药学学报, 2020, 55(12): 2869-2882
江翠平, 王媛, 肖海燕, 赵海越, 刘强. 非病毒型载体聚乙烯亚胺在基因递送应用中的研究进展[J]. 药学学报, 2020, 55(12): 2869-2882.
JIANG Cui-ping, WANG Yuan, XIAO Hai-yan, ZHAO Hai-yue, LIU Qiang. Recent progress of non-viral vector polyethylenimine in the application of gene delivery[J]. Acta Pharmaceutica Sinica, 2020, 55(12): 2869-2882.

江翠平, 王媛, 肖海燕, 赵海越, 刘强
南方医科大学中医药学院, 广东省中药制剂重点实验室, 广东省中药制剂技术工程实验室, 广东 广州 510515
关键词:    基因载体      非病毒类载体      基因传递系统      聚乙烯亚胺      靶向治疗     
Recent progress of non-viral vector polyethylenimine in the application of gene delivery
JIANG Cui-ping, WANG Yuan, XIAO Hai-yan, ZHAO Hai-yue, LIU Qiang
Guangdong Provincial Engineering Laboratory of Chinese Medicine Preparation Technology, Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, School of Traditional Chinese medicine, Southern Medical University, Guangzhou 510515, China
In recent years, non-viral gene vectors have attracted great attention for efficient gene delivery due to the advantages, including low toxicity, low immunogenicity and simple preparation. Polyethylenimine (PEI) is one of the typical non-viral gene carriers that have been widely utilized for gene delivery owing to its superior capabilities in gene compression and buffering capacity. This article discusses the processes of gene delivery and the barriers of PEI-based carrier during the gene delivery, such as low biocompatibility, cytotoxicity, lack of specific targeting and insufficient gene release, etc. Therefore, we summarize the multiple approaches for the modifications of PEI in terms of improved biocompatibility, degradability, specific targeting and buffering capacity. Furthermore, we also review on the recent impressive progresses of smart stimuli-responsive PEI carriers, including endogenous stimuli (pH, reactive oxygen species, glutathione, biomolecular, etc), exogenous stimuli (light, temperature, magnetic field, etc) and dual-responsive strategies, which might provide guidance for the development of more efficient and safer non-viral gene vectors.
Key words:    gene vector    non-viral vector    gene delivery system    polyethylenimine    targeting therapy   
收稿日期: 2020-05-12
DOI: 10.16438/j.0513-4870.2020-0740
基金项目: 国家自然科学基金资助项目(81874346);广东省中医药局科研课题(20200430105634).
通讯作者: 刘强,Tel/Fax:86-20-61648263,E-mail:cuipingjiangcpu@163.com
Email: cuipingjiangcpu@163.com
PDF(1283KB) Free
江翠平  在本刊中的所有文章
王媛  在本刊中的所有文章
肖海燕  在本刊中的所有文章
赵海越  在本刊中的所有文章
刘强  在本刊中的所有文章

[1] Friedmann T, Roblin R. Gene therapy for human genetic disease?[J]. Science, 1972, 175:949-955.
[2] Xu JJ, Wang S, Kou PX, et al. Research progress of tumor gene therapy[J]. Chin J General Pract (中华全科医学), 2017, 15:655-658.
[3] Gowing G, Svendsen S, Svendsen CN. Ex vivo gene therapy for the treatment of neurological disorders[J]. Prog Brain Res, 2017, 230:99-132.
[4] Philippidis A. Kymriah, first CAR-T cancer immunotherapy approved by FDA[J]. Clinic Omics, 2017, 4:8.
[5] Fraldi A, Serafini M, Sorrentino NC, et al. Gene therapy for mucopolysaccharidoses:in vivo and ex vivo approaches[J]. Ital J Pediatr, 2018, 44:130.
[6] Ibraheem D, Elaissari A, Fessi H. Gene therapy and DNA delivery systems[J]. Int J Pharm, 2014, 459:70-83.
[7] Yang LP, Cao L, Zhao T, et al. The progress of multifunctional envelope-type nano device[J]. Acta Pharm Sin (药学学报), 2018, 53:50-56.
[8] Qin LH, Cao DW, Pan SR, et al. Construction of serum-resistant cationic polymer α-CD-PAMAM and evaluation of its performances as gene delivery vector[J]. Acta Pharm Sin (药学学报), 2017, 52:139-145.
