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两性离子聚合物的研究进展

闫树鹏 张冲 吕华

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两性离子聚合物的研究进展

    作者简介: 闫树鹏(1995—),男,博士生,天津人,研究方向为两性离子聚氨基酸在蛋白质改性中的应用。E-mail: yanshupeng@pku.edu.cn;吕华,男,1983 年出生。2006 年于北京大学获学士学位,2011 年于美国伊利诺伊大学香槟分校获博士学位,2011 ~ 2014 年在美国斯克里普斯研究所从事博士后研究。2014年任北京大学化学与分子工程学院研究员,曾获中国化学会青年化学奖(2017),国家优秀青年科学基金(2017),中国化学会高分子青年学者奖(2019)。研究方向为基于氨基酸单体的可控开环聚合、聚氨基酸等生态高分子材料、蛋白质-高分子偶联物.
    通讯作者: 张冲, chongzhang@pku.edu.cn ; 吕华
  • 中图分类号: O631

Advances in Zwitterionic Polymers

    Corresponding author: ZHANG Chong, chongzhang@pku.edu.cn ;LYU Hua
  • CLC number: O631

  • 摘要: 两性离子聚合物是一类整体呈电中性,在同一单体侧链上同时含有阴、阳离子基团的高分子材料。因其水化能力强、生物相容性好等特点,在生物医药等领域得到了广泛研究和应用。本综述首先对两性离子聚合物的性质、分类、合成等方面进行了简单的概述;然后针对两性离子聚合物在防污涂层、蛋白质改性、药物递送、膜分离材料等4个方面的应用介绍其研究进展;最后对两性离子聚合物未来的发展进行了简单的评述和展望。
  • 图 1  具有不同骨架结构(a~e)和阴、阳离子基团(f, g)的两性离子聚合物

    Figure 1.  Zwitterionic polymers with different backbones (a—e) and ionic groups (f, g)

    图 2  间接合成法制备两性离子聚合物[11,33-41]

    Figure 2.  Typical indirect synthetic routes for zwitterionic polymers[11,33-41]

    图 3  (a)具有不同链接长度两性离子聚氨基酸P(CB-EGxGlu)(x = 1,2,3)的结构及其表面防污涂层示意图; (b)两性离子聚氨基酸涂层表面的水接触角; (c)牛血清蛋白(BSA)和纤维蛋白原(fibrinogen)在裸金片和两性离子聚氨基酸涂层表面的吸附情况[58]

    Figure 3.  (a) Structure of zwitterionic P(CB-EGxGlu) (x =1, 2, 3) with different linker lengths and illustration of self-assembled zwitterionic P(CB-EGxGlu) antifouling coatings on gold surfaces; (b) Static water contact angles of gold surfaces before and after modification with the zwitterionic polypeptides P(CB-EGxGlu). The indicated p value (*p < 0.05) was calculated by two-way ANOVA analysis; (c) The amount of BSA and fibrinogen adsorption on bare and different polymer-coated gold surfaces[58]

    图 4  (a)两性离子聚合物促进酶与底物疏水-疏水相互作用示意图[74];(b)α-糜蛋白酶及其偶联物的米氏常数(Km[74];(c)尿酸氧化酶及其偶联物诱导的抗尿酸氧化酶的IgG水平[63];(d)尿酸氧化酶偶联物诱导的抗聚合物的IgM水平[63]

    Figure 4.  (a)Schematic illustration of zwitterionic polymers increasing the hydrophobic-hydrophobic interactions between enzyme and the substrates[74];(b) Michaelis constants Km of α-chymotrypsin and its conjugates[74]; (c) Anti-uricase IgG response induced by uricase and its conjugates[63]; (d) Anti-polymer IgM response induced by the conjugates of uricase[63]

    图 5  (a)两性离子聚合物偶联物通过有效消除非特异性相互作用避免生物活性降低的示意图[77];(b)不同偶联物的抗细胞增殖实验[77](系列稀释的偶联物与人体Daudi细胞在96孔细胞培养板中37 ℃下共同孵育4 d,使用MTT方法进行细胞存活检测);(c)HRP两性离子纳米胶囊的合成示意图[78](HRP(用青色表示)包含1个血红素基团,其中卟啉基团与铁原子分别用紫色短棍和橙色球体表示);(d)30 ℃下HRP与其纳米胶囊形态去除酚类化合物的效率[78](体系中包含1 mmol/L的过氧化氢,反应时间为60 min)

