细菌小细胞在癌症治疗中的应用
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摘要
癌症一直是危害人类健康的主要疾病之一。传统的癌症治疗方法包括放疗、化疗和手术,均具有明显的毒副作用或局限性。脂质体和纳米颗粒作为被广泛研究的药物递送载体,在人体临床试验中也出现了药物渗漏和装载功能不全等问题。目前而言,应用具有肿瘤靶向性的载体递送抗肿瘤药物或小分子,是有希望介导安全、有效的肿瘤治疗的策略之一。近年来,细菌来源的非复制型小细胞已受到越来越多的关注。小细胞是细菌异常分裂时期产生的纳米级无核细胞,其直径为200–400 nm,因而具有较大的药物装载能力。对小细胞的表面进行修饰,例如,装配能与肿瘤细胞表面特异性抗原或受体结合的抗体/配体,可显著提高小细胞的肿瘤靶向性。这种具有靶向性的纳米材料能将抗肿瘤的化疗药物、功能性核酸或编码功能性小分子的质粒靶向递送至肿瘤,而减少药物在正常组织器官的集聚。因此,使用小细胞作为靶向递送载体有助于降低药物对机体的毒性,从而最大限度地发挥药物分子在体内的抗肿瘤活性。文中将对小细胞的产生与纯化、药物装载、肿瘤细胞靶向性、内化过程以及其用于递送抗肿瘤药物的研究进展等方面进行综述,为开发基于小细胞的癌症治疗策略提供一定的参考。
Cancer is one of the most important diseases threatening human health. Frequently-used traditional cancer treatment methods, like radiotherapy, chemotherapy and surgery, have serious toxic side effects and limitations. The widely-used drug delivery carriers(liposomes, nanoparticles, etc.) have also possessed many issues such as drug leakage and incomplete loading in the late clinical stage. Currently, using tumor-targeting vectors to deliver anti-tumor drugs or small molecules is one of the promising strategies for mediating safe and effective tumor therapy. In recent years, bacterial-derived non-replicating minicells, which are nanoscale non-nucleated cells produced during abnormal bacterial division, have got more and more attention. With a diameter of 200–400 nm, minicells have a large drug loading capacity. Meanwhile, the surface of minicells are able to be modified to load the assembly of antibodies/ligands that bind to tumor cell surface specific antigens or receptors, which can significantly improve tumor targeting of minicells. This tumor-targeting nanomaterials of minicells not only are used to deliver anti-tumor chemotherapeutic drugs, functional nucleic acids or plasmids encoding functional small molecules to mammalian cells, but also greatly increase drug loading and reduce drug penetration. Thus, the use of minicells combining with chemical therapy could help reduce the toxicity and maximize the effectiveness of the drug in the body. This paper summarizes the research and development of production purification, drug loading, tumor cells targeting, and internalization process of minicells, as well as its use in the delivery of anti-tumor drugs, to provide some information for the development and utilization of minicell carriers.
Cancer is one of the most important diseases threatening human health. Frequently-used traditional cancer treatment methods, like radiotherapy, chemotherapy and surgery, have serious toxic side effects and limitations. The widely-used drug delivery carriers(liposomes, nanoparticles, etc.) have also possessed many issues such as drug leakage and incomplete loading in the late clinical stage. Currently, using tumor-targeting vectors to deliver anti-tumor drugs or small molecules is one of the promising strategies for mediating safe and effective tumor therapy. In recent years, bacterial-derived non-replicating minicells, which are nanoscale non-nucleated cells produced during abnormal bacterial division, have got more and more attention. With a diameter of 200–400 nm, minicells have a large drug loading capacity. Meanwhile, the surface of minicells are able to be modified to load the assembly of antibodies/ligands that bind to tumor cell surface specific antigens or receptors, which can significantly improve tumor targeting of minicells. This tumor-targeting nanomaterials of minicells not only are used to deliver anti-tumor chemotherapeutic drugs, functional nucleic acids or plasmids encoding functional small molecules to mammalian cells, but also greatly increase drug loading and reduce drug penetration. Thus, the use of minicells combining with chemical therapy could help reduce the toxicity and maximize the effectiveness of the drug in the body. This paper summarizes the research and development of production purification, drug loading, tumor cells targeting, and internalization process of minicells, as well as its use in the delivery of anti-tumor drugs, to provide some information for the development and utilization of minicell carriers.
