微液滴制备技术在功能化纳米载体构建中的应用
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摘要
以微流控芯片为基础的微液滴技术在制备结构和粒径均一的功能纳米载体方面具有独特优势。本文总结了目前利用微液滴技术和不同制备材料构建的具有不同结构和功能的纳米载体在药物递送方面的研究进展。纳米载体主要包括纳米脂质体、聚合物纳米粒、固体脂质纳米粒、杂化纳米复合物、Janus纳米粒等。
Nanocarriers are generally prepared by conventional "bottom-up" and "top-down" methods, which need multi-stage processing and input large amount of mechanic energy and/or thermal energy. The quality control and industrial production of nanocarriers are limited by the difficulties of manipulating structures precisely on the molecular scale. Micro-droplet technology based on microfluidic chip, which has unique advantages in the preparation of nanoparticles with uniformed size, defined structures and morphology, may provide an alternative way. In this paper, we summarize the representative structures of micro-droplet generation devices and review the research development of current nanocarriers with various structures and functions, including nanoliposomes, polymeric nanoparticles, solid lipid nanoparticles, hybrid nano-complex and Janus nanoparticles. The influences of geometry parameters of microtube, flow rate, liquid viscosity,mixing way and dimensionality on the nanocarrier size, polydispersity index, precise structures and morphology of nanocarriers as well as the nanocarrier behaviors at the whole-organism, cellular and molecular level are fully discussed.The micro-droplet based technology has shown a promising prospect in the preparation of multi-functional nanocarriers by flexible combination and scale integration.
Nanocarriers are generally prepared by conventional "bottom-up" and "top-down" methods, which need multi-stage processing and input large amount of mechanic energy and/or thermal energy. The quality control and industrial production of nanocarriers are limited by the difficulties of manipulating structures precisely on the molecular scale. Micro-droplet technology based on microfluidic chip, which has unique advantages in the preparation of nanoparticles with uniformed size, defined structures and morphology, may provide an alternative way. In this paper, we summarize the representative structures of micro-droplet generation devices and review the research development of current nanocarriers with various structures and functions, including nanoliposomes, polymeric nanoparticles, solid lipid nanoparticles, hybrid nano-complex and Janus nanoparticles. The influences of geometry parameters of microtube, flow rate, liquid viscosity,mixing way and dimensionality on the nanocarrier size, polydispersity index, precise structures and morphology of nanocarriers as well as the nanocarrier behaviors at the whole-organism, cellular and molecular level are fully discussed.The micro-droplet based technology has shown a promising prospect in the preparation of multi-functional nanocarriers by flexible combination and scale integration.
引文
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[21]JIANG C X,LI X,JIN Q F,et al.Mass Production of Monodisperse Ultrasound Contrast Microbubbles in Integrated Microfluidic Devices[C]//The 4th International Conference on Bioinformatics and Biomedical Engineering.Chengdu:IEEE Eng.in Medicine and Biology Society,2010.
[22]BAINS A,WULFF J E,MOFFITT M G.Microfluidic synthesis of dye-loaded poly caprolactone-bloc kpoly(ethylene oxide)nanoparticles:Insights into flowdirected loading and in vitro release for drug delivery[J].JColloid Interface Sci,2016,475:136-148.
[23]FENG Q,LIU J,LI X,et al.One-step microfluidic synthesis of nanocomplex with tunable rigidity and acid-switchable surface charge for overcoming drug resistance[J].Small,2017,13(9):1603109.
[24]ENDRES T,ZHENG M,BECK-BROICHSITTER M,et al.Optimising the self-assembly of siRNA loaded PEG-PCL-lPEI nano-carriers employing different preparation techniques[J].J Controlled Release,2012,160(3):583-591.
[25]FELDMANN D P,XIE Y,JONES S K,et al.The impact of microfluidic mixing of triblock micelleplexes on in vitro/in vivo gene silencing and intracellular trafficking[J].Nanotechnology,2017,28(22):224001.
[26]WILSON D R,MOSENIA A,SUPRENANT M P,et al.Continuous microfluidic assembly of biodegradable poly(beta-amino ester)/DNA nanoparticles for enhanced gene delivery[J].J Biomed Mater Res A,2017,105(6):1813-1825.