    Figure 5.  (a) Schematic illustration of the mechanism of a zwitterionic conjugate reducing bioactivity loss by effectively eliminating nonspecific interactions[77]; (b) Antiproliferation assay of the conjugates[77] (Conjugates with serial dilutions were incubated with human Daudi cells for 4 d at 37 °C in 96-well tissue culture plates. MTT assay was used for cell viability assay); (c) Scheme of the synthesis of HRP zwitterionic nanocapsule[78] (The free HRP (in cyan) contains one hemin group, in which porphyrin and iron atom are rendered as purple sticks and orange sphere, respectively); (d) Removal efficiencies of phenol compound by free HRP and nanocapsule formulation at 30 °C[78] (H2O2 concentration is 1 mmol/L and the reaction time is 60 min)

    图 6  生物可降解的两性离子聚合物-药物偶联物PLA-SB/PTX用于细胞内的药物释放[85]

    Figure 6.  Biodegradable zwitterionic polymer-drug conjugate PLA-SB/PTX for intracellular cell drug release[85]

    图 7  (a)构建PCBMA修饰的TE膜过程示意图[37];(b)构建两性离子超滤膜及抗蛋白吸附示意图[102];(c)PSBMA与PDA的一步共沉积法构建两性离子聚合物修饰的MPPM材料示意图[103]

    Figure 7.  (a) Schematic illustration of the preparation of PCBMA modified TE membrane[37]; (b) Illustration of the preparation of zwitterionic ultrafiltration membranes and its resistance adsorption against protein during ultrafiltration[102]; (c) Illustration of the one-step co-deposition of PSBMA/PDA towards zwitterionic polymer-modified MPPM[103]

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  • 收稿日期:  2018-12-10
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两性离子聚合物的研究进展

    通讯作者: 张冲, chongzhang@pku.edu.cn
    通讯作者: 吕华
    作者简介: 闫树鹏(1995—),男,博士生,天津人,研究方向为两性离子聚氨基酸在蛋白质改性中的应用。E-mail: yanshupeng@pku.edu.cn;吕华,男,1983 年出生。2006 年于北京大学获学士学位,2011 年于美国伊利诺伊大学香槟分校获博士学位,2011 ~ 2014 年在美国斯克里普斯研究所从事博士后研究。2014年任北京大学化学与分子工程学院研究员,曾获中国化学会青年化学奖(2017),国家优秀青年科学基金(2017),中国化学会高分子青年学者奖(2019)。研究方向为基于氨基酸单体的可控开环聚合、聚氨基酸等生态高分子材料、蛋白质-高分子偶联物
  • 北京大学化学与分子工程学院,软物质科学与工程中心,北京分子科学国家实验室,高分子化学与物理教育部重点实验室,北京 100871

摘要: 两性离子聚合物是一类整体呈电中性,在同一单体侧链上同时含有阴、阳离子基团的高分子材料。因其水化能力强、生物相容性好等特点,在生物医药等领域得到了广泛研究和应用。本综述首先对两性离子聚合物的性质、分类、合成等方面进行了简单的概述;然后针对两性离子聚合物在防污涂层、蛋白质改性、药物递送、膜分离材料等4个方面的应用介绍其研究进展;最后对两性离子聚合物未来的发展进行了简单的评述和展望。

English Abstract

  • 两性离子聚合物是一类整体呈电中性,且在同一单体侧链上同时含有阴、阳离子基团的聚电解质[1, 2]。自1950年Alfrey等[3]首次报道合成了两性离子聚合物以来,两性离子聚合物因其独特的分子结构和理化性质引起了人们广泛的关注和研究。两性离子聚合物的特征之一是其具有极强的水化能力,通过结合水分子可以在材料表面形成一层致密的水化层[4, 5]。此外,两性离子聚合物还具有独特的“反聚电解质效应”。McCormick等[6, 7]研究表明,在两性离子聚合物水溶液中加入小分子盐会使其黏度增大,这一现象区别于阴、阳离子聚电解质所体现出的“聚电解质效应”,因而被称为“反聚电解质效应”。迄今为止,两性离子聚合物已在防污涂层、蛋白质改性、药物递送、膜分离材料等多个领域表现出良好的应用前景。