[9] Chen Y, Hu JF, Zhang CL, et al. Synthesis and evaluation of a dendritic poly (L-glutamic acid) -graft-polyethylenimine copolymer as an efficient gene delivery vector[J]. Acta Pharm Sin (药学学报), 2019, 54:173-180.
[10] Tong HJ, Fernandes JC, Liu L, et al. Progress and prospects of chitosan and its derivatives as non-viral gene vectors in gene therapy[J]. Curr Gene Ther, 2009, 9:495-502.
[11] Jiang C, Chen J, Li Z, et al. Recent advances in the development of polyethylenimine-based gene vectors for safe and efficient gene delivery[J]. Expert Opin Drug Deliv, 2019, 16:363-376.
[12] Yang D, Zhou Q, Fan GT. Research advances of polyethylenimine as gene transfection vector[J]. Chin Med Biotechnol (中国医药生物技术), 2007, 2:308-309.
[13] Patnaik S, Gupta KC. Novel polyethylenimine-derived nanoparticles for in vivo gene delivery[J]. Expert Opin Drug Deliv, 2013, 10:215-228.
[14] Zhang YH, Chen Y, Zhang YM, et al. Recycling gene carrier with high efficiency and low toxicity mediated by L-cystine-bridged bis(beta-cyclodextrin)s[J]. Sci Rep, 2014, 4:7471.
[15] Li JM, Wang YY, Zhang W, et al. Low-weight polyethylenimine cross-linked 2-hydroxypopyl-beta-cyclodextrin and folic acid as an efficient and nontoxic siRNA carrier for gene silencing and tumor inhibition by VEGF siRNA[J]. Int J Nanomed, 2013, 8:2101-2117.
[16] Ihm JE, Krier I, Lim JM, et al. Improved biocompatibility of polyethylenimine (PEI) as a gene carrier by conjugating urocanic acid:in vitro and in vivo[J]. Macromol Res, 2015, 23:387-395.
[17] Doura T, Tamanoi F, Nakamura M. Miniaturization of thiol-organosilica nanoparticles induced by an anionic surfactant[J]. J Colloid Interface Sci, 2018, 526:51-62.
[18] Chithrani BD, Chan WCW. Elucidating the mechanism of cellular uptake and removal of protein-coated gold nanoparticles of different sizes and shapes[J]. Nano Lett, 2007, 7:1542-1550.
[19] Shi W, Wang J, Fan X, et al. Size and shape effects on diffusion and absorption of colloidal particles near a partially absorbing sphere:implications for uptake of nanoparticles in animal cells[J]. Phys Rev E Stat Nonlin Soft Matter Phys, 2008, 78:061914.
[20] Frohlich E. The role of surface charge in cellular uptake and cytotoxicity of medical nanoparticles[J]. Int J Nanomed, 2012, 7:5577-5591.
[21] Han S, Wan H, Lin D, et al. Contribution of hydrophobic/hydrophilic modification on cationic chains of poly(ε-caprolactone)-graft-poly(dimethylamino ethylmethacrylate) amphiphilic co-polymer in gene delivery[J]. Acta Biomater, 2014, 10:670-679.
[22] Martens TF, Remaut K, Demeester J, et al. Intracellular delivery of nanomaterials:how to catch endosomal escape in the act[J]. Nano Today, 2014, 9:344-364.
[23] Lechardeur D, Lukacs GL. Intracellular barriers to non-viral gene transfer[J]. Curr Gene Ther, 2002, 2:183-194.
[24] Lu J, Zhao Y, Zhou X, et al. Biofunctional polymer-lipid hybrid high density lipoprotein-mimicking nanoparticles loading anti-miR155 for combined antiatherogenic effects on macrophages[J]. Biomacromolecules, 2017, 18:2286-2295.
[25] Rejman J, Bragonzi A, Conese M. Role of clathrin- and caveolae-mediated endocytosis in gene transfer mediated by lipo- and polyplexes[J]. Mol Ther, 2005, 12:468-474.
[26] Vongersdorff K, Sanders N, Vandenbroucke R, et al. The internalization route resulting in successful gene expression depends on both cell line and polyethylenimine polyplex type[J]. Mol Ther, 2006, 14:745-753.
[27] Pei D, Buyanova M. Overcoming endosomal entrapment in drug delivery[J]. Bioconjug Chem, 2018, 30:273-283.