[27]MAJEDI F S,HASANI-SADRABADI M M,EMAMI S H,et al.Microfluidic assisted self-assembly of chitosan based nanoparticles as drug delivery agents[J].Lab Chip,2013,13(2):204-207.
[28]SHAMSI M,ZAHEDI P,GHOURCHIAN H,et al.Microfluidic-aided fabrication of nanoparticles blend based on chitosan for a transdermal multidrug delivery application[J].Int J Biol Macromol,2017,99:433-442.
[29]ROY A,ERNSTING M J,UNDZYS E,et al.A highly tumor-targeted nanoparticle of podophyllotoxin penetrated tumor core and regressed multidrug resistant tumors[J].Biomaterials,2015,52:335-346.
[30]LEUNG A K K,TAM Y Y C,CHEN S,et al.Microfluidic mixing:a general method for encapsulating macromolecules in lipid nanoparticle systems[J].J Phys Chem B,2015,119(28):8698-8706.
[31]LI Y,LEE R J,HUANG X,et al.Single-step microfluidic synthesis of transferrin-conjugated lipid nanoparticles for siRNA delivery[J].Nanomedicine,2017,13(2):371-381.
[32]HONG J S,STAVIS S M,DEPAOLI LACERDA S H,et al.Microfluidic directed self-assembly of liposome-hydrogel hybrid nanoparticles[J].Langmuir,2010,26(13):11581-11588.
[33]ZHANG L,FENG Q,WANG J,et al.Microfluidic synthesis of hybrid nanoparticles with controlled lipid layers:understanding flexibility-regulated cell-nanoparticle interaction[J].ACS Nano,2015,9(10):9912-9921.
[34]KIM Y,LEE CHUNG B,MA M,et al.Mass production and size control of lipid-polymer hybrid nanoparticles through controlled microvortices[J].Nano Lett,2012,12(7):3587-3591.
[35]LIU D,ZHANG H,HERRANZ-BLANCO B,et al.Microfluidic assembly of monodisperse multistage pH-responsive polymer/porous silicon composites for precisely controlled multi-drug delivery[J].Small,2014,10(10):2029-2038.
[36]LIU D,ZHANG H,M?KIL?E,et al.Microfluidic assisted one-step fabrication of porous silicon@acetalated dextran nanocomposites for precisely controlled combination chemotherapy[J].Biomaterials,2015,39:249-259.
[37]YANG C H,WANG L S,CHEN S Y,et al.Microfluidic assisted synthesis of silver nanoparticle-chitosan composite microparticles for antibacterial applications[J].Int JPharm,2016,510(2):493-500.
[38]杨兴远,夏曾子露,温维佳,等.基于微流控液滴技术的载药缓释微球研究进展[J].自然杂志,2017,39(2):115-119.
[39]NIE Z,LI W,SEO M,et al.Janus and ternary particles generated by microfluidic synthesis:design,synthesis,and self-assembly[J].J Am Chem Soc,2006,128(29):9408-9412.
[40]SHEPHERD R F,CONRAD J C,RHODES S K,et al.Microfluidic assembly of homogeneous and Janus colloidfilled hydrogel granules[J].Langmuir,2006,22(21):8618-8622.
[41]MARQUIS M,RENARD D,CATHALA B.Microfluidic generation and selective degradation of biopolymer-based Janus microbeads[J].Biomacromolecules,2012,13(4):1197-1203.
[42]GE X H,HUANG J P,XU J H,et al.Water-oil Janus emulsions:microfluidic synthesis and morphology design[J].Soft Matter,2016,12(14):3425-3430.
[2]郭希颖,魏巍,王坚成,等.微流控技术在纳米药物输送系统中的应用[J].药学学报,2017,52(10):1515-1523.
[3]申峰,李易,刘赵淼,等.基于微流控技术的微液滴融合研究进展[J].分析化学,2015,43(12):1942-1954.
[4]李战华,吴健康,胡国庆,等.微流控芯片中的流体流动[M].北京:科学出版社,2012:12-58.
[5]刘赵淼,杨洋,杜宇,等.微流控液滴技术及其应用的研究进展[J].分析化学,2017,45(2):282-296.
