-
我国是农业大国,农药使用量居世界第一,农药的使用直接关系到农产品的产量、质量和生态环境。然而我国农药利用率比欧美等农业发达国家低15% — 20%,且不像欧美等发达国家有严格的土地休耕计划[1-3]。较低的农药利用率势必造成农药大量使用,导致农作物体内农药残留量高,土地污染非常严重;同时,过量的农药随农田排水进入沟、渠、河流,造成水体富营养化和污染。为此,我国2017年修订《农药管理条例》,鼓励生产和使用安全、高效、经济的农药,推进农药专业化使用,促进农药产业升级[4]。
为了实现农药的安全减量增效,主要改进方式有两种:开发新型农药和合理利用现有农药。开发出符合安全、高效、低毒等要求的新型农药,这种方法周期长、难度相对较大,任重道远。而另一种较为快捷的方式是合理利用现有农药,即在不改变农药分子结构和主要功效的情况下,通过将农药包覆在纳米载体中,能够减少外界环境因素(光、热等)的影响,增强了农药稳定性,从而可以提高农药的有效利用率、减缓农药对环境和生物的毒性[5-7]。目前,纳米载体法因其可以直接利用现有农药、开发周期相对较短而受到许多研究者的广泛关注,其中农药微乳剂、农药悬浮剂、纳米农药粒子等被相继开发[8-10]。制备这类农药纳米材料的方法有多种,如乳化法、高压均质法、共沉淀法等,但主要是基于热力学自组装的原理,其存在载药率低、制备过程耗时较长、不易大规模连续化生产等问题[11-14]。近年来的研究表明,纳米载体的微观结构对载体的生物应用效果有非常重要的影响[15-16],如非球形形状可显著提升药物纳米载体的靶标性能,但纳米载体结构的简易调控较难,因此开发出一种快速制备纳米材料并能有效控制纳米材料的微观结构的方法十分必要。
2003年兴起的瞬时纳米沉淀法(Flash Nanoprecipitation, FNP),恰好可以解决这些难题[17-18]。与上述的热力学控制方法相比,FNP法是基于动力学控制的原理、通过利用化学工程的流体湍流混合从而实现纳米材料的快速制备,具有载药率高、制备时间短(毫秒级)、易于控制纳米材料的尺寸大小、易于放大和连续化生产等特点[19-23]。FNP法还可以简易、系统化地调控纳米材料的微观结构,进一步提升纳米材料在靶标给药、缓控释等方面的性能,在农药高效利用、低毒使用上具有巨大潜力[24-27]。
-
FNP法是在2003年由普林斯顿大学的Prud'Homme教授与Johnson等提出[17-18],其原理是:非水溶性溶质(如大部分的农药、抗癌药等)首先溶解于少量的有机溶剂中,再与大量的水剧烈混合会快速沉淀、成核、形成疏水核心,随即快速被溶液体系中存在的两亲性物质(通常是两亲性嵌段聚合物)覆盖、保护,从而形成水分散性的纳米粒子,这整个过程在几十毫秒内完成[28-31]。在这个过程中,一旦非水溶性溶质沉淀出来,就会被两亲性物质保护起来,因此溶质的有效利用率(载药率)非常高,通常在90%以上;同时,由于两亲性物质的主要作用是稳定住疏水的沉淀核心,用量不需过大,因此纳米粒子的载药量也比较高,可以做到50%以上[32-36]。同时,由于FNP法是借助于流体流动的原理,因此易于连续化生产与放大,是一种用于工业生产载体型纳米粒子的有效技术[37-40]。此外,通过控制FNP法制备过程的宏观工艺参数,如流速、雷诺数、浓度等,可以轻易地调控纳米粒子的形成过程,进而控制其微观结构(图1)。这些优势使得FNP法十分适合用来制备农药纳米粒子。
实现FNP法制备纳米粒子的第1代装置是封闭撞击流混合器(Confined Impinging Jets,简称CIJ),如图2(a)所示。通过两股高速流动的液流在CIJ的混合腔中对撞式撞击混合,制备纳米粒子。之后,为了增加操作的自由度,刘颖与Prud'Homme等[20]研制出第2代的MIVM,如图2(b)、2(c)所示。在MIVM中,剧烈的混合是发生在混合腔的流出孔处附近[41-43]。
起初,FNP法适用的溶质是非水溶性物质,对水溶性药物的包载能力非常有限。最近,Prud'Homme教授等[44]开发出iFNP(inverse FNP,逆向FNP)的技术,可以良好的将水溶性的药物、蛋白质、DNA等封装在纳米粒子中,进一步拓展了FNP法的适用物质范围与应用前景,如图3所示。
图 3 逆向FNP包载亲水性溶质[44]