[28] Lee Y, Miyata K, Oba M, et al. Charge-conversion ternary polyplex with endosome disruption moiety:a technique for efficient and safe gene delivery[J]. Angew Chem, 2008, 47:5163-5166.
[29] Neu M, Fischer D, Kissel T. Recent advances in rational gene transfer vector design based on poly(ethylene imine) and its derivatives[J]. J Gene Med, 2005, 7:992-1009.
[30] Beyerle A, Irmler M, Beckers J, et al. Toxicity pathway focused gene expression profiling of PEI-based polymers for pulmonary applications[J]. Mol Pharm, 2010, 7:727-737.
[31] Grandinetti G, Ingle NP, Reineke TM. Interaction of poly(ethylenimine)-DNA polyplexes with mitochondria:implications for a mechanism of cytotoxicity[J]. Mol Pharm, 2011, 8:1709-1719.
[32] Shi S, Guo Q, Kan B, et al. A novel poly(ε-caprolactone)-pluronic-poly(ε-caprolactone) grafted polyethyleneimine (PCFC-g-PEI), part 1, synthesis, cytotoxicity, and in vitro transfection study[J]. BMC Biotechnol, 2009, 9:65.
[33] Suk JS, Xu Q, Kim N, et al. PEGylation as a strategy for improving nanoparticle-based drug and gene delivery[J]. Adv Drug Deliv Rev, 2015, 99:28-51.
[34] Somani S, Laskar P, Altwaijry N, et al. PEGylation of polypropylenimine dendrimers:effects on cytotoxicity, DNA condensation, gene delivery and expression in cancer cells[J]. Sci Rep, 2018, 8:9410.
[35] Wang Y, Zhao D, Wei X, et al. PEGylated polyethylenimine derivative-mediated local delivery of the shSmad3 inhibits intimal thickening after vascular injury[J]. Biomed Res Int, 2019, 2019:8483765.
[36] Cai J, Chen J, Huang P, et al. Study on PEGylated polyethylenimine as a non-viral gene delivery vector[J]. Chin J Pharm (中国医药工业杂志), 2006, 38:22-26.
[37] Hatakeyama H, Akita H, Harashima H. The polyethyleneglycol dilemma:advantage and disadvantage of PEGylation of liposomes for systemic genes and nucleic acids delivery to tumors[J]. Biol Pharm Bull, 2013, 36:892-899.
[38] Nie Y, Günther M, Gu Z, et al. Pyridylhydrazone-based PEGylation for pH-reversible lipopolyplex shielding[J]. Biomaterials, 2011, 32:858-869.
[39] Patnaik S, Aggarwal A, Nimesh S, et al. PEI-alginate nanocomposites as efficient in vitro gene transfection agents[J]. J Control Release, 2006, 114:398-409.
[40] Yao J, Fan Y, Du R, et al. Amphoteric hyaluronic acid derivative for targeting gene delivery[J]. Biomaterials, 2010, 31:9357-9365.
[41] Lo YL, Lo PC, Chiu CC, et al. Folic acid linked chondroitin sulfate-polyethyleneimine copolymer based gene delivery system[J]. J Biomed Nanotechnol, 2015, 11:1385-1400.
[42] Jeon O, Yang HS, Lee TJ, et al. Heparin-conjugated polyethylenimine for gene delivery[J]. J Control Release, 2008, 132:236-242.
[43] Haiping J, Sujuan W, Xuefei Z, et al. New path to treating pancreatic cancer:TRAIL gene delivery targeting the fibroblast-enriched tumor microenvironment[J]. J Control Release, 2018, 286:254-263.
[44] Yang S, Guo Z, Yang X, et al. Enhanced survivin siRNA delivery using cationic liposome incorporating fatty acid-modified polyethylenimine[J]. Chem Res Chin Univ, 2015, 31:401-405.
[45] Lin L, Gou ZP, Chen J, et al. Synthesis and characterization of polyphenylalanine grafted low molecular weight PEI as efficient gene carriers[J]. Acta Polym Sin (高分子学报), 2017, 48:191-198.
[46] Yuan CC, Zhong SY, Wang YH, et al. Low molecular weight PEI of α-tocopherol-modification as gene delivery vectors[J]. Sci Technol Eng (科学技术与工程), 2018, 18:35-39.
