biochim Biophys Acta, 2007, 1758: 1211-1217.
[49] Mellert K, Lamla M, Scheffzek K, et al. Enhancing endosomal escape of transduced proteins by photochemical internalization [J]. PLoS One, 2012, 7: e52473.