Figure 3. The iFNP encapsulates water-soluble solute
-
载体型纳米粒子的常见形貌为球形粒子,但近年的研究发现对于载体型纳米粒子的生物与医学应用来说,非球形结构的实际应用效果会比球形的结构更好[15-16]。然而,如何简易、系统地控制纳米材料的微观形貌,本身也是纳米材料领域的一个难点。Wang等[45]发现,FNP法可以快速、简易地实现纳米粒子形貌的系统控制(图4a)。Wang等使用多糖类两亲性嵌段聚合物Dextran-b-Poly(lactic acid)和Dextran-b-Polycaprolactone作为保护性的聚合物,通过调节FNP过程中的混合浓度以及两亲性嵌段聚合物中疏水嵌段的玻璃化转化温度,可以调控聚集诱导发光型荧光分子ED和QM-2的微观聚集结构在“球形—纳米棒—微米棒”之间转变。同时他们证实,纳米棒的形貌在癌细胞的细胞摄取上以及体内循环时的肿瘤组织富集上远远优于常见的纳米球结构。
-
载体型纳米粒子的重要用途是在药物(医药、农药等)包覆后,当纳米粒子到达指定位置后将药物释放出来,而药物的释放与粒子的内部结构、构建方式息息相关。通常基于热力学自组装法制备出的纳米粒子的结构主要是核-壳型结构,内部结构的调控不易实现,因此难以建立内部结构与药物的释放行为之间的关系。然而,Wang等[46]发现FNP法的混合过程恰好可以控制纳米粒子的内部结构(图4b)。通过调节混合过程的混合剧烈程度(Reynolds number,雷诺数)、保护性的聚合物与药物之间的摩尔比等,就可以控制内部结构由堆积密度较高的紧密型结构向堆积密度较低的松散型结构之间的转变,并且证实紧密型结构有助于药物的长期缓释。这些结构的可控性以及实现过程的简易程度,是传统的制备方法难以达到的。
另外,Nikoubashman等[47-50]在没有两亲性物质的协助下,仅使用聚苯乙烯实现了大小均匀的聚苯乙烯纳米粒子的定向组装与制备,为制备各种聚合物微球提供了思路(图5(a))。Lee与Priestley等[51]利用两种单嵌段聚合物,制备出内部分相、表面各向异性的Janus结构纳米粒子(图5(b))。此外,FNP法还可以用于制备囊泡结构[52-54]。
除了利用亲-疏水作用力制备出这些纳米载体外,FNP法还可以使用带电高分子,借助电荷作用力得到更多纳米结构[55-58]。Chen等[59]利用带正电的壳聚糖与带负电的三聚磷酸钠,制备出可以稳定包覆胰岛素的聚电解质纳米粒子,如图5(c)。
-
实现载体型纳米粒子的靶向输送能力,不仅可以借助尺寸、形貌等结构带来的被动靶向能力,还可以通过表面接枝靶向分子获得主动靶向能力。通过在纳米粒子的表面引入特异性的靶标分子,可以针对性的将纳米粒子与靶向的生物器官或组织相定向结合,实现靶向输送[60-62]。Zhang等通过纳米粒子表面修饰上叠氮基团,进一步引入了具有肿瘤靶向能力的叶酸基团,从而使纳米粒子具有肿瘤靶向能力,如图6[63]。
图 6 表面修饰有叶酸基团的纳米粒子[63]
Figure 6. Nanoparticle modified with folic group on surface
-
纳米粒子微观结构的调控离不开两亲性嵌段聚合物,表(1)示出了适用于调控纳米粒子微观结构的两亲性嵌段聚合物。
Block Copolymer Full Name of Block Copolymer Molecular Structure PEG-b-PCL Polyethylene Glycol-b- Polycaprolactone PEG-b-PLA Polyethylene Glycol-b- Polylactide PEG-b-PLGA Polyethylene Glycol-b-Poly (lactic-co-glycolic acid) Dextran-b-PCL Dextran-b-Polycaprolactone Dextran-b-PLA Dextran-b-Polylactide Dextran-b-PLGA Dextran-b-Poly (lactic-co-glycolic acid) 表 1 用于调控纳米粒子微观结构的两亲性嵌段聚合物
Table 1. Diblock copolymer used for controlling the nanostructure