[47] Taranejoo S, Chandrasekaran R, Cheng W, et al. Bioreducible PEI-functionalized glycol chitosan:a novel gene vector with reduced cytotoxicity and improved transfection efficiency[J]. Carbohydr Polym, 2016, 153:160-168.
[48] Yamada H, Loretz B, Lehr CM. Design of starch-graft-PEI polymers:an effective and biodegradable gene delivery platform[J]. Biomacromolecules, 2014, 15:1753-1761.
[49] Zhang Y, Jiang Q, Bi B, et al. A bioreducible supramolecular nanoparticle gene delivery system based on cyclodextrin-conjugated polyaspartamide and adamantyl-terminated polyethylenimine[J]. J Mater Chem B, 2018, 6:797-808.
[50] Li Y, Zhang X, Zhang J, et al. Synthesis and characterization of a hyperbranched grafting copolymer PEI-g-PLeu for gene and drug co-delivery[J]. J Mater Sci Mater Med, 2018, 29:47.
[51] Noga M, Edinger D, Wagner E, et al. Characterization and compatibility of hydroxyethyl starch-polyethylenimine copolymers for DNA delivery[J]. J Biomater Sci Polym Ed, 2014, 25:855-871.
[52] Wang H, Li X, Ling C, et al. Cationic starch/pDNA nanocomplexes assembly and their nanostructure changes on gene transfection efficiency[J]. Sci Rep, 2017, 7:14844.
[53] Giron-Gonzalez MD, Salto-Gonzalez R, Lopez-Jaramillo FJ, et al. Polyelectrolyte complexes of low molecular weight PEI and citric acid as efficient and nontoxic vectors for in vitro and in vivo gene delivery[J]. Bioconjug Chem, 2016, 27:549-561.
[54] Adachi M, Kai K, Yamaji K, et al. Transferrin receptor 1 overexpression is associated with tumour de-differentiation and acts as a potential prognostic indicator of hepatocellular carcinoma[J]. Histopathology, 2019, 75:63-73.
[55] Normanno N, De Luca A, Bianco C, et al. Epidermal growth factor receptor (EGFR) signaling in cancer[J]. Gene, 2006, 366:2-16.
[56] Ribeiro RSG, Belderbos S, Danhier P, et al. Targeting tumor cells and neovascularization using RGD-functionalized magnetoliposomes[J]. Int J Nanomed, 2019, 14:5911-5924.
[57] Sun Y, Zhao Y, Teng S, et al. Folic acid receptor-targeted human serum albumin nanoparticle formulation of cabazitaxel for tumor therapy[J]. Int J Nanomed, 2018, 14:135-148.
[58] Chen XA, Deng YB. Progress of nanometer vector polyethylenimine applied in gene therapy[J]. J Biomed Eng (生物医学工程学杂志), 2011, 28:195-198.
[59] Jhaveri A, Deshpande P, Pattni B, et al. Transferrin-targeted, resveratrol-loaded liposomes for the treatment of glioblastoma[J]. J Control Release, 2018, 277:89-101.
[60] Ayyappan S, Prabhakar D, Sharma N. Epidermal growth factor receptor (EGFR)-targeted therapies in esophagogastric cancer[J]. Anticancer Res, 2013, 33:4139-4155.
[61] Lei Y, Wang J, Xie C, et al. Glutathione-sensitive RGD-poly(ethylene glycol)-ss-polyethylenimine for intracranial glioblastoma targeted gene delivery[J]. J Gene Med, 2013, 15:291-305.
[62] Li Z, Liu X, Chen X, et al. Targeted delivery of Bcl-2 conversion gene by MPEG-PCL-PEI-FA cationic copolymer to combat therapeutic resistant cancer[J]. Mater Sci Eng C, 2017, 76:66-72.
[63] Zhu XW, Su TJ, Zhang YH, et al. In vitro gene transfection of human transferrin coupled crosslinked PEI as tumor targeted gene vector[J]. J Biol (生物学杂志), 2013, 30:14-17.
[64] Gersdorff KV, Ogris M, Wagner E. Cryoconserved shielded and EGF receptor targeted DNA polyplexes:cellular mechanisms[J]. Eur J Pharm Biopharm, 2005, 60:279-285.
[65] Kunath K, Merdan T, Hegener O, et al. Integrin targeting using RGD-PEI conjugates for in vitro gene transfer[J]. J Gene Med, 2003, 5:588-599.