    • 两性离子聚合物有多种分类方式。根据聚合物的结构特点,可按照骨架结构和阴、阳离子基团的类型对其进行大体上的分类。此外,还可根据两性离子聚合物对pH的响应性以及阴、阳离子基团的间隔距离等对其进行分类[8]

      两性离子聚合物的骨架结构类型十分多样。较为常见的为聚烯烃骨架,包括聚(甲基)丙烯酰胺骨架[9]、聚(甲基)丙烯酸酯骨架[10]图1(a))等。此外,一些新颖的、具有独特结构的聚合物骨架也被应用到两性离子聚合物之中,包括多肽[11]或类多肽[12]骨架(图1(b))、聚酯骨架[13]图1(c))、多糖骨架[14]图1(d))以及含杂原子的主链骨架[15]图1(e))等。不同结构类型和特性的聚合物骨架的引入极大地丰富了两性离子聚合物的性质。

      图  1  具有不同骨架结构(a~e)和阴、阳离子基团(f, g)的两性离子聚合物

      Figure 1.  Zwitterionic polymers with different backbones (a—e) and ionic groups (f, g)

      两性离子聚合物的阳离子基团类型主要有4种:季铵盐阳离子[16]、季鏻盐阳离子[17]、吡啶鎓离子[18]、咪唑鎓离子[19];阴离子基团类型主要有3种:磺酸根负离子[20]、羧酸根负离子[21]、磷酸根负离子[22]。阴、阳离子基团之间的两两组合可以构建出不同的两性离子,其中以季铵盐阳离子与不同类型的阴离子组合得到的磺酸甜菜碱(SB)、羧酸甜菜碱(CB)和磷酰胆碱(PC)(图1(f))的应用最为广泛[23]。此外,α-氨基酸作为一类天然的两性离子,也可以应用到两性离子聚合物的侧链之中[24]((图1(g))。

      CB、SB、PC等3种常见的两性离子基团各有其独特的性质。Jiang等[8]总结比较了SB和CB基团在水化作用、离子相互作用、自缔合方面的差异,指出SB基团的水化层能够保留较多数量的水分子,其与离子间的相互作用和阳离子类型无关,并且具有一定程度的自缔合行为;而CB基团的水化层可以延长单个水分子的保留时间,其与离子间的相互作用和阳离子类型有关,并且具有较弱的自缔合行为。此外,SB基团还具有不易受溶液pH影响的特点[1, 25],而CB基团则具有可进一步功能化修饰[26]、易于进行蛋白质固定[27]等优点。

      PC基团是磷脂分子的重要组成部分,而后者又是生物膜的主要组分。含有PC基团的两性离子聚合物具有与磷脂分子类似的性质,可作为仿生物膜的高分子材料[28]。2-甲基丙烯酰氧乙基磷酰胆碱(MPC)是最经典的PC型两性离子单体,由其聚合得到的PMPC因具有较好的生物相容性[29]而得到了广泛的应用[30]。此外,将PC的阴、阳离子基团互换位置得到的磷酸胆碱(CP)基团也可应用到两性离子聚合物中,其与PC的互补性[31]及功能的多样性[32]是CP型两性离子聚合物研究中的亮点。

    • 根据聚合物主链骨架与侧链两性离子基团合成的先后顺序,两性离子聚合物的合成方法主要分为两种:一种是前体聚合物的两性离子功能化,又称作间接合成法;一种是直接用两性离子聚合物单体进行聚合,又称作直接合成法。