-
使用FNP法制备纳米农药的第1份研究由刘颖等[64]报道,其使用联苯菊酯作为非水溶性农药,制备出联苯菊酯纳米粒子,尺寸在60~200 nm之间,联苯菊酯的负载率可达到91%,并可以稳定半个月。Fu等采用FNP法制备出形貌可控的阿维菌素纳米粒子,包封率可达95%,同时发现纺锤型纳米农药由于其优异的渗透性和粘附性,能够有效的降低南方根结线虫(Meloidogyne incognita,生物营养寄生虫)的存活率(图7(a))[65]。这是因为相比于一般的球形纳米农药,非球型纳米农药(如纺锤型,棒状等)具有更加优异的流动性,能有效的黏附作用于生物活体,显著减低有害生物的存活率[65]。Chen等制备出负载λ-氯氟氰菊酯的纳米粒子,其包封率能够达到99%,具有有效防治蚜虫(Aphis craccivora)的能力(图7(b))[66-67]。
-
综上所述,瞬时纳米沉淀技术是一种基于化学工程流体流动混合的动力学控制的制备纳米粒子的方法,不仅可以有效地提高药物的载药率、控制纳米粒子的尺寸等,还易于控制纳米粒子的微观结构。通过控制纳米粒子的形貌,可以提升纳米材料的生物靶向性能;控制纳米粒子的内部结构与构建方式,可以提升纳米材料的药物缓控释性能以及包载药物的多样性;控制纳米粒子的表面结构,可以进一步增强纳米材料的主动靶标能力。以上这些结构的控制,有利于纳米粒子技术在农药特别是现有的农药上实现“减量、增效”,并为农药的可持续发展提供帮助。
瞬时纳米沉淀法调控纳米结构及其在农业上的应用
Nanostructure Controlled by Flash Nanoprecipitation and Application on Agriculture
-
摘要: 农药的减量增效是近年来农药领域的关键问题,使用纳米载体技术将农药制成纳米农药为解决这一难题提供了新思路。不同于大多数基于热力学平衡组装的纳米载体技术,新兴的瞬时纳米沉淀法基于动力学控制原理、通过化学工程上的流体湍流混合制备纳米材料。这种方法不仅具有载药率高、制备时间短、易于放大与连续化等特点,还可以系统地调控纳米微观结构,如形貌、内部结构、表面结构等,为纳米材料在农药上进一步的高效和低毒利用提供帮助。Abstract: The pesticide reducing has been a key issue in pesticides area in recent years. The use of nano-carrier technology to incorporate pesticides into nanoparticle provides new route for solving the problem. Different from most nano-carrier technologies which are based on thermodynamic equilibrium self-assembly, the emerging Flash Nanoprecipitation (FNP) method is based on kinetic control, preparing nanoparticles through turbulent mixing of chemical engineering fluids. It has advantages like high drug loading efficiency, short preparation time (milliseconds), easy to scale-up and continuously production, etc. Moreover, it could also systematically control the microstructures of nanoparticle, such as morphology, internal structure and surface structure, which could provide help for further improving the efficiency and low-toxic utilization of pesticide nanoparticle.