[66] Leroueil PR, Dimaggio S, Leistra AN, et al. Characterization of folic acid and poly(amidoamine) dendrimer interactions with folate binding protein:a force-pulling study[J]. J Phys Chem B, 2015, 119:11506-11512.
[67] Wang Y, Sun G, Gong Y, et al. Functionalized folate-modified graphene oxide/PEI siRNA nanocomplexes for targeted ovarian cancer gene therapy[J]. Nanoscale Res Lett, 2020, 15:57.
[68] Iqbal N, Iqbal N. Human epidermal growth factor receptor 2(HER2) in cancers:overexpression and therapeutic implications[J]. Mol Biol Int, 2014, 2014:852748.
[69] Chiu SJ, Ueno NT, Lee RJ. Tumor-targeted gene delivery via anti-HER2 antibody (trastuzumab, Herceptin) conjugated polyethylenimine[J]. J Control Release, 2004, 97:357-369.
[70] Lai WF, Wong WT. Design of polymeric gene carriers for effective intracellular delivery[J]. Trends Biotechnol, 2018, 36:713-728.
[71] Shi B, Zheng M, Tao W, et al. Challenges in DNA delivery and recent advances in multifunctional polymeric DNA delivery system[J]. Biomacromolecules, 2017, 18:2231-2246.
[72] Wang YJ, Zhou Q, Cao S, et al. Efficient gene therapy with a combination of ultrasound‑targeted microbubble destruction and PEI/DNA/NLS complexes[J]. Mol Med Rep, 2016, 68:C55.
[73] Zhang MP, Ding BY, Chen RB, et al. Application of polyethyleneimine and its derivatives in non-viral gene therapy[J]. Clin J Chin Med (中医临床研究), 2015, 7:126-128.
[74] Fan Y, Yao J, Zhou JP. Preparation of nucleus-targeting polyethyleneimine-dexamethasone conjugates and their application for gene delivery[J]. Chem J Chin Univ (高等学校化学学报), 2011, 32:220-226.
[75] Ihm JE, Krier I, Lim JM. Improved biocompatibility of polyethylenimine (PEI) as a gene carrier by conjugating urocanic acid:in vitro and in vivo[J]. Macromol Res, 2015, 23:387-395.
[76] Huang G, Chen Q, Wu W, et al. Reconstructed chitosan with alkylamine for enhanced gene delivery by promoting endosomal escape[J]. Carbohydr Polym, 2019, 227:115339.
[77] Hu Y, Wang HF, Song HQ, et al. Peptide-grafted dextran vectors for efficient and high-loading gene delivery[J]. Biomater Sci, 2019, 7:1543-1553.
[78] Deng QR, Li XD, Zhu LP, et al. Serum-resistant, reactive oxygen species (ROS)-potentiated gene delivery in cancer cells mediated by fluorinated, diselenide-crosslinked polyplexes[J]. Biomater Sci, 2017, 5:1174-1182.
[79] Liu MR, Du HL, Zhang WJ, et al. Internal stimuli-responsive nanocarriers for drug delivery:design strategies and applications[J]. Mater Sci Eng C, 2017, 71:1267-1280.
[80] Dehnel N, Moral J, Namgaladzel D, et al. Cancer cell and macrophage cross-talk in the tumor microenvironment[J]. Curr Opin Pharm, 2017, 35:12-19.
[81] Yahara T, Koga T, Yoshida S, et al. Relationship between microvessel density and thermographic hot areas in breast cancer[J]. Surg Today, 2003, 33:243-248.
[82] Liao LF, Jiang G. Research progress for stimuli-responsive combination therapy system based on nanocarriers[J]. Chin J Hosp Pharm (中国医院药学杂志), 2019, 39:109-113.
[83] Kanamala M, Wilson WR, Yang MM, et al. Mechanisms and biomaterials in pH-responsive tumour targeted drug delivery:a review[J]. Biomaterials, 2016, 85:152-167.
[84] Huang DC, Qian HL, Qiao HS, et al. Bioresponsive functional nanogels as an emerging platform for cancer therapy[J]. Expert Opin Drug Deliv, 2018, 15:703-716.
[85] Che HL, van Hest JCM. Stimuli-responsive polymersomes and nanoreactors[J]. J Mater Chem B, 2016, 4:4632-4647.