    • 间接合成法是先将侧链带有叔胺基团的单体进行聚合形成前体聚合物,再利用叔胺基团与不同小分子化合物间的反应引入两性离子基团(图2(a))。其中,SB型两性离子基团的引入,一种是通过叔胺与烷基磺酸内酯发生开环反应,常用的磺酸内酯为1,3-磺酸丙内酯[33]或1,4-磺酸丁内酯[34];另一种是叔胺与卤代烷基磺酸盐发生取代反应[35]。CB型两性离子聚合物的合成方式主要有3种:(1)叔胺与α,β-不饱和酸进行加成反应,但这种方法容易生成盐类副产物[36];(2)叔胺与卤代烷基羧酸盐发生取代反应[37];(3)叔胺对羧酸内酯的开环反应[38]。PC/CP型两性离子聚合物的合成方式较多,较为常见的是用叔胺与2-烷氧基-2-氧代-1,3,2-二氧磷杂环戊烷进行开环反应制得[39]

      图  2  间接合成法制备两性离子聚合物[11,33-41]

      Figure 2.  Typical indirect synthetic routes for zwitterionic polymers[11,33-41]

      除上述方法外,还可以通过预先合成带有活性端基的两性离子小分子,然后利用端基与聚合物侧链上的基团反应制备得到两性离子聚合物。其中最常见的是利用带有巯基的两性离子基团与侧链含有烯烃或炔基官能团聚合物之间的“thiol-ene”[11]图2(b))或“thiol-yne”“点击化学”[40]图2(c))反应得到两性离子聚合物。此外,也可以首先制备出带有保护基团的聚合物前体,进一步采用脱保护得到两性离子聚合物。如羧酸甲酯化的两性离子聚合物前体,通过酯键的水解得到目标产物[41]图2(d))。

      间接合成法的优势在于前体聚合物的制备较易,聚合过程可控且聚合物表征较为方便。然而,邻基效应可能会影响后续两性离子化反应的动力学,且两性离子的功能化率很难达到100%[42]

    • 直接合成法所用的两性离子单体一般通过含有叔胺基团的单体与小分子的反应获得,之后通过两性离子单体的自由基聚合来制备得到聚合物。该方法能耐受许多类型的官能团以及少量水,对于本身具有一定吸湿性的两性离子单体而言是较为合适的一种聚合方法。近年来,活性可控自由基聚合法(CRP)被广泛应用到两性离子聚合物的合成之中,如原子转移自由基聚合法(ATRP)[43]和可逆加成-断裂链转移自由基聚合法(RAFT)[44]等。需要注意的是,该方法主要适用于烯烃类的两性离子聚合物单体。

      直接合成法能保证聚合物所有单体的侧链上均含有两性离子基团,但聚合物的表征较为困难。例如,两性离子聚合物在水相中的构象会受到离子强度和盐离子类型的影响,对于CB型的聚合物来说还会受到溶液pH的影响。此外,两性离子聚合物与色谱柱具有较强的相互作用,因而难以用凝胶渗透色谱(GPC)或高效液相色谱(HPLC)对其进行进一步的表征[42]

    • 生物污染主要是指蛋白质、细胞、微生物等在治疗和诊断设备或其他医用材料表面的非特异性吸附[45]。生物污染会引起溶血、血栓、免疫反应、感染以及组织细胞在植入设备上的过度生长等诸多问题[23, 46, 47]。目前最为常用的解决方法是在材料表面引入防污聚合物,如聚乙二醇(PEG)。然而,PEG材料的稳定性相对较差,在生物体环境中容易被氧化[48]。两性离子聚合物是PEG的一种理想替代物,其超强的亲水性能使其在材料表面形成紧密结合的水化层,从而有效阻碍蛋白质等生物分子的吸附[49]。华盛顿大学Jiang课题组在这方面进行了大量开创性的研究,他们设计合成了多种两性离子单体并通过表面原子转移自由基聚合(SI-ATRP)和基于邻苯二酚锚点的一步涂膜法制备出不同类型的防污涂层,均展现出良好的防污效果[50-53]。对两性离子聚合物表面修饰方法学的研究还包括:四川大学赵长生等开发的分别基于单宁酸(TA)[54]和聚多巴胺(PDA)[55]的简单通用的表面修饰策略、Ajou大学Park等[56]构建的酪氨酸酶介导的表面修饰手段以及中国科学院兰州化学物理研究所的周峰等[57]采用电化学表面原子转移自由基聚合(e-SIATRP)所制备的咪唑基两性离子聚合物防污涂层。