-
Key words:
- Flash Nanoprecipitation /
- Pesticide Nanoparticle /
- Microstructure /
- Fluid Mixing
-
图 3 逆向FNP包载亲水性溶质[44]
Figure 3. The iFNP encapsulates water-soluble solute
图 6 表面修饰有叶酸基团的纳米粒子[63]
Figure 6. Nanoparticle modified with folic group on surface
表 1 用于调控纳米粒子微观结构的两亲性嵌段聚合物
Table 1. Diblock copolymer used for controlling the nanostructure
Block Copolymer Full Name of Block Copolymer Molecular Structure PEG-b-PCL Polyethylene Glycol-b- Polycaprolactone PEG-b-PLA Polyethylene Glycol-b- Polylactide PEG-b-PLGA Polyethylene Glycol-b-Poly (lactic-co-glycolic acid) Dextran-b-PCL Dextran-b-Polycaprolactone Dextran-b-PLA Dextran-b-Polylactide Dextran-b-PLGA Dextran-b-Poly (lactic-co-glycolic acid) -
[1] 邢艳辉. 我国绿色农业发展存在的问题及对策[J]. 乡村科技, 2020, 11(23): 33-35. doi: 10.3969/j.issn.1674-7909.2020.23.018
[2] 宋俊华, 顾宝根. 国际农药管理的现状及趋势(下)[J]. 农药科学与管理, 2020, 41(1): 8-13.
[3] 宋俊华, 顾宝根. 国际农药管理的现状及趋势(上)[J]. 农药科学与管理, 2019, 40(12): 9-14. doi: 10.3969/j.issn.1002-5480.2019.12.004
[4] 中国农药信息网. 李克强签署国务院令公布修订后的《农药管理条例》[J]. 世界农药, 2017, 39(2): 13.
[5] ZHAO L, LU L, WANG A, et al. Nano-Biotechnology in Agriculture: Use of Nanomaterials to Promote Plant Growth and Stress Tolerance[J]. Journal of Agricultural and Food Chemistry, 2020, 68(7): 1935-1947. doi: 10.1021/acs.jafc.9b06615 [6] ZHAO L, LU L, WANG A, et al. Nano-Biotechnology in Agriculture: Use of Nanomaterials to Promote Plant Growth and Stress Tolerance[J]. Journal of Agricultural and Food Chemistry, 2020, 68(7): 1935-1947. doi: 10.1021/acs.jafc.9b06615 [7] KAH M, HOFMANN T. Nanopesticide research: Current trends and future priorities[J]. Environment International, 2014, 63: 224-235. doi: 10.1016/j.envint.2013.11.015 [8] LIU W, ZEB A, LIAN J, et al. Interactions of metal-based nanoparticles (MBNPs) and metal-oxide nanoparticles (MONPs) with crop plants: a critical review of research progress and prospects[J]. Environmental Reviews, 2020, 28(3): 294-310. doi: 10.1139/er-2019-0085 [9] GOGOS A, KNAUER K, BUCHELI T D. Nanomaterials in Plant Protection and Fertilization: Current State, Foreseen Applications, and Research Priorities[J]. Journal of Agricultural and Food Chemistry, 2012, 60(39): 9781-9792. doi: 10.1021/jf302154y [10] KUMAR S, NEHRA M, DILBAGHI N, et al. Nanovehicles for Plant Modifications towards Pest- and Disease-Resistance Traits[J]. Trends in Plant Science, 2020, 25(2): 198-212. doi: 10.1016/j.tplants.2019.10.007 [11] JEROBIN J, SURESHKUMAR R S, ANJALI C H, et al. Biodegradable polymer based encapsulation of neem oil nanoemulsion for controlled release of Aza-A[J]. Carbohydrate Polymers, 2012, 90(4): 1750-1756. doi: 10.1016/j.carbpol.2012.07.064 [12] ADAK T, KUMAR J, SHAKIL N A, et al. Development of controlled release formulations of imidacloprid employing novel nano-ranged amphiphilic polymers[J]. Journal of Environmental Science and Health, Part B, 2012, 47(3): 217-225. doi: 