[86] Guo X, Yuan Z, Xu Y, et al. A Low-molecular-weight polyethylenimine/pDNA-VEGF polyplex system constructed in a one-pot manner for hindlimb ischemia therapy[J]. Pharmaceutics, 2019, 11:171.
[87] Long RM, Dai QL, Zhou X, et al. Bacterial magnetosomes-based nanocarriers for co-delivery of cancer therapeutics in vitro[J]. Int J Nanomed, 2018, 13:8269-8279.
[88] Benns JM, Choi JS, Mahato RI, et al. pH-sensitive cationic polymer gene delivery vehicle:N-Ac-poly(L-histidine)-graft-poly(L-lysine) comb shaped polymer[J]. Bioconjug Chem, 2000, 11:637-645.
[89] Liao SC, Ting CW, Chiang WH. Functionalized polymeric nanogels with pH-sensitive benzoic-imine cross-linkages designed as vehicles for indocyanine green delivery[J]. J. Colloid Interface Sci, 2020, 561:11-22.
[90] Guo AJ, Wang Y, Xu SH, et al. Preparation and evaluation of pH-responsive charge-convertible ternary complex FA-PEI-CCA/PEI/DNA with low cytotoxicity and efficient gene delivery[J]. Colloids Surf B, 2017, 152:58-67.
[91] Lu J, Zhao Y, Zhou XJ, et al. Biofunctional polymer lipid hybrid high-density lipoprotein mimicking nanoparticles loading anti-miR155 for combined antiatherogenic effects on macrophages[J]. Biomacromolecules, 2017, 18:2286-2295.
[92] Tan DQ, Suda T. Reactive oxygen species and mitochondrial homeostasis as regulators of stem cell fate and function[J]. Antioxid Redox Signal, 2018, 29:149-168.
[93] Xu XD, Saw PE, Tao W, et al. ROS-responsive polyprodrug nanoparticles for triggered drug delivery and effective cancer therapy[J]. Adv Mater, 2017, 29:201700141.
[94] Zheng N, Xie D, Zhang ZY, et al. Thioketal-crosslinked:ROS-degradable polycations for enhanced in vitro and in vivo gene delivery with self-diminished cytotoxicity[J]. J Biomater Appl, 2019, 34:326-338.
[95] Lin GQ, Yi WJ, Liu Q, et al. Aromatic thioacetal-bridged ROS-responsive nanoparticles as novel gene delivery vehicles[J]. Molecules, 2018, 23:2061.
[96] Zhang WX, Zhou Y, Li XD, et al. Macrophage-targeting and reactive oxygen species (ROS)-responsive nanopolyplexes mediate anti-inflammatory siRNA delivery against acute liver failure (ALF)[J]. Biomater Sci, 2018, 6:1986-1993.
[97] Ruan C, Liu L, Wang Q, et al. Reactive oxygen species-biodegradable gene carrier for the targeting therapy of breast cancer[J]. ACS Appl Mater Interfaces, 2018, 10:10398-10408.
[98] Wang LH, Wu T, Wu DC, et al. Bioreducible gene delivery vector capable of self-scavenging the intracellular-generated ROS exhibiting high gene transfection[J]. ACS Appl Mater Interfaces, 2016, 8:19238-19244.
[99] Zintchenko A, Ogris M, Wagner E. Temperature dependent gene expression induced by PNIPAM-based copolymers:potential of hyperthermia in gene transfer[J]. Bioconjug Chem, 2006, 17:766-772.
[100] Schafer FQ, Buettner GR. Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple[J]. Free Radical Biol Med, 2001, 30:1191-1212.
[101] Cheng R, Feng F, Meng FH, et al. Glutathione-responsive nano-vehicles as a promising platform for targeted intracellular drug and gene delivery[J]. J Control Release, 2011, 152:2-12.
[102] Chen GJ, Ma B, Wang YY, et al. A universal GSH-responsive nanoplatform for the delivery of DNA, mRNA, and Cas9/sgRNA ribonucleoprotein[J]. ACS Appl Mater Interfaces, 2018, 10:18515-18523.
[103] Chen HC, Liu DY, Guo ZJ. Endogenous stimuli-responsive nanocarriers for drug delivery[J]. Chem Lett, 2016, 45:242-249.