引文
[1]Chen WQ,Sun KX,Zheng RS,et al.Report of cancer incidence and mortality in different areas of China,2014.China Cancer,2018,27(1):1-14(in Chinese).陈万青,孙可欣,郑荣寿,等.2014年中国分地区恶性肿瘤发病和死亡分析.中国肿瘤,2018,27(1):1-14.
[2]Parveen S,Sahoo SK.Polymeric nanoparticles for cancer therapy.J Drug Target,2008,16(2):108-123.
[3]Nguyen THK.Cell division gene from bacteria in minicell production for therapy//Gali-Muhtasib H,Ed.Advances in Cancer Therapy.Croatia:InTech Press,2011:83-98.
[4]Jivrajani M,Shrivastava N,Nivsarkar M.A combination approach for rapid and high yielding purification of bacterial minicells.J Microbiol Methods,2013,92(3):340-343.
[5]Solomon BJ,Desai J,Rosenthal M,et al.Afirst-time-in-human phase I clinical trial of bispecific antibody-targeted,paclitaxel-packaged bacterial minicells.PLoS ONE,2015,10(12):e0144559.
[6]Macdiarmid JA,Mugridge NB,Weiss JC,et al.Bacterially derived 400 nm particles for encapsulation and cancer cell targeting of chemotherapeutics.Cancer Cell,2007,11(5):431-445.
[7]Giacalone MJ,Zapata JC,Berkley NL,et al.Immunization with non-replicating E.coli minicells delivering both protein antigen and DNA protects mice from lethal challenge with lymphocytic choriomeningitis virus.Vaccine,2007,25(12):2279-2287.
[8]Carleton HA,Lara-Tejero M,Liu XY,et al.Engineering the type III secretion system in non-replicating bacterial minicells for antigen delivery.Nat Commun,2013,4(3):1590.
[9]MacDiarmid JA,Brahmbhatt H.Minicells:versatile vectors for targeted drug or si/shRNA cancer therapy.Curr Opin Biotechnol,2011,22(6):909-916.
[10]Gemski P,Griffin DE.Isolation and characterization of minicell-producing mutants of Shigella spp.Infect Immun,1980,30(1):297-302.
[11]Lee JY,Choy HE,Lee JH,et al.Generation of minicells from an endotoxin-free gram positive strain Corynebacterium glutamicum.J Microbiol Biotechnol,2015,25(4):554-558.
[12]Nguyen HN,Jovel SR,Nguyen THK.Nanosized minicells generated by lactic acid bacteria for drug delivery.J Nanomater,2017:6847297.
[13]Matthew J.Jacalone,Stanley Maloi,Jin Jinwu.Adjustable gene compositions and methods of suicide mechanism:CN,102131927 B.2015-11-25(in Chinese).马修·J·贾卡洛内,斯坦利·马洛伊,辻晋吾.可调型基因自杀机制组合物和方法:中国,102131927 B.2015-11-25.
[14]Jivrajani M,Nivsarkar M.Ligand-targeted bacterial minicells:futuristic nano-sized drug delivery system for the efficient and cost effective delivery of shRNA to cancer cells.Nanomedicine,2016,12(8):2485-2498.
[15]Koppelman CM,Den Blaauwen T,Duursma MC,et al.Escherichia coli minicell membranes are enriched in cardiolipin.J Bacteriol,2001,183(20):6144-6147.
[16]Kim OY,Dinh NTH,Park HT,et al.Bacterial protoplast-derived nanovesicles for tumor targeted delivery of chemotherapeutics.Biomaterials,2017,113:68-79.