      最近,本课题组合成了一系列具有不同侧链链接长度的寡聚乙二醇化两性离子聚氨基酸P(CB-EGxGlu) (x = 1, 2, 3)(图3(a)[58]。研究表明,含有较长侧链的P(CB-EG3Glu)表现出较高的表面亲水性(图3(b))和最优的防污性能(图3(c))。我们通过调节寡聚乙二醇的链接长度以及整合氢键水合和两性离子基团的离子溶剂化作用,赋予了该聚氨基酸材料优异的防污性能。

      图  3  (a)具有不同链接长度两性离子聚氨基酸P(CB-EGxGlu)(x = 1,2,3)的结构及其表面防污涂层示意图; (b)两性离子聚氨基酸涂层表面的水接触角; (c)牛血清蛋白(BSA)和纤维蛋白原(fibrinogen)在裸金片和两性离子聚氨基酸涂层表面的吸附情况[58]

      Figure 3.  (a) Structure of zwitterionic P(CB-EGxGlu) (x =1, 2, 3) with different linker lengths and illustration of self-assembled zwitterionic P(CB-EGxGlu) antifouling coatings on gold surfaces; (b) Static water contact angles of gold surfaces before and after modification with the zwitterionic polypeptides P(CB-EGxGlu). The indicated p value (*p < 0.05) was calculated by two-way ANOVA analysis; (c) The amount of BSA and fibrinogen adsorption on bare and different polymer-coated gold surfaces[58]

      近年来,一些具有刺激响应性的多功能型两性离子聚合物防污材料成为研究的热点。Akron大学Zheng等[59]合成了具有盐离子响应性的两性离子聚合物并将其修饰到硅片基质上,得到摩擦性能和防污性能可调控的表面;Wageningen大学Zuilhof等[60]开发出了一类具有自我修复能力和防污性能的两性离子聚合物交联网络(ZPN)涂层;武汉大学刘传军等[61]将具有杀菌性能的三氯生引入两性离子聚合物中,制得具有防污和抗菌性能的两性离子聚合物材料;南京师范大学沈健等[62]采用表面引发反相原子转移自由基聚合法(SI-RATRP)将两性离子聚合物修饰到聚氨酯材料表面,得到具有防污和抗凝血双重性能的材料。

    • 蛋白质是一类用途广泛的生物大分子,然而其稳定性差、易丧失活性、易聚集沉淀、外源性蛋白易引起免疫反应等问题极大程度上限制了它的应用[63]。PEG修饰是一种较为常见的蛋白质改性手段,可以增加蛋白质溶解性和水合粒径,降低肾清除率,从而延长体内循环时间[64],然而近年来的研究表明PEG会导致过敏反应和免疫应答[65, 66]。采用两性离子聚合物对蛋白质进行改性则可有效改善上述问题。日本科学技术院Matsumura等[67, 68]研究表明两性离子聚合物的引入可有效避免溶菌酶在加热条件下的聚集,并可维持其一定的溶解度和酶活性;杜克大学Chilkoti等[69]利用两性离子聚合物对肌红蛋白进行位点特异性修饰,有效延长了肌红蛋白在体内的循环时间;美国韦恩州立大学Cao等[70]制备了胰岛素蛋白与两性离子聚合物的偶联物,可减缓胰岛素生物活性的丧失;上海交通大学王辉等[71, 72]利用磷酰胆碱类的两性离子聚合物构建的纳米胶囊可以有效延长药物蛋白的循环时间并降低其免疫原性;清华大学高卫平等[73]利用位点特异性原位生长(SIG)策略将两性离子聚合物PMPC高效连接至治疗性蛋白干扰素-α(IFN-α)上,得到的偶联物与PEG修饰的干扰素-α(PEGASYS)相比具有较长的循环半衰期和较好的疗效。