10.1080/03601234.2012.634365 [13] CHOUDHURY S R, PRADHAN S, GOSWAMI A. Preparation and characterisation of acephate nano-encapsulated complex[J]. Nanoscience Methods, 2012, 1(1): 9-15. doi: 10.1080/17458080.2010.533443 [14] AKBULUT M, GINART P, GINDY M E, et al. Generic method of preparing multifunctional fluorescent nanoparticles using flash NanoPrecipitation[J]. Advanced Functional Materials, 2009, 19(5): 718-725. doi: 10.1002/adfm.200801583 [15] HINDE E, THAMMASIRAPHOP K, DUONG H T T, et al. Pair correlation microscopy reveals the role of nanoparticle shape in intracellular transport and site of drug release[J]. Nature Nanotechnology, 2017, 12(1): 81-89. doi: 10.1038/nnano.2016.160 [16] BLANCO E, SHEN H, FERRARI M. Principles of nanoparticle design for overcoming biological barriers to drug delivery[J]. Nature Biotechnology, 2015, 33(9): 941-951. doi: 10.1038/nbt.3330 [17] JOHNSON B K, PRUD'HOMME R K. Chemical processing and micromixing in confined impinging jets[J]. AIChE Journal, 2003, 49(9): 2264-2282. doi: 10.1002/aic.690490905 [18] JOHNSON B K, PRUD'HOMME R K. Mechanism for Rapid Self-Assembly of Block Copolymer Nanoparticles.[J]. Physical Review Letters, 2003, 91(11): 118301-118302. doi: 10.1103/PhysRevLett.91.118301 [19] GINDY M E, PRUD'HOMME R K. Multifunctional nanoparticles for imaging, delivery and targeting in cancer therapy[J]. Expert Opinion On Drug Delivery, 2009, 6(8): 865-878. doi: 10.1517/17425240902932908 [20] FENG J, MARKWALTER C E, TIAN C, et al. Translational formulation of nanoparticle therapeutics from laboratory discovery to clinical scale[J]. Journal of Translational Medicine, 2019, 17(200). [21] ZHU Z. Flash Nanoprecipitation: Prediction and Enhancement of Particle Stability via Drug Structure[J]. Molecular Pharmaceutics, 2014, 11(3): 776-786. doi: 10.1021/mp500025e [22] LIU Y, YANG G, BABY T, et al. Stable Polymer Nanoparticles with Exceptionally High Drug Loading by Sequential Nanoprecipitation[J]. Angewandte Chemie-International Edition, 2020, 59(12): 4720-4728. doi: 10.1002/anie.201913539 [23] LIU Z, RAMEZANI M, FOX R O, et al. Flow Characteristics in a Scaled-up Multi-inlet Vortex Nanoprecipitation Reactor[J]. Industrial & Engineering Chemistry Research, 2015, 54(16): 4512-4525. [24] SAAD W S, PRUD'HOMME R K. Principles of nanoparticle formation by flash nanoprecipitation[J]. Nano Today, 2016, 11(2): 212-227. doi: 10.1016/j.nantod.2016.04.006 [25] D'ADDIO S M, PRUD'HOMME R K. Controlling drug nanoparticle formation by rapid precipitation[J]. Advanced Drug Delivery Reviews, 2011, 63(6): 417-426. doi: 10.1016/j.addr.2011.04.005 [26] HICKEY J W, SANTOS J L, WILLIFORD J, et al. Control of polymeric nanoparticle size to improve therapeutic delivery[J]. Journal of Controlled Release, 2015, 219: 536-547. doi: 10.1016/j.jconrel.2015.10.006 [27] 刘靖康, 李猛, 王铭纬, 等. 基于瞬时纳米沉淀法的球形纳米粒子电荷及粒径调控[J]. 华东理工大学学报(自然科学版), 2020, 46(3): 334-340.
