PEG修饰在基因递送系统中的应用:优势、不足及改善策略
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摘要
基因治疗是治疗多种疾病的一种强有力的手段。有效递送目的基因至病灶治疗部位是基因治疗成功的关键。目前常用的基因载体大多为阳离子纳米微粒,会引起细胞毒性和体内免疫反应,其表面通常需要PEG修饰来掩蔽部分正电荷,以降低血液循环途径中与内源性阴离子物质的非特异性结合,延长载药粒子的血液循环时间和降低毒性。然而,PEG修饰也会带来一系列的问题,如降低基因递送载体的细胞摄取、阻碍基因药物"内吞体逃逸"而降低转染效率,以及重复注射PEG化载体引起的"加速血液清除"(accelerated blood clearance,ABC)现象等。本文综述了PEG修饰应用在基因递送系统中的优势和不足,并对PEG修饰改善策略和寻找有潜力的PEG替代物进行了探讨。
Gene therapy is a new potent biomedical technology for treating various diseases. Developing a targeted gene delivery system is the crucial scientific problem for successful gene therapy. Cationic nanocarriers are usually used for gene delivery,but they may cause in vivo toxicity and immune response. In order to acquire long circulation in blood as well as reduce in vivo toxicity of the cationic nanocarriers,PEGylation is the most wide strategy,which can shield surface positive charges and reduce the non-specific interaction between endogenous protein and nanocarrier during circulation based on the presence of PEG on the surface of nanocarrier. Unfortunately,lower cellular uptake,lower transfection efficacy caused by inefficient "endosomal escape"and accelerated blood clearance( ABC) phenomenon after repeated administration are found in PEGylation nanocarriers. This review will summarize the advantages and limitations of PEGylation in gene delivery system,and discuss the possible improvement strategies or potential PEG alternatives to overcome these limitations.
Gene therapy is a new potent biomedical technology for treating various diseases. Developing a targeted gene delivery system is the crucial scientific problem for successful gene therapy. Cationic nanocarriers are usually used for gene delivery,but they may cause in vivo toxicity and immune response. In order to acquire long circulation in blood as well as reduce in vivo toxicity of the cationic nanocarriers,PEGylation is the most wide strategy,which can shield surface positive charges and reduce the non-specific interaction between endogenous protein and nanocarrier during circulation based on the presence of PEG on the surface of nanocarrier. Unfortunately,lower cellular uptake,lower transfection efficacy caused by inefficient "endosomal escape"and accelerated blood clearance( ABC) phenomenon after repeated administration are found in PEGylation nanocarriers. This review will summarize the advantages and limitations of PEGylation in gene delivery system,and discuss the possible improvement strategies or potential PEG alternatives to overcome these limitations.
引文
[1]BEHZAD M,SIAMAK SS,BEHZAD B.RNA interference and its role in cancer therapy[J].Adv Pharm Bull,2014,4(4):313-321.
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[3]GE Q,FILIP L,BAI A,et al.Inhibition of influenza virus production in virus-infected mice by RNA interference[J].ProcNatl Acad Sci USA,2004,101(23):8676-8681.
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[6]PATIL SD,RHODES DG,BURGESS DJ.DNA-based therapeutics and DNA delivery systems:a comprehensive review[J].The AAPS Journal,2005,7(1):E61-E77.
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[11]LU T,SUN J,CHEN X,et al.Folate-conjugated micelles and their folate-receptor-mediated endocytosis[J].Macromolecular Bioscience,2009,9(11):1059-1068.
[12]ZHAO Z,GAO S,WANG J,et al.Self-assembly nanomicelles based on cationic m PEG-PLA-b-Polyarginine(R15)triblock copolymer for siRNA delivery[J].Biomaterials,2012,33(28):6793-6807.
[13]YOON HY,KOO H,CHOI K,et al.Photo-crosslinked hyaluronic acid nanoparticles with improved stability for in vivo tumor-targeted drug delivery[J].Biomaterials,2013,34(21):5273-5280.
[14]SATO A,TAKAGI M,SHIMAMOTO A,et al.Small interfering RNA delivery to the liver by intravenous administration of galactosylated cationic liposomes in mice[J].Biomaterials,2007,28(7):1434-1442.
[15]GAO L,LIU X,CHEN C,et al.Core-Shell type lipid/r PAA-Chol copolymer hybrid nanoparticles for in vivo siRNA delivery[J].Biomaterials,2014,35(6):2066-2078.
[16]CAO N,CHENG D,ZOU S,et al.The synergistic effect of hierarchical assemblies of siRNA and chemotherapeutic drugs co-delivered into hepatic cancer cells[J].Biomaterials,2011,32(8):2222-2232.