[6]CAPRETTO L,CARUGO D,MAZZITELLI S,et al.Microfluidic and lab-on-a-chip preparation routes for organic nanoparticles and vesicular systems for nanomedicine applications[J].Adv Drug Deliv Rev,2013,65(11/12):1496-1532.
[7]KHAN I U,SERRA C A,ANTON N,et al.Production of nanoparticle drug delivery systems with microfluidics tools[J].Expert Opin Drug Deliv,2015,12(4):547-562.
[8]托尔钦林·V P,魏西希·V.脂质体[M].邓意辉,徐晖,主译.北京:化学工业出版社,2007.
[9]KASTNER E,KAUR R,LOWRY D,et al.High throughput manufacturing of size-tuned liposomes by a new microfluidics method using enhanced statistical tools for characterization[J].Int J Pharm,2014,477(1/2):361-368.
[10]ZHIGALTSEV I V,TAM Y K,LEUNG A K,et al.Production of limit size nanoliposomal systems with potential utility as ultra-small drug delivery agents[J].J Liposome Res,2016,26(2):96-102.
[11]JAHN A,STAVIS S M,HONG J S,et al.Microfluidic mixing and the formation of nanoscale lipid vesicles[J].ACS Nano,2010,4(4):2077-2087.
[12]ZHIGALTSEV I V,BELLIVEAU N,HAFEZ I,et al.Bottom-up design and synthesis of limit size lipid nanoparticle systems with aqueous and triglyceride cores using millisecond microfluidic mixing[J].Langmuir,2012,28(7):3633-3640.
[13]MüLLNER M,DODDS S J,NGUYEN T H,et al.Size and rigidity of cylindrical polymer brushes dictate long circulating properties in vivo[J].ACS Nano,2015,9(2):1294-1304.
[14]HOOD R R,KENDALL E L,JUNQUEIRA M,et al.Microfluidic-enabled liposomes elucidate size-dependent transdermal transport[J].PLo S One,2014,9(3):e92978.
[15]DONG Y D,TCHUNG E,NOWELL C,et al.Microfluidic preparation of drug-loaded PEGylated liposomes,and the impact of liposome size on tumour retention and penetration[J].J Liposome Res,2017,1-9.
[16]HOOD R R,DEVOE D L,ATENCIA J,et al.A facile route to the synthesis of monodisperse nanoscale liposomes using3D microfluidic hydrodynamic focusing in a concentric capillary array[J].Lab Chip,2014,14(14):2403-2409.
[17]KARNIK R,GU F,BASTO P,et al.Microfluidic platform for controlled synthesis of polymeric nanoparticles[J].Nano Lett,2008,8(9):2906-2912.
[18]RHEE M,VALENCIA P M,RODRIGUEZ M I,et al.Synthesis of size-tunable polymeric nanoparticles enabled by 3D hydrodynamic flow focusing in single-layer microchannels[J].Adv Mater,2011,23(12):H79-H83.
[19]HSU M N,LUO R,KWEK K Z,et al.Sustained release of hydrophobic drugs by the microfluidic assembly of multistage microgel/poly(lactic-co-glycolic acid)nanoparticle composites[J].Biomicrofluidics,2015,9(5):052601.
[20]LIM J M,BERTRAND N,VALENCIA P M,et al.Parallel microfluidic synthesis of size-tunable polymeric nanoparticles using 3D flow focusing towards in vivo study[J].Nanomedicine,2014,10(2):401-409.
[21]JIANG C X,LI X,JIN Q F,et al.Mass Production of Monodisperse Ultrasound Contrast Microbubbles in Integrated Microfluidic Devices[C]//The 4th International Conference on Bioinformatics and Biomedical Engineering.Chengdu:IEEE Eng.in Medicine and Biology Society,2010.
[22]BAINS A,WULFF J E,MOFFITT M G.Microfluidic synthesis of dye-loaded poly caprolactone-bloc kpoly(ethylene oxide)nanoparticles:Insights into flowdirected loading and in vitro release for drug delivery[J].JColloid Interface Sci,2016,475:136-148.
[23]FENG Q,LIU J,LI X,et al.One-step microfluidic synthesis of nanocomplex with tunable rigidity and acid-switchable surface charge for overcoming drug resistance[J].Small,2017,13(9):1603109.