[28] ZHU Z. Effects of amphiphilic diblock copolymer on drug nanoparticle formation and stability[J]. Biomaterials, 2013, 34(38): 10238-10248. doi: 10.1016/j.biomaterials.2013.09.015 [29] LAVINO A D, DI PASQUALE N, CARBONE P, et al. A novel multiscale model for the simulation of polymer flash nano-precipitation[J]. Chemical Engineering Science, 2017, 171: 485-494. doi: 10.1016/j.ces.2017.04.047 [30] CHENG J C, FOX R O. Kinetic Modeling of Nanoprecipitation using CFD Coupled with a Population Balance[J]. Industrial & Engineering Chemistry Research, 2010, 49(21): 10651-10662. [31] HAO Y, SEO J, HU Y, et al. Flow physics and mixing quality in a confined impinging jet mixer[J]. AIP Advances, 2020, 10(0451054). [32] LIU Y, KATHAN K, SAAD W, et al. Ostwald Ripening of β-Carotene Nanoparticles[J]. Physical Review Letters, 2007, 98(3): 36102. doi: 10.1103/PhysRevLett.98.036102 [33] JOHNSON B K, PRUD'HOMME R K. Flash NanoPrecipitation of organic actives and block copolymers using a confined impinging jets mixer[J]. Australian Journal of Chemistry, 2003, 56(10): 1021-1024. doi: 10.1071/CH03115 [34] YORK A W, ZABLOCKI K R, LEWIS D R, et al. Kinetically Assembled Nanoparticles of Bioactive Macromolecules Exhibit Enhanced Stability and Cell-Targeted Biological Efficacy[J]. Advanced Materials, 2012, 24(6): 733. doi: 10.1002/adma.201103348 [35] CHENG J C, OLSEN M G, FOX R O. A microscale multi-inlet vortex nanoprecipitation reactor: Turbulence measurement and simulation[J]. Applied Physics Letters, 2009, 94(20410420). [36] KALKOWSKI J, LIU C, LEON-PLATA P, et al. In Situ Measurements of Polymer Micellization Kinetics with Millisecond Temporal Resolution[J]. Macromolecules, 2019, 52(9): 3151-3157. doi: 10.1021/acs.macromol.8b02257 [37] ZENG Z, DONG C, ZHAO P, et al. Scalable Production of Therapeutic Protein Nanoparticles Using Flash Nanoprecipitation[J]. Advanced Healthcare Materials, 2019, 8(18010106SI). [38] VALENTE I, CELASCO E, MARCHISIO D L, et al. Nanoprecipitation in confined impinging jets mixers: Production, characterization and scale-up of pegylated nanospheres and nanocapsules for pharmaceutical use[J]. Chemical Engineering Science, 2012, 77: 217-227. doi: 10.1016/j.ces.2012.02.050 [39] WANG M, YANG N, GUO Z, et al. Facile Preparation of AIE-Active Fluorescent Nanoparticles through Flash Nanoprecipitation[J]. Industrial & Engineering Chemistry Research, 2015, 54(17): 4683-4688. [40] 马俊, 李莉, 王铭纬, 等. 基于瞬时纳米沉淀法制备尺寸可控载药纳米粒子[J]. 华东理工大学学报(自然科学版), 2017, 43(5): 597-605.