[17]GUO S,HUANG Y,ZHANG W,et al.Ternary complexes of amphiphilic polycaprolactone-graft-poly(N,N-dimethylaminoethyl methacrylate),DNA and polyglutamic acid-graft-poly(ethylene glycol)for gene delivery[J].Biomaterials,2011,32(18):4283-4292.
[18]SZEBENI J,BARANYI L,SAVAY S,et al.Role of complement activation in hypersensitivity reactions to doxil and hynic PEG liposomes:experimental and clinical studies[J].J Liposome Res,2002,12(1-2):165-1672.
[19]ISHIDA T,MASUDA K,ICHIKAWA T,et al.Accelerated clearance of a second injection of PEGylated liposomes in mice[J].Int J Pharm,2003,255(1-2):167-174.
[20]HSU HJ,SEN S,PEARSON RM,et al.Poly(ethylene glycol)corona chain length controls end-group-dependent cell interactions of dendron micelles[J].Macromolecules,2014,47(19):6911-6918.
[21]张迪,徐缓,胡美娜,等.脂质体面临的聚乙二醇“窘境”及解决方法[J].药学学报,2015,50(3):252-260.
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[23]ZHANG M,ISHII A,NISHIYAMA N,et al.PEGylated calcium phosphate nanocomposites as smart environment-sensitive carriers for siRNA delivery[J].Advanced Materials,2009,21(34):3520-3525.
[24]TAKAE S,MIYATA K,OBA M,et al.PEG-detachable polyplex micelles based on disulfidelinked block catiomers as bioresponsive nonviral gene vectors[J].J Am Chem Soc,2009,130(18):6001-6009.
[25]LIN D,JIANG Q,CHENG Q,et al.Polycation-detachable nanoparticles self-assembled from m PEG-PCL-g-SS-PDMAEMA for in vitro and in vivo siRNA delivery[J].Acta Biomater,2013,9(8):7746-7757.
[26]HATAKEYAMA H,ITO E,AKITA H,et al.A p H-sensitive fusogenic peptide facilitates endosomal escape and greatly enhances the gene silencing of siRNA-containing nanoparticles in vitro and in vivo[J].J Control Release,2009,139(2):127-132.
[27]WANG H,YANG X,SUN C,et al.Matrix metalloproteinase 2-responsive micelle for siRNA delivery[J].Biomaterials,2014,35(26):7622-7634.
[28]ZHU L,PERCHE F,WANG T,et al.Matrix metalloproteinase 2-sensitive multifunctional polymeric micelles for tumor-specific codelivery of siRNA and hydrophobic drugs[J].Biomaterials,2014,35(13):4213-4222.
[29]LI Y,XIAO K,ZHU W,et al.Stimuli-responsive cross-linked micelles for on-demand drug delivery against cancers[J].Adv Drug Deliv Rev,2014,66:58-73.
[30]SETHURAMAN VA,NA K,BAE YH.p H-responsive sulfonamide/PEI system for tumor specific gene delivery:an in vitro study[J].Biomacromolecules,2006,7(1):64-70.
[31]GUO J,CHENG WP,GU J,et al.Systemic delivery of therapeutic small interfering RNA using a p H-triggered amphiphilic poly-Llysine nanocarrier to suppress prostate cancer growth in mice[J].Eur J Pharm Sci,2012,45(5):521-532.
[32]NIE Y,GüNTHER M,GU Z,et al.Pyridylhydrazone-based PEGylation for p H-reversible lipopolyplex shielding[J].Biomaterials,2011,32(3):858-869.
[33]KNORR V,ALLMENDINGER L,WALKER GF,et al.An acetalbased PEGylation reagent for p H-sensitive shielding of DNA polyplexes[J].Bioconjugate Chem,2007,18(4):1218-1225.
[34]OISHI M,NAGASAKI Y,ITAKA K,et al.Lactosylated poly(ethylene glycol)-siRNA conjugate through acid-labileβ-thiopropionate linkage to construct p H-sensitive polyion complex micelles achieving enhanced gene silencing in hepatoma cells[J].J Am Chem Soc,2005,127(6):1624–1625.
[35]FEENER EP,SHEN WC,RYSER H.Cleavage of disulfide bonds in endocytosed macromolecules,a processing not associated with lysosomes or endosomes[J].J Biol Chem,1990,265(31):18780-18785.
[36]OSADA K,CHRISTIE RJ,KATAOKA K,et al.Polymeric micelles from poly(ethylene glycol)-poly(amino acid)block copolymer for drug and gene delivery[J].J R Soc Interface,2009,6(Suppl 3):S325-S339.