[104] Taranejoo S, Chandrasekaran R, Cheng WL, et al. Bioreducible PEI-functionalized glycol chitosan:a novel gene vector with reduced cytotoxicity and improved transfection efficiency[J]. Carbohydr Polym, 2016, 153:160-168.
[105] Dai Y, Zhang XJ. MicroRNA delivery with bioreducible polyethylenimine as a non-viral vector for breast cancer gene therapy[J]. Macromol Biosci, 2019, 19:e1800445.
[106] Saravanakumar K, Hu XW, Ali DM, et al. Emerging strategies in stimuli-responsive nanocarriers as the drug delivery system for enhanced cancer therapy[J]. Curr Pharm Des, 2019, 25:2609-2625.
[107] Yuan ZQ, Gobeil PAM, Campo MS, et al. Equine sarcoid fibroblasts over-express matrix metalloproteinases and are invasive[J]. Virology, 2010, 396:143-151.
[108] Yu JE, Han SY, Wolfson B, et al. The role of endothelial lipase in lipid metabolism, inflammation, and cancer[J]. Histol Histopathol, 2018, 33:1-10.
[109] Gao J, Yu H, Chen FY, et al. A hyaluronidase/ATP tandem stimuli-responsive supramolecular assembly[J]. Chem Commun, 2019, 55:14387-14390.
[110] Yin T, Liu J, Zhao Z, et al. Smart nanoparticles with a detachable outer shell for maximized synergistic antitumor efficacy of therapeutics with varying physicochemical properties[J]. J Control Release, 2016, 243:54-68.
[111] Qian CG, Chen YL, Zhu S, et al. ATP-responsive and near-infrared-emissive nanocarriers for anticancer drug delivery and real-time imaging[J]. Theranostics, 2016, 6:1053-1064.
[112] Jiang CP, Qi ZT, Jia HB, et al. ATP-responsive low-molecular-weight polyethylenimine-based supramolecular assembly via host-guest interaction for gene delivery[J]. Biomacromolecules, 2019, 20:1132-1133.
[113] Yoshida K, Kashimura Y, Kamijo T, et al. Decomposition of glucose-sensitive layer-by-layer films using hemin, DNA, and glucose oxidase[J]. Polymers, 2020, 12:319.
[114] Jochum FD, Theato P. Temperature- and light-responsive smart polymer materials[J]. Chem Soc Rev, 2013, 42:7468-7483.
[115] Jia S, Fong WK, Graham B, et al. Photoswitchable molecules in long-wavelength light-responsive drug delivery:from molecular design to applications[J]. Chem Mater, 2018, 30:2873-2887.
[116] Fomina N, McFearin C, Sermsakdi M, et al. UV and near-IR triggered release from polymeric nanoparticles[J]. J Am Chem Soc, 2010, 132:9540-9542.
[117] Jiang BC, He H, Yao L, et al. Harmonizing the intracellular kinetics toward effective gene delivery using cancer cell-targeted and light-degradable polyplexes[J]. Biomacromolecules, 2017, 18:877-885.
[118] Menon S, Das S. Photoresponsive self-assembling structures from a pyrene-based triblock copolymer[J]. Polym Chem, 2011, 49:4448-4457.
[119] Wang H, Miao WJ, Wang F, et al. A Self-assembled coumarin-anchored dendrimer for efficient gene delivery and light-responsive drug delivery[J]. Biomacromolecules, 2018, 19:2194-2201.
[120] Tung ST, Cheng HT, Inthasot A, et al. Interlocked photo-degradable macrocycles allow one-off photo-triggerable gelation of organo- and hydrogelators[J]. Chemistry, 2018, 24:1522-1527.
[121] Lee H, Kim Y, Schweickert PG, et al. A photo-degradable gene delivery system for enhanced nuclear gene transcription[J]. Biomaterials, 2014, 35:1040-1049.
[122] Zhou Q, Zhang L, Yang TH, et al. Stimuli-responsive polymeric micelles for drug delivery and cancer therapy[J]. Int J Nanomed, 2018, 13:2921-2942.
[123] Sponchioni M, Palmiero UC, Moscatelli D. Thermo-responsive polymers:applications of smart materials in drug delivery and tissue engineering[J]. Mater Sci Eng C, 2019, 102:589-605.
[124] Raza A, Rasheed T, Nabeel F, et al. Endogenous and exogenous stimuli-responsive drug delivery systems for programmed site-specific release[J]. Molecules, 2019, 24:1117.