[24]ENDRES T,ZHENG M,BECK-BROICHSITTER M,et al.Optimising the self-assembly of siRNA loaded PEG-PCL-lPEI nano-carriers employing different preparation techniques[J].J Controlled Release,2012,160(3):583-591.
[25]FELDMANN D P,XIE Y,JONES S K,et al.The impact of microfluidic mixing of triblock micelleplexes on in vitro/in vivo gene silencing and intracellular trafficking[J].Nanotechnology,2017,28(22):224001.
[26]WILSON D R,MOSENIA A,SUPRENANT M P,et al.Continuous microfluidic assembly of biodegradable poly(beta-amino ester)/DNA nanoparticles for enhanced gene delivery[J].J Biomed Mater Res A,2017,105(6):1813-1825.
[27]MAJEDI F S,HASANI-SADRABADI M M,EMAMI S H,et al.Microfluidic assisted self-assembly of chitosan based nanoparticles as drug delivery agents[J].Lab Chip,2013,13(2):204-207.
[28]SHAMSI M,ZAHEDI P,GHOURCHIAN H,et al.Microfluidic-aided fabrication of nanoparticles blend based on chitosan for a transdermal multidrug delivery application[J].Int J Biol Macromol,2017,99:433-442.
[29]ROY A,ERNSTING M J,UNDZYS E,et al.A highly tumor-targeted nanoparticle of podophyllotoxin penetrated tumor core and regressed multidrug resistant tumors[J].Biomaterials,2015,52:335-346.
[30]LEUNG A K K,TAM Y Y C,CHEN S,et al.Microfluidic mixing:a general method for encapsulating macromolecules in lipid nanoparticle systems[J].J Phys Chem B,2015,119(28):8698-8706.
[31]LI Y,LEE R J,HUANG X,et al.Single-step microfluidic synthesis of transferrin-conjugated lipid nanoparticles for siRNA delivery[J].Nanomedicine,2017,13(2):371-381.
[32]HONG J S,STAVIS S M,DEPAOLI LACERDA S H,et al.Microfluidic directed self-assembly of liposome-hydrogel hybrid nanoparticles[J].Langmuir,2010,26(13):11581-11588.
[33]ZHANG L,FENG Q,WANG J,et al.Microfluidic synthesis of hybrid nanoparticles with controlled lipid layers:understanding flexibility-regulated cell-nanoparticle interaction[J].ACS Nano,2015,9(10):9912-9921.
[34]KIM Y,LEE CHUNG B,MA M,et al.Mass production and size control of lipid-polymer hybrid nanoparticles through controlled microvortices[J].Nano Lett,2012,12(7):3587-3591.
[35]LIU D,ZHANG H,HERRANZ-BLANCO B,et al.Microfluidic assembly of monodisperse multistage pH-responsive polymer/porous silicon composites for precisely controlled multi-drug delivery[J].Small,2014,10(10):2029-2038.
[36]LIU D,ZHANG H,M?KIL?E,et al.Microfluidic assisted one-step fabrication of porous silicon@acetalated dextran nanocomposites for precisely controlled combination chemotherapy[J].Biomaterials,2015,39:249-259.
[37]YANG C H,WANG L S,CHEN S Y,et al.Microfluidic assisted synthesis of silver nanoparticle-chitosan composite microparticles for antibacterial applications[J].Int JPharm,2016,510(2):493-500.
[38]杨兴远,夏曾子露,温维佳,等.基于微流控液滴技术的载药缓释微球研究进展[J].自然杂志,2017,39(2):115-119.
[39]NIE Z,LI W,SEO M,et al.Janus and ternary particles generated by microfluidic synthesis:design,synthesis,and self-assembly[J].J Am Chem Soc,2006,128(29):9408-9412.
[40]SHEPHERD R F,CONRAD J C,RHODES S K,et al.Microfluidic assembly of homogeneous and Janus colloidfilled hydrogel granules[J].Langmuir,2006,22(21):8618-8622.
[41]MARQUIS M,RENARD D,CATHALA B.Microfluidic generation and selective degradation of biopolymer-based Janus microbeads[J].Biomacromolecules,2012,13(4):1197-1203.
[42]GE X H,HUANG J P,XU J H,et al.Water-oil Janus emulsions:microfluidic synthesis and morphology design[J].Soft Matter,2016,12(14):3425-3430.
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