[17]Lu L,Xiong SB.The research progress of EPR effect in solid tumor targeted therapy.Northern Pharmacy,2014,11(7):73(in Chinese).卢琳,熊素彬.EPR效应在实体瘤靶向治疗中的研究进展.北方药学,2014,11(7):73.
[18]Du SS,Lutkenhaus J.Assembly and activation of the Escherichia coli divisome.Mol Microbiol,2017,105(2):177-187.
[19]Buddelmeijer N,Beckwith J.Assembly of cell division proteins at the E.coli cell center.Curr Opin Microbiol,2002,5(6):553-557.
[20]Park KT,Dajkovic A,Wissel M,et al.MinC and FtsZmutant analysis provides insight into MinC/MinD-mediated Z ring disassembly.J Biol Chem,2018,293(16):5834-5846.
[21]Treuner-Lange A,Aguiluz K,van der Does C,et al.PomZ,a ParA-like protein,regulates Z-ring formation and cell division in Myxococcus xanthus.Mol Microbiol,2013,87(2):235-253.
[22]Barák I,Prepiak P,Schmeisser F.MinCD proteins control the septation process during sporulation of Bacillus subtilis.J Bacteriol,1998,180(20):5327-5333.
[23]Labie C,BouchéF,BouchéJP.Minicell-forming mutants of Escherichia coli:suppression of both DicB-and MinD-dependent division inhibition by inactivation of the minC gene product.J Bacteriol,1990,172(10):5852-5855.
[24]van Baarle S,Bramkamp M.The MinCDJ system in Bacillus subtilis prevents minicell formation by promoting divisome disassembly.PLoS ONE,2010,5(3):e9850.
[25]Martos A,Raso A,Jiménez M,et al.FtsZ polymers tethered to the membrane by ZipA are susceptible to spatial regulation by min waves.Biophys J,2015,108(9):2371-2383.
[26]Cha JH,Stewart GC.The divIVA minicell locus of Bacillus subtilis.J Bacteriol,1997,179(5):1671-1683.
[27]Park SY,Lee JY,Chang WS,et al.A coupling process for improving purity of bacterial minicells by holin/lysin.J Microbiol Methods,2011,86(1):108-110.
[28]Davie E,Sydnor K,Rothfield LI.Genetic basis of minicell formation in Escherichia coli K-12.J Bacteriol,1984,158(3):1202-1203.
[29]Saier MH Jr,Reddy BL.Holins in bacteria,eukaryotes,and archaea:multifunctional xenologues with potential biotechnological and biomedical applications.JBacteriol,2015,197(1):7-17.
[30]Rang CU,Proenca A,Buetz C,et al.Minicells as a damage disposal mechanism in Escherichia coli.mSphere,2018,3(5):e00428-18.
[31]Mattick KL,J?rgensen F,Legan JD,et al.Survival and filamentation of Salmonella enterica serovar enteritidis PT4 and Salmonella enterica serovar typhimurium DT104 at low water activity.Appl Environ Microbiol,2000,66(4):1274-1279.
[32]Park JW.Liposome-based drug delivery in breast cancer treatment.Breast Cancer Res,2002,4(3):95-99.
[33]El-Rayes BF,LoRusso PM.Targeting the epidermal growth factor receptor.Br J Cancer,2004,91(3):418-424.
[34]Prajapati JD,Solano CJF,Winterhalter M,et al.Enrofloxacin permeation pathways across the porin OmpC.J Phys Chem B,2018,122(4):1417-1426.
[35]Kojima S,Nikaido H.High salt concentrations increase permeability through OmpC channels of Escherichia coli.J Biol Chem,2014,289(38):26464-26473.
[36]van den Berg B,Black PN,Clemons WM Jr,et al.Crystal structure of the long-chain fatty acid transporter FadL.Science,2004,304(5676):1506-1509.
[37]van den Berg B.The FadL family:unusual transporters for unusual substrates.Curr Opin Struct Biol,2005,15(4):401-407.
[38]Torchilin VP.Passive and active drug targeting:drug delivery to tumors as an example//Sch?fer-Korting M,Ed.Handbook of Experimental Pharmacology,vol.197.Berlin,Heidelberg:Springer,2010:3-53.