[41] LIU Y, CHENG C, LIU Y, et al. Mixing in a multi-inlet vortex mixer (MIVM) for flash nano-precipitation[J]. Chemical Engineering Science, 2008, 63(11): 2829-2842. doi: 10.1016/j.ces.2007.10.020 [42] LIU Z, PASSALACQUA A, OLSEN M G, et al. Dynamic Delayed Detached Eddy Simulation of a Multi-Inlet Vortex Reactor[J]. AICHE Journal, 2016, 62(7): 2570-2578. doi: 10.1002/aic.15230 [43] SHI Y, FOX R O, OLSEN M G. Micromixing visualization and quantification in a microscale multi-inlet vortex nanoprecipitation reactor using confocal-based reactive micro laser-induced fluorescence[J]. Biomicrofluidics, 2014, 8(0441024). [44] MARKWALTER C E, PAGELS R F, HEJAZI A N, et al. Polymeric Nanocarrier Formulations of Biologics Using Inverse Flash NanoPrecipitation[J]. AAPS Journal, 2020, 22(182). [45] WANG M, XU Y, LIU Y, et al. Morphology Tuning of Aggregation-Induced Emission Probes by Flash Nanoprecipitation: Shape and Size Effects on in Vivo Imaging[J]. ACS Applied Materials & Interfaces, 2018, 10(30): 25186-25193. [46] WANG M, LIN S, WANG J, et al. Controlling Morphology and Release Behavior of Sorafenib-Loaded Nanocarriers Prepared by Flash Nanoprecipitation[J]. Industrial & Engineering Chemistry Research, 2018, 57(35): 11911-11919. [47] NIKOUBASHMAN A, LEE V E, SOSA C, et al. Directed Assembly of Soft Colloids through Rapid Solvent Exchange[J]. ACS Nano, 2016, 10(1): 1425-1433. doi: 10.1021/acsnano.5b06890 [48] LI N, NIKOUBASHMAN A, PANAGIOTOPOULOS A Z. Self-Assembly of Polymer Blends and Nanoparticles through Rapid Solvent Exchange[J]. Langmuir, 2019, 35(10): 3780-3789. doi: 10.1021/acs.langmuir.8b04197 [49] GRUNDY L S, LEE V E, LI N, et al. Rapid Production of Internally Structured Colloids by Flash Nanoprecipitation of Block Copolymer Blends[J]. ACS Nano, 2018, 12(5): 4660-4668. doi: 10.1021/acsnano.8b01260 [50] ZHANG C, PANSARE V J, PRUD'HOMME R K, et al. Flash nanoprecipitation of polystyrene nanoparticles[J]. Soft Matter, 2012, 8(1): 86-93. doi: 10.1039/C1SM06182H [51] LEE V E, SOSA C, LIU R, et al. Scalable Platform for Structured and Hybrid Soft Nanocolloids by Continuous Precipitation in a Confined Environment[J]. Langmuir, 2017, 33(14): 3444-3449. doi: 10.1021/acs.langmuir.7b00249 [52] DU F, BOBBALA S, YI S, et al. Sequential intracellular release of water-soluble cargos from Shell-crosslinked polymersomes[J]. Journal of Controlled Release, 2018, 282: 90-100. doi: 10.1016/j.jconrel.2018.03.027 [53] ALLEN S D, LIU Y, BOBBALA S, et al. Polymersomes scalably fabricated via flash nano-precipitation are non-toxic in non-human primates and associate with leukocytes in the spleen and kidney following intravenous administration[J]. Nano Research, 2018, 11(10SI): 5689-5703. [54] YILDIZ M E, PRUD'HOMME R K, ROBB I, et al. Formation and characterization of polymersomes made by a solvent injection method[J]. Polymers for Advanced Technologies, 2007, 18(6): 427-432. doi: 