[125] Kuo CY, Liu TY, Wang KS, et al. Magnetic and thermal-sensitive poly(N-isopropylacrylamide)-based microgels for magnetically triggered controlled release[J]. J Visual Exp, 2017, 125:55648.
[126] Zhang HZ, Li QB, Zhang YY, et al. A nanogel with passive targeting function and adjustable polyplex surface properties for efficient anti-tumor gene therapy[J]. Rsc Adv, 2016, 6:84445-84456.
[127] Gupta AK, Naregalkar RR, Vaidya VD, et al. Recent advances on surface engineering of magnetic iron oxide nanoparticles and their biomedical applications[J]. Nanomedicine, 2007, 2:23-39.
[128] Guruprasath P, Kim J, Gunassekaran GR, et al. Interleukin-4 receptor-targeted delivery of Bcl-xL siRNA sensitizes tumors to chemotherapy and inhibits tumor growth[J]. Biomaterials, 2017, 142:101-111.
[129] Lo YL, Chou HL, Liao ZX, et al. Chondroitin sulfate-polyethylenimine copolymer-coated superparamagnetic iron oxide nanoparticles as an efficient magneto-gene carrier for microRNA-encoding plasmid DNA delivery[J]. Nanoscale, 2015, 7:8554-8565.
[130] Jia N, Wu HA, Duan JL, et al. Polyethyleneimine-coated iron oxide nanoparticles as a vehicle for the delivery of small interfering RNA to macrophages in vitro and in vivo[J]. J Visual Exp, 2019. DOI:10.3791/58660.
[131] Karimi M, Zangabad PS, Ghasemi A, et al. Temperature-responsive smart nanocarriers for delivery of therapeutic agents:applications and recent advances[J]. ACS Appl Mater Interfaces, 2016, 8:21107-21133.
[132] Morey M, Pandit A. Responsive triggering systems for delivery in chronic wound healing[J]. Adv Drug Del Rev, 2018, 129:169-193.
[133] Wang DL, Jin Y, Zhu XY, et al. Synthesis and applications of stimuli-responsive hyperbranched polymers[J]. Prog Polym Sci, 2017, 64:114-153.
[134] Xu F, Zhong H, Chang Y, et al. Targeting death receptors for drug-resistant cancer therapy:codelivery of pTRAIL and monensin using dual-targeting and stimuli-responsive self-assembling nanocomposites[J]. Biomaterials, 2018, 158:56.
[135] Wang T, Yu X, Han L, et al. Tumor microenvironment dual-responsive core-shell nanoparticles with hyaluronic acid-shield for efficient co-delivery of doxorubicin and plasmid DNA[J]. Int J Nanomed, 2017, 12:4773-4788.
[136] Kim J, Lee YM, Kim H, et al. Phenylboronic acid-sugar grafted polymer architecture as a dual stimuli-responsive gene carrier for targeted anti-angiogenic tumor therapy[J]. Biomaterials, 2016, 75:102-111.
[137] Wang F, Shen Y, Zhang W, et al. Efficient, dual-stimuli responsive cytosolic gene delivery using a RGD modified disulfide-linked polyethylenimine functionalized gold nanorod[J]. J Control Release, 2014, 196:37-51.
[138] He Y, Guo S, Wu L, et al. Near-infrared boosted ROS responsive siRNA delivery and cancer therapy with sequentially peeled upconversion nano-onions[J]. Biomaterials, 2019, 225:119501.
[139] Zhang P, Xu Q, Li X, et al. pH-responsive polydopamine nanoparticles for photothermally promoted gene delivery[J]. Mater Sci Eng C, 2020, 108:110396.
[140] Mok H, Veiseh O, Fang C, et al. pH-sensitive siRNA nanovector for targeted gene silencing and cytotoxic effect in cancer cells[J]. Mol Pharm, 2010, 7:1930-1939.
1.陈英, 胡锦芳, 张长林, 曹端文, 魏筱华.聚酰胺-胺-聚谷氨酸-聚乙烯亚胺共聚物的制备及作为基因载体的性能研究[J]. 药学学报, 2019,54(5): 919-926
2.陈建海;.阳离子聚合物在基因传递系统中的应用阳离子聚合物在基因传递系统中的应用[J]. 药学学报, 2003,38(4): 316-320