[39]Hashizume H,Baluk P,Morikawa S,et al.Openings between defective endothelial cells explain tumor vessel leakiness.Am J Pathol,2000,156(4):1363-1380.
[40]Slamon DJ,Clark GM,Wong SG,et al.Human breast cancer:correlation of relapse and survival with amplification of the HER-2/neu oncogene.Science,1987,235(4785):177-182.
[41]Alotaibi AM,Alqarni MA,Alnobi A,et al.Human epidermal growth factor receptor 2(HER2/neu)in salivary gland carcinomas:a review of literature.J Clin Diagn Res,2015,9(2):ZE04-ZE08.
[42]Van Dessel N,Swofford CA,Forbes NS.Potent and tumor specific:arming bacteria with therapeutic proteins.Ther Deliv,2015,6(3):385-399.
[43]Himanshu B,Jennifer M.Compositions and methods for targeted in vitro and in vivo drug delivery to mammalian cells via bacterially derived intact minicells:US,20080051469.2008-02-28.
[44]Xue S,Dong JC,Wu Q,et al.Development and application of microbial surface display technology.Shanghai Journal of Animal Husbandry and Veterinary Medicine,2008,(3):50-51(in Chinese).薛双,董加才,吴青,等.微生物表面展示技术的发展及应用.上海畜牧兽医通讯,2008,(3):50-51.
[45]Zhang YL,Ji W,He L,et al.E.coli nissle 1917-derived minicells for targeted delivery of chemotherapeutic drug to hypoxic regions for cancer therapy.Theranostics,2018,8(6):1690-1705.
[46]Hu B,Lara-Tejero M,Kong QK,et al.In situ molecular architecture of the salmonella type III secretion machine.Cell,2017,168(6):1065-1074.
[47]MacDiarmid JA,Amaro-Mugridge NB,Madrid-Weiss J,et al.Sequential treatment of drug-resistant tumors with targeted minicells containing siRNA or a cytotoxic drug.Nat Biotechnol,2009,27(7):643-651.
[48]Tsuji S,Chen XG,Hancock B,et al.Preclinical evaluation of VAX-IP,a novel bacterial minicell-based biopharmaceutical for nonmuscle invasive bladder cancer.Mol Ther Oncolytics,2016,3:16004.
[49]Karagiannis ED,Anderson DG.Minicells overcome tumor drug-resistance.Nat Biotechnol,2009,27(7):620-621.
[50]Van Zandwijk N,Pavlakis N,Kao SC,et al.Safety and activity of microRNA-loaded minicells in patients with recurrent malignant pleural mesothelioma:a first-in-man,phase 1,open-label,dose-escalation study.Lancet Oncol,2017,18(10):1386-1396.
[51]Fernandez-Pi?eiro I,Badiola I,Sanchez A.Nanocarriers for microRNA delivery in cancer medicine.Biotechnol Adv,2017,35(3):350-360.
[52]Parsa S,Pfeifer B.Engineering bacterial vectors for delivery of genes and proteins to antigen-presenting cells.Mol Pharmaceutics,2007,4(1):4-17.
[53]Hesse M,Weber R,Glünder G.Antibody titers in turkeys increase after multiple booster vaccinations with an attenuated Salmonella live vaccine.BMC Res Notes,2018,11(1):367.
[54]Giacalone MJ,Sabbadini RA,Chambers AL,et al.Immune responses elicited by bacterial minicells capable of simultaneous DNA and protein antigen delivery.Vaccine,2006,24(33/34):6009-6017.
[55]Lu W,Yang RQ,Wang L.Research progerss of exosomes.Chem Life,2013,33(4):438-442(in Chinese).卢婉,杨人强,王伶.外泌体的研究进展.生命的化学,2013,33(4):438-442.
[56]M?nkem?ller V,Schüttpelz M,McCourt P,et al.Imaging fenestrations in liver sinusoidal endothelial cells by optical localization microscopy.Phys Chem Chem Phys,2014,16(24):12576-12581.