      华盛顿大学Jiang课题组同样对两性离子聚合物改性蛋白质进行了大量的研究。他们发现聚羧酸甜菜碱(pCB)的修饰不仅可以增加α-糜蛋白酶的稳定性,还可以通过增强酶与底物之间的疏水作用提高两者之间的亲和力(图4(a)),进而提高酶的活性(图4(b)[74]。之后,他们分别采用两性离子聚合物凝胶封装[75]和化学偶联[63]的方式对尿酸氧化酶进行修饰,结果表明两者均可以在保持蛋白质稳定性的同时降低其免疫原性(图4(c)),且与PEG修饰相比能够有效降低聚合物引起的免疫反应(图4(d))。上述研究中的两性离子聚合物虽然都能够有效改善蛋白质性质,但存在生物不可降解的缺点。为此,他们开发出了以聚氨基酸为骨架的两性离子聚合物,通过化学偶联的方式将其修饰到尿酸氧化酶上,有效增强了蛋白的药代动力学性质并降低其免疫原性[76]。Jiang课题组还构建了干扰素-α2a (IFN-α2a)与两性离子聚合物的偶联物[77]。两性离子聚合物的引入有效地消除了聚合物与干扰素结合区域或干扰素受体之间的非特异性相互作用(图5(a))。与PEG修饰相比,两性离子聚合物的修饰能够减缓干扰素生物活性的降低(图5(b)),并且具有延长体内循环时间以及减缓加速血液清除(ABC)现象的优势。此外,他们进一步将两性离子聚合物纳米封装技术应用于辣根过氧化物酶(HRP)(图5(c))的改性,有效地保持了HRP的稳定性和活性,使其在含酚化合物的污水处理领域能够得到更广泛的应用(图5(d)[78]

      图  4  (a)两性离子聚合物促进酶与底物疏水-疏水相互作用示意图[74];(b)α-糜蛋白酶及其偶联物的米氏常数(Km[74];(c)尿酸氧化酶及其偶联物诱导的抗尿酸氧化酶的IgG水平[63];(d)尿酸氧化酶偶联物诱导的抗聚合物的IgM水平[63]

      Figure 4.  (a)Schematic illustration of zwitterionic polymers increasing the hydrophobic-hydrophobic interactions between enzyme and the substrates[74];(b) Michaelis constants Km of α-chymotrypsin and its conjugates[74]; (c) Anti-uricase IgG response induced by uricase and its conjugates[63]; (d) Anti-polymer IgM response induced by the conjugates of uricase[63]

      图  5  (a)两性离子聚合物偶联物通过有效消除非特异性相互作用避免生物活性降低的示意图[77];(b)不同偶联物的抗细胞增殖实验[77](系列稀释的偶联物与人体Daudi细胞在96孔细胞培养板中37 ℃下共同孵育4 d,使用MTT方法进行细胞存活检测);(c)HRP两性离子纳米胶囊的合成示意图[78](HRP(用青色表示)包含1个血红素基团,其中卟啉基团与铁原子分别用紫色短棍和橙色球体表示);(d)30 ℃下HRP与其纳米胶囊形态去除酚类化合物的效率[78](体系中包含1 mmol/L的过氧化氢,反应时间为60 min)

      Figure 5.  (a) Schematic illustration of the mechanism of a zwitterionic conjugate reducing bioactivity loss by effectively eliminating nonspecific interactions[77]; (b) Antiproliferation assay of the conjugates[77] (Conjugates with serial dilutions were incubated with human Daudi cells for 4 d at 37 °C in 96-well tissue culture plates. MTT assay was used for cell viability assay); (c) Scheme of the synthesis of HRP zwitterionic nanocapsule[78] (The free HRP (in cyan) contains one hemin group, in which porphyrin and iron atom are rendered as purple sticks and orange sphere, respectively); (d) Removal efficiencies of phenol compound by free HRP and nanocapsule formulation at 30 °C[78] (H2O2 concentration is 1 mmol/L and the reaction time is 60 min)