[37]KUROSAKI T,KITAHARA T,FUMOTO S,et al.Ternary complexes of p DNA,polyethylenimine,and gamma-polyglutamic acid for gene delivery systems[J].Biomaterials,2009,30(14):2846-2853.
[38]HELLMUND M,ZHOU H,SAMSONVA O,et al.Functionalized polyglycerol amine nanogels as nanocarriers for DNA[J].Macromol Biosci,2014,14(9):1215-1221.
[39]BURKE RS,PUN SH.Synthesis and characterization of biodegradable HPMA-oligolysine copolymers for improved gene delivery[J].Bioconjug Chem,2010,21(1):140-150.
[2]MILLER VM,GOUVION CM,DAVIDSON BL,et al.Targeting Alzheimer's disease genes with RNA interference:an efficient strategy for silencing mutant alleles[J].Nucleic Acids Res,2004,32(2):661-668.
[3]GE Q,FILIP L,BAI A,et al.Inhibition of influenza virus production in virus-infected mice by RNA interference[J].ProcNatl Acad Sci USA,2004,101(23):8676-8681.
[4]TAN SJ,KIATWUTHINON P,ROH YH,et al.Engineering nanocarriers for siRNA delivery[J].Small,2011,7(7):841-856.
[5]SOUTSCHEK J,AKINC A,BRAMLAGE B,et al.Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs[J].Nature,2004,432(7014):173-178.
[6]PATIL SD,RHODES DG,BURGESS DJ.DNA-based therapeutics and DNA delivery systems:a comprehensive review[J].The AAPS Journal,2005,7(1):E61-E77.
[7]PARK TG,JEONG JH,KIM SW.Current status of polymeric gene delivery systems[J].Adv Drug Deliv Rev,2006,58(4):467-486.
[8]DASH PR,READ ML,BARRETT LB,et al.Factors affecting blood clearance and in vivo distribution of polyelectrolyte complexes for gene delivery[J].Gene Ther,1999,6(4):643-650.
[9]KURSA M,WALKER GF,ROESSLER V,et al.Novel shielded transferrin-polyehtylene glycol-polyethylenimine/DNA complexes for systemic tumor-targeted gene transfer[J].Bioconjug Chem,2003,14(1):222-231.
[10]ENDRES T,ZHENG M,KILIC A,et al.Amphiphilic biodegradable PEG-PCL-PEI triblock copolymers for FRET-capable in vitro and in vivo delivery of siRNA and quantum dots[J].Molecular Pharmceutics,2014,11(4):1273-1281.
[11]LU T,SUN J,CHEN X,et al.Folate-conjugated micelles and their folate-receptor-mediated endocytosis[J].Macromolecular Bioscience,2009,9(11):1059-1068.
[12]ZHAO Z,GAO S,WANG J,et al.Self-assembly nanomicelles based on cationic m PEG-PLA-b-Polyarginine(R15)triblock copolymer for siRNA delivery[J].Biomaterials,2012,33(28):6793-6807.
[13]YOON HY,KOO H,CHOI K,et al.Photo-crosslinked hyaluronic acid nanoparticles with improved stability for in vivo tumor-targeted drug delivery[J].Biomaterials,2013,34(21):5273-5280.
[14]SATO A,TAKAGI M,SHIMAMOTO A,et al.Small interfering RNA delivery to the liver by intravenous administration of galactosylated cationic liposomes in mice[J].Biomaterials,2007,28(7):1434-1442.
[15]GAO L,LIU X,CHEN C,et al.Core-Shell type lipid/r PAA-Chol copolymer hybrid nanoparticles for in vivo siRNA delivery[J].Biomaterials,2014,35(6):2066-2078.
[16]CAO N,CHENG D,ZOU S,et al.The synergistic effect of hierarchical assemblies of siRNA and chemotherapeutic drugs co-delivered into hepatic cancer cells[J].Biomaterials,2011,32(8):2222-2232.
[17]GUO S,HUANG Y,ZHANG W,et al.Ternary complexes of amphiphilic polycaprolactone-graft-poly(N,N-dimethylaminoethyl methacrylate),DNA and polyglutamic acid-graft-poly(ethylene glycol)for gene delivery[J].Biomaterials,2011,32(18):4283-4292.
[18]SZEBENI J,BARANYI L,SAVAY S,et al.Role of complement activation in hypersensitivity reactions to doxil and hynic PEG liposomes:experimental and clinical studies[J].J Liposome Res,2002,12(1-2):165-1672.
[19]ISHIDA T,MASUDA K,ICHIKAWA T,et al.Accelerated clearance of a second injection of PEGylated liposomes in mice[J].Int J Pharm,2003,255(1-2):167-174.