[57]Cognet I,de Coignac AB,Magistrelli G,et al.Expression of recombinant proteins in a lipid A mutant of Escherichia coli BL21 with a strongly reduced capacity to induce dendritic cell activation and maturation.J Immunol Methods,2003,272(1/2):199-210.
[2]Parveen S,Sahoo SK.Polymeric nanoparticles for cancer therapy.J Drug Target,2008,16(2):108-123.
[3]Nguyen THK.Cell division gene from bacteria in minicell production for therapy//Gali-Muhtasib H,Ed.Advances in Cancer Therapy.Croatia:InTech Press,2011:83-98.
[4]Jivrajani M,Shrivastava N,Nivsarkar M.A combination approach for rapid and high yielding purification of bacterial minicells.J Microbiol Methods,2013,92(3):340-343.
[5]Solomon BJ,Desai J,Rosenthal M,et al.Afirst-time-in-human phase I clinical trial of bispecific antibody-targeted,paclitaxel-packaged bacterial minicells.PLoS ONE,2015,10(12):e0144559.
[6]Macdiarmid JA,Mugridge NB,Weiss JC,et al.Bacterially derived 400 nm particles for encapsulation and cancer cell targeting of chemotherapeutics.Cancer Cell,2007,11(5):431-445.
[7]Giacalone MJ,Zapata JC,Berkley NL,et al.Immunization with non-replicating E.coli minicells delivering both protein antigen and DNA protects mice from lethal challenge with lymphocytic choriomeningitis virus.Vaccine,2007,25(12):2279-2287.
[8]Carleton HA,Lara-Tejero M,Liu XY,et al.Engineering the type III secretion system in non-replicating bacterial minicells for antigen delivery.Nat Commun,2013,4(3):1590.
[9]MacDiarmid JA,Brahmbhatt H.Minicells:versatile vectors for targeted drug or si/shRNA cancer therapy.Curr Opin Biotechnol,2011,22(6):909-916.
[10]Gemski P,Griffin DE.Isolation and characterization of minicell-producing mutants of Shigella spp.Infect Immun,1980,30(1):297-302.
[11]Lee JY,Choy HE,Lee JH,et al.Generation of minicells from an endotoxin-free gram positive strain Corynebacterium glutamicum.J Microbiol Biotechnol,2015,25(4):554-558.
[12]Nguyen HN,Jovel SR,Nguyen THK.Nanosized minicells generated by lactic acid bacteria for drug delivery.J Nanomater,2017:6847297.
[13]Matthew J.Jacalone,Stanley Maloi,Jin Jinwu.Adjustable gene compositions and methods of suicide mechanism:CN,102131927 B.2015-11-25(in Chinese).马修·J·贾卡洛内,斯坦利·马洛伊,辻晋吾.可调型基因自杀机制组合物和方法:中国,102131927 B.2015-11-25.
[14]Jivrajani M,Nivsarkar M.Ligand-targeted bacterial minicells:futuristic nano-sized drug delivery system for the efficient and cost effective delivery of shRNA to cancer cells.Nanomedicine,2016,12(8):2485-2498.
[15]Koppelman CM,Den Blaauwen T,Duursma MC,et al.Escherichia coli minicell membranes are enriched in cardiolipin.J Bacteriol,2001,183(20):6144-6147.
[16]Kim OY,Dinh NTH,Park HT,et al.Bacterial protoplast-derived nanovesicles for tumor targeted delivery of chemotherapeutics.Biomaterials,2017,113:68-79.
[17]Lu L,Xiong SB.The research progress of EPR effect in solid tumor targeted therapy.Northern Pharmacy,2014,11(7):73(in Chinese).卢琳,熊素彬.EPR效应在实体瘤靶向治疗中的研究进展.北方药学,2014,11(7):73.
[18]Du SS,Lutkenhaus J.Assembly and activation of the Escherichia coli divisome.Mol Microbiol,2017,105(2):177-187.