10.1002/pat.858 [55] KOZUCH D J, RISTROPH K, PRUD'HOMME R K, et al. Insights into Hydrophobic Ion Pairing from Molecular Simulation and Experiment[J]. ACS Nano, 2020, 14(5): 6097-6106. doi: 10.1021/acsnano.0c01835 [56] YUAN Y, HUANG Y. Ionically crosslinked polyelectrolyte nanoparticle formation mechanisms: the significance of mixing[J]. Soft Matter, 2019, 15(48): 9871-9880. doi: 10.1039/C9SM01441A [57] PINKERTON N M, BEHAR L, HADRI K, et al. Ionic Flash NanoPrecipitation (iFNP) for the facile, one-step synthesis of inorganic-organic hybrid nanoparticles in water[J]. Nanoscale, 2017, 9(4): 1403-1408. doi: 10.1039/C6NR09364G [58] ZHU Z, MARGULIS-GOSHEN K, MAGDASSI S, et al. Polyelectrolyte Stabilized Drug Nanoparticles via Flash Nanoprecipitation: A Model Study With beta-Carotene[J]. Journal of Pharmaceutical Sciences, 2010, 99(10): 4295-4306. doi: 10.1002/jps.22090 [59] HE Z, SANTOS J L, TIAN H, et al. Scalable fabrication of size-controlled chitosan nanoparticles for oral delivery of insulin[J]. Biomaterials, 2017, 130: 28-41. doi: 10.1016/j.biomaterials.2017.03.028 [60] BIAN W, WANG M, AHSAN B, et al. Gefitinib-loaded Nanoparticles with Folic Acid-modified Dextran Surface Prepared by Flash Nanoprecipitation[J]. Chemistry Letters, 2018, 47(11): 1405-1408. doi: 10.1246/cl.180686 [61] GU L, FAIG A, ABDELHAMID D, et al. Sugar-Based Amphiphilic Polymers for Biomedical Applications: From Nanocarriers to Therapeutics[J]. Accounts of Chemical Research, 2014, 47(10): 2867-2877. doi: 10.1021/ar4003009 [62] CHIU S, WANG S, CHOU H, et al. Versatile Synthesis of Thiol- and Amine-Bifunctionalized Silica Nanoparticles Based on the Ouzo Effect[J]. Langmuir, 2014, 30(26): 7676-7686. doi: 10.1021/la501571u [63] ZHANG S, CHAN K H, PRUD'HOMME R K, et al. Synthesis and Evaluation of Clickable Block Copolymers for Targeted Nanoparticle Drug Delivery[J]. Molecular Pharmaceutics, 2012, 9(8): 2228-2236. doi: 10.1021/mp3000748 [64] LIU Y, TONG Z, PRUD'HOMME R K. Stabilized polymeric nanoparticles for controlled and efficient release of bifenthrin[J]. Pest Management Science, 2008, 64(8): 808-812. doi: 10.1002/ps.1566 [65] FU Z, CHEN K, LI L, et al. Spherical and Spindle-Like Abamectin-Loaded Nanoparticles by Flash Nanoprecipitation for Southern Root-Knot Nematode Control: Preparation and Characterization[J]. Nanomaterials, 2018, 8(4496). [66] CHEN K, WANG Y, CUI H, et al. Difunctional Fluorescence Nanoparticles for Accurate Tracing of Nanopesticide Fate and Crop Protection Prepared by Flash Nanoprecipitation[J]. Journal of Agricultural and Food Chemistry, 2020, 68(3): 735-741. doi: 10.1021/acs.jafc.9b06744 [67] CHEN K, FU Z, WANG M, et al. Preparation and Characterization of Size-Controlled Nanoparticles for High-Loading lambda-Cyhalothrin Delivery through Flash Nanoprecipitation[J]. Journal of Agricultural and Food Chemistry, 2018, 66(31): 8246-8252. doi: 10.1021/acs.jafc.8b02851 -