[20]HSU HJ,SEN S,PEARSON RM,et al.Poly(ethylene glycol)corona chain length controls end-group-dependent cell interactions of dendron micelles[J].Macromolecules,2014,47(19):6911-6918.
[21]张迪,徐缓,胡美娜,等.脂质体面临的聚乙二醇“窘境”及解决方法[J].药学学报,2015,50(3):252-260.
[22]LEI Y,WANG J,XIE C,et al.Glutathione-sensitive RGD-poly(ethyleneglycol)-SS-polyethylenimine for intracranial glioblastoma targeted gene delivery[J].J Gene Med,2013,15(8-9):291-305.
[23]ZHANG M,ISHII A,NISHIYAMA N,et al.PEGylated calcium phosphate nanocomposites as smart environment-sensitive carriers for siRNA delivery[J].Advanced Materials,2009,21(34):3520-3525.
[24]TAKAE S,MIYATA K,OBA M,et al.PEG-detachable polyplex micelles based on disulfidelinked block catiomers as bioresponsive nonviral gene vectors[J].J Am Chem Soc,2009,130(18):6001-6009.
[25]LIN D,JIANG Q,CHENG Q,et al.Polycation-detachable nanoparticles self-assembled from m PEG-PCL-g-SS-PDMAEMA for in vitro and in vivo siRNA delivery[J].Acta Biomater,2013,9(8):7746-7757.
[26]HATAKEYAMA H,ITO E,AKITA H,et al.A p H-sensitive fusogenic peptide facilitates endosomal escape and greatly enhances the gene silencing of siRNA-containing nanoparticles in vitro and in vivo[J].J Control Release,2009,139(2):127-132.
[27]WANG H,YANG X,SUN C,et al.Matrix metalloproteinase 2-responsive micelle for siRNA delivery[J].Biomaterials,2014,35(26):7622-7634.
[28]ZHU L,PERCHE F,WANG T,et al.Matrix metalloproteinase 2-sensitive multifunctional polymeric micelles for tumor-specific codelivery of siRNA and hydrophobic drugs[J].Biomaterials,2014,35(13):4213-4222.
[29]LI Y,XIAO K,ZHU W,et al.Stimuli-responsive cross-linked micelles for on-demand drug delivery against cancers[J].Adv Drug Deliv Rev,2014,66:58-73.
[30]SETHURAMAN VA,NA K,BAE YH.p H-responsive sulfonamide/PEI system for tumor specific gene delivery:an in vitro study[J].Biomacromolecules,2006,7(1):64-70.
[31]GUO J,CHENG WP,GU J,et al.Systemic delivery of therapeutic small interfering RNA using a p H-triggered amphiphilic poly-Llysine nanocarrier to suppress prostate cancer growth in mice[J].Eur J Pharm Sci,2012,45(5):521-532.
[32]NIE Y,GüNTHER M,GU Z,et al.Pyridylhydrazone-based PEGylation for p H-reversible lipopolyplex shielding[J].Biomaterials,2011,32(3):858-869.
[33]KNORR V,ALLMENDINGER L,WALKER GF,et al.An acetalbased PEGylation reagent for p H-sensitive shielding of DNA polyplexes[J].Bioconjugate Chem,2007,18(4):1218-1225.
[34]OISHI M,NAGASAKI Y,ITAKA K,et al.Lactosylated poly(ethylene glycol)-siRNA conjugate through acid-labileβ-thiopropionate linkage to construct p H-sensitive polyion complex micelles achieving enhanced gene silencing in hepatoma cells[J].J Am Chem Soc,2005,127(6):1624–1625.
[35]FEENER EP,SHEN WC,RYSER H.Cleavage of disulfide bonds in endocytosed macromolecules,a processing not associated with lysosomes or endosomes[J].J Biol Chem,1990,265(31):18780-18785.
[36]OSADA K,CHRISTIE RJ,KATAOKA K,et al.Polymeric micelles from poly(ethylene glycol)-poly(amino acid)block copolymer for drug and gene delivery[J].J R Soc Interface,2009,6(Suppl 3):S325-S339.
[37]KUROSAKI T,KITAHARA T,FUMOTO S,et al.Ternary complexes of p DNA,polyethylenimine,and gamma-polyglutamic acid for gene delivery systems[J].Biomaterials,2009,30(14):2846-2853.
[38]HELLMUND M,ZHOU H,SAMSONVA O,et al.Functionalized polyglycerol amine nanogels as nanocarriers for DNA[J].Macromol Biosci,2014,14(9):1215-1221.
[39]BURKE RS,PUN SH.Synthesis and characterization of biodegradable HPMA-oligolysine copolymers for improved gene delivery[J].Bioconjug Chem,2010,21(1):140-150.