[19]Buddelmeijer N,Beckwith J.Assembly of cell division proteins at the E.coli cell center.Curr Opin Microbiol,2002,5(6):553-557.
[20]Park KT,Dajkovic A,Wissel M,et al.MinC and FtsZmutant analysis provides insight into MinC/MinD-mediated Z ring disassembly.J Biol Chem,2018,293(16):5834-5846.
[21]Treuner-Lange A,Aguiluz K,van der Does C,et al.PomZ,a ParA-like protein,regulates Z-ring formation and cell division in Myxococcus xanthus.Mol Microbiol,2013,87(2):235-253.
[22]Barák I,Prepiak P,Schmeisser F.MinCD proteins control the septation process during sporulation of Bacillus subtilis.J Bacteriol,1998,180(20):5327-5333.
[23]Labie C,BouchéF,BouchéJP.Minicell-forming mutants of Escherichia coli:suppression of both DicB-and MinD-dependent division inhibition by inactivation of the minC gene product.J Bacteriol,1990,172(10):5852-5855.
[24]van Baarle S,Bramkamp M.The MinCDJ system in Bacillus subtilis prevents minicell formation by promoting divisome disassembly.PLoS ONE,2010,5(3):e9850.
[25]Martos A,Raso A,Jiménez M,et al.FtsZ polymers tethered to the membrane by ZipA are susceptible to spatial regulation by min waves.Biophys J,2015,108(9):2371-2383.
[26]Cha JH,Stewart GC.The divIVA minicell locus of Bacillus subtilis.J Bacteriol,1997,179(5):1671-1683.
[27]Park SY,Lee JY,Chang WS,et al.A coupling process for improving purity of bacterial minicells by holin/lysin.J Microbiol Methods,2011,86(1):108-110.
[28]Davie E,Sydnor K,Rothfield LI.Genetic basis of minicell formation in Escherichia coli K-12.J Bacteriol,1984,158(3):1202-1203.
[29]Saier MH Jr,Reddy BL.Holins in bacteria,eukaryotes,and archaea:multifunctional xenologues with potential biotechnological and biomedical applications.JBacteriol,2015,197(1):7-17.
[30]Rang CU,Proenca A,Buetz C,et al.Minicells as a damage disposal mechanism in Escherichia coli.mSphere,2018,3(5):e00428-18.
[31]Mattick KL,J?rgensen F,Legan JD,et al.Survival and filamentation of Salmonella enterica serovar enteritidis PT4 and Salmonella enterica serovar typhimurium DT104 at low water activity.Appl Environ Microbiol,2000,66(4):1274-1279.
[32]Park JW.Liposome-based drug delivery in breast cancer treatment.Breast Cancer Res,2002,4(3):95-99.
[33]El-Rayes BF,LoRusso PM.Targeting the epidermal growth factor receptor.Br J Cancer,2004,91(3):418-424.
[34]Prajapati JD,Solano CJF,Winterhalter M,et al.Enrofloxacin permeation pathways across the porin OmpC.J Phys Chem B,2018,122(4):1417-1426.
[35]Kojima S,Nikaido H.High salt concentrations increase permeability through OmpC channels of Escherichia coli.J Biol Chem,2014,289(38):26464-26473.
[36]van den Berg B,Black PN,Clemons WM Jr,et al.Crystal structure of the long-chain fatty acid transporter FadL.Science,2004,304(5676):1506-1509.
[37]van den Berg B.The FadL family:unusual transporters for unusual substrates.Curr Opin Struct Biol,2005,15(4):401-407.
[38]Torchilin VP.Passive and active drug targeting:drug delivery to tumors as an example//Sch?fer-Korting M,Ed.Handbook of Experimental Pharmacology,vol.197.Berlin,Heidelberg:Springer,2010:3-53.
[39]Hashizume H,Baluk P,Morikawa S,et al.Openings between defective endothelial cells explain tumor vessel leakiness.Am J Pathol,2000,156(4):1363-1380.