    • 药物递送是现代医学中一个重要的议题,选择合适的药物载体能够有效增强药物的溶解性、延长体内循环时间、增强药物疗效、降低副作用等[79]。两性离子聚合物的超亲水性和抗蛋白质吸附等性能使其成为一种重要的药物递送材料。此外,两性离子聚合物还具有良好的生物相容性,对机体的免疫刺激较弱[80],产生的抗体水平较低[81],并且具有较长的体内循环时间。由于肿瘤组织的pH与正常组织不同,且肿瘤细胞的细胞内基质含有较高浓度的谷胱甘肽(GSH),因此制备具有pH和氧化还原等响应性的两性离子聚合物在抗癌药物的定向递送方面具有潜在的应用前景。

      一种常见的药物递送策略是利用含有两性离子单元的两亲型嵌段共聚物通过自组装作用形成具有核壳结构的胶束,进而将药物包埋在其疏水性内核,如常见的抗癌药物阿霉素(DOX)。两性离子单元的存在不仅能够增加胶束的溶解度、抵抗蛋白质的吸附,而且能够降低ABC现象的发生。四川大学罗祥林等[82]利用含有多个功能性嵌段的两性离子共聚物材料构建了具有pH和氧化还原双重响应性的胶束结构,用于DOX在肿瘤微环境的定向递送和释放;天津大学姚芳莲和军事医学科学院李俊杰等[83]基于单分子胶束结构设计合成了性质稳定且具有pH响应性的两性离子药物递送体系;南开大学伍国琳等[84]合成了以聚多肽为骨架且具有pH响应性的两性离子聚合物药物递送材料;浙江大学计剑和金桥等[10]利用含有PC基团和四苯基乙烯基团的两性离子共聚物构建出了具有pH响应性和聚集诱导发光(AIE)功能的药物递送/荧光成像体系。

      除胶束结构外,两性离子聚合物还可用于构建其他结构形式的药物递送体系。纽约州立大学布法罗分校Wu和Cheng等[85]以生物可降解的聚乳酸(PLA)为主链,合成了抗癌药物紫杉醇(PTX)与两性离子聚合物的偶联物PLA-SB/PTX。该偶联物可通过生物降解作用释放出PTX,从而杀死肿瘤细胞,达到抗癌的目的(图6)。浙江大学陈圣福等[86]以聚氨基酸为骨架制备了具有离子强度、pH、酶三重响应性的两性离子聚合物水凝胶,有望实现药物的定点释放。上海交通大学董频和复旦大学庞志清、杨武利等[87]开发了一类具有长循环且生物可降解的两性离子聚合物纳米凝胶用于DOX在肿瘤部位的有效递送。华盛顿大学Jiang等[88]和Akron大学Liu等[89]分别基于荧光染料和可交联碳量子点(CCDs)开发出具有生物成像功能的两性离子聚合物药物递送体系。

      图  6  生物可降解的两性离子聚合物-药物偶联物PLA-SB/PTX用于细胞内的药物释放[85]

      Figure 6.  Biodegradable zwitterionic polymer-drug conjugate PLA-SB/PTX for intracellular cell drug release[85]

      基于两性离子聚合物的药物递送体系还可应用于核酸类药物的递送。新加坡国立大学Li等[90]设计并合成了具有氧化还原响应性的多功能两性离子嵌段共聚物用于DNA的高效递送;中国科学院大学的张欣和郑州大学张振中等[91]开发了基于两性离子聚合物的阳离子脂质体,并用于小干扰RNA(siRNA)的高效递送,可有效降低ABC效应;此外,天津大学刘文广等[92]构建了星型两性离子聚合物用于DOX和抑瘤基因p53的共递送。

    • 膜分离材料因其低能耗、高效率、易操作、环境友好等优点成为一类用途十分广泛的高分子材料[93],在污水处理、海水淡化、血液透析设施、人造器官等多个领域均有实际应用。膜分离材料主要采用聚偏二氟乙烯(PVDF)[94]、聚醚砜(PES)[95]、聚砜(PSF)[96]、聚氯乙烯(PVC)[97]、聚醚酰亚胺(PEI)[98]等作为基质,这些基质具有热稳定性高、力学强度高、化学性质稳定等优点[99]。然而,这些材料的疏水性使得膜材料表面易被污染,进而引起膜的透过性和选择性的大幅下降,降低了膜材料的使用寿命,增加了成本[100, 101]。将具有超亲水性和防污性能的两性离子聚合物修饰到膜分离材料表面,可有效地解决膜表面污染的问题。此外,两性离子材料较好的生物相容性又使其能够应用于生物医用膜分离材料[96]