[40]Slamon DJ,Clark GM,Wong SG,et al.Human breast cancer:correlation of relapse and survival with amplification of the HER-2/neu oncogene.Science,1987,235(4785):177-182.
[41]Alotaibi AM,Alqarni MA,Alnobi A,et al.Human epidermal growth factor receptor 2(HER2/neu)in salivary gland carcinomas:a review of literature.J Clin Diagn Res,2015,9(2):ZE04-ZE08.
[42]Van Dessel N,Swofford CA,Forbes NS.Potent and tumor specific:arming bacteria with therapeutic proteins.Ther Deliv,2015,6(3):385-399.
[43]Himanshu B,Jennifer M.Compositions and methods for targeted in vitro and in vivo drug delivery to mammalian cells via bacterially derived intact minicells:US,20080051469.2008-02-28.
[44]Xue S,Dong JC,Wu Q,et al.Development and application of microbial surface display technology.Shanghai Journal of Animal Husbandry and Veterinary Medicine,2008,(3):50-51(in Chinese).薛双,董加才,吴青,等.微生物表面展示技术的发展及应用.上海畜牧兽医通讯,2008,(3):50-51.
[45]Zhang YL,Ji W,He L,et al.E.coli nissle 1917-derived minicells for targeted delivery of chemotherapeutic drug to hypoxic regions for cancer therapy.Theranostics,2018,8(6):1690-1705.
[46]Hu B,Lara-Tejero M,Kong QK,et al.In situ molecular architecture of the salmonella type III secretion machine.Cell,2017,168(6):1065-1074.
[47]MacDiarmid JA,Amaro-Mugridge NB,Madrid-Weiss J,et al.Sequential treatment of drug-resistant tumors with targeted minicells containing siRNA or a cytotoxic drug.Nat Biotechnol,2009,27(7):643-651.
[48]Tsuji S,Chen XG,Hancock B,et al.Preclinical evaluation of VAX-IP,a novel bacterial minicell-based biopharmaceutical for nonmuscle invasive bladder cancer.Mol Ther Oncolytics,2016,3:16004.
[49]Karagiannis ED,Anderson DG.Minicells overcome tumor drug-resistance.Nat Biotechnol,2009,27(7):620-621.
[50]Van Zandwijk N,Pavlakis N,Kao SC,et al.Safety and activity of microRNA-loaded minicells in patients with recurrent malignant pleural mesothelioma:a first-in-man,phase 1,open-label,dose-escalation study.Lancet Oncol,2017,18(10):1386-1396.
[51]Fernandez-Pi?eiro I,Badiola I,Sanchez A.Nanocarriers for microRNA delivery in cancer medicine.Biotechnol Adv,2017,35(3):350-360.
[52]Parsa S,Pfeifer B.Engineering bacterial vectors for delivery of genes and proteins to antigen-presenting cells.Mol Pharmaceutics,2007,4(1):4-17.
[53]Hesse M,Weber R,Glünder G.Antibody titers in turkeys increase after multiple booster vaccinations with an attenuated Salmonella live vaccine.BMC Res Notes,2018,11(1):367.
[54]Giacalone MJ,Sabbadini RA,Chambers AL,et al.Immune responses elicited by bacterial minicells capable of simultaneous DNA and protein antigen delivery.Vaccine,2006,24(33/34):6009-6017.
[55]Lu W,Yang RQ,Wang L.Research progerss of exosomes.Chem Life,2013,33(4):438-442(in Chinese).卢婉,杨人强,王伶.外泌体的研究进展.生命的化学,2013,33(4):438-442.
[56]M?nkem?ller V,Schüttpelz M,McCourt P,et al.Imaging fenestrations in liver sinusoidal endothelial cells by optical localization microscopy.Phys Chem Chem Phys,2014,16(24):12576-12581.
[57]Cognet I,de Coignac AB,Magistrelli G,et al.Expression of recombinant proteins in a lipid A mutant of Escherichia coli BL21 with a strongly reduced capacity to induce dendritic cell activation and maturation.J Immunol Methods,2003,272(1/2):199-210.