      为了构建两性离子聚合物修饰的膜分离材料,人们发展出多种不同的修饰方法,如表面接枝法[104]、表面偏析法、仿生黏附法等[93]。表面接枝法是指通过聚合物与膜表面形成稳定化学键而实现修饰的方法。天津大学王志等[37]利用氧化还原反应引发体系将聚羧酸甜菜碱甲基丙烯酸酯(PCBMA)修饰到芳香族聚酰胺反渗透膜(TE membrane)表面,有效地提高了水通量及抗生物污染的性能(图7(a));天津工业大学孟建强等[105]采用紫外光引发体系制备了含有两性离子聚合物的高渗透性膜分离材料。表面偏析法主要应用于两亲型嵌段共聚物,共聚物的疏水链段嵌入到膜基质中,而亲水链段则迁移到膜表面[106]。吉林大学庞金辉等[102]图7(b))和东华大学何春菊等[107]分别利用非溶剂诱导相分离(NIPS)技术制备出防污性能良好的超滤膜;广州中国科学院先进技术研究所沈鹏等[99]开发了热致相分离法用来构建防污PVDF膜。仿生黏附法则主要受贻贝的启发,利用聚多巴胺能够附着在几乎所有的无机和有机材料表面的性质[108],将其开发为一种优良的黏着剂。浙江大学徐志康等[103]利用聚磺酸甜菜碱甲基丙烯酸酯(PSBMA)与PDA的一步共沉积法得到两性离子聚合物修饰的聚丙烯微孔膜(MPPM)材料。相比于紫外光引发表面接枝法,该方法对两性离子聚合物的利用效率更高(图7(c))。

      图  7  (a)构建PCBMA修饰的TE膜过程示意图[37];(b)构建两性离子超滤膜及抗蛋白吸附示意图[102];(c)PSBMA与PDA的一步共沉积法构建两性离子聚合物修饰的MPPM材料示意图[103]

      Figure 7.  (a) Schematic illustration of the preparation of PCBMA modified TE membrane[37]; (b) Illustration of the preparation of zwitterionic ultrafiltration membranes and its resistance adsorption against protein during ultrafiltration[102]; (c) Illustration of the one-step co-deposition of PSBMA/PDA towards zwitterionic polymer-modified MPPM[103]

      除上述领域外,两性离子聚合物还在医疗诊断[109]、生物传感器[110]、石油工业[111]、电池电极[112]、结晶控制[113]等众多研究领域有着广泛的应用。如麻省理工学院Anderson等[110]在动态血糖检测仪(CGMs)的传感器上修饰上两性离子聚合物,有效降低了测量噪声,避免频繁的校准。此外,两性离子聚合物还可以用来制备新颖有趣的功能型材料。四川大学赵长生和张翔等[114]构建出双向pH响应性的两性离子聚合物水凝胶,可以在不同的pH下吸收带有不同电性的染料分子,从而显示出不同的颜色。这些应用显示出了两性离子聚合物的无限潜力。

    • 早期,人们对于两性离子聚合物的研究主要停留在对两性离子结构的设计、防污涂层的制备以及性能优化等初级阶段。近年来,随着现代聚合方法学的发展和人们对于新材料需求的日益增加,一些新型的两性离子聚合物被研发出来,并被迅速应用于生物医药、膜科学技术等多个领域。

      对于两性离子聚合物未来的发展,我们认为,在进一步拓宽其种类和应用领域的基础上,主要可从以下几个方面进行考虑:(1)进一步探讨两性离子聚合物的构效关系及作用机理,如离子种类、离子间间距、亲疏水性、主链结构等对材料性能的影响;(2)简化合成工艺,降低两性离子聚合物的制备成本;(3)合成结构精确的两性离子聚合物。通过与其他不同性质的材料相结合,制备性能优异且能满足多种需求的复合材料。

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