CN104737018B - 配体接枝基底 - Google Patents
配体接枝基底 Download PDFInfo
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- CN104737018B CN104737018B CN201380049968.7A CN201380049968A CN104737018B CN 104737018 B CN104737018 B CN 104737018B CN 201380049968 A CN201380049968 A CN 201380049968A CN 104737018 B CN104737018 B CN 104737018B
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Abstract
本发明公开了可用于从生物样品中选择性结合并除去生物物质的配体官能化基底,以及用于制备这些配体官能化基底的方法。
Description
技术领域
本公开涉及配体接枝基底以及用于制备该基底的方法。该接枝官能化基底可用于从生物样品中选择性结合并除去生物物质,诸如蛋白质。
背景技术
靶标生物物质,诸如微生物和生物大分子(包括活细胞的组分或产物,例如蛋白质、碳水化合物、脂质和核酸)的检测、定量、分离和纯化一直以来都是研究人员的目标。从诊断上来讲,检测和量化是重要的,例如,作为各种生理状况诸如疾病的指示。生物靶标的分离和纯化对治疗性使用和生物医学研究十分重要。生物分子诸如酶(其为特殊的一类能催化化学反应的蛋白质)在工业上也是有用的。
在活的有机体内的天然状态下,生物分子的结构和相应的生物活性通常保持在相当窄的pH和离子强度范围内。因此,任何分离和纯化操作必须考虑这些因素以得到具有效力的处理后生物大分子。
色谱分离和纯化操作已成为生物医药工业中用于分离生物分子的主要方法。最当前的色谱法是通过常规柱技术来完成,并且以结合和洗脱模式(例如,当靶标物质是纯化的对象时)或以流通模式(例如,当靶标物质是待除去的污染物时)来操作。这些技术在下游纯化中具有严重的瓶颈问题,因为使用这种技术的通过量比较低。对于缓解这些问题的尝试包括增加色谱柱的直径,但这继而会由于装柱有效性和再生性困难而面临挑战。较大的色谱柱直径还会增加难以解决的沟流发生率。同样,在传统的色谱柱中,当检测到所需要产物的漏过量高于某一水平时,所述吸附操作会被停止。这会引起吸附介质的动态吸附或有效吸附容量将显著小于总吸附或静态吸附容量。鉴于一些色谱树脂成本较高,这种有效性的缩减会导致严重的经济后果。
由于通过材料的流体流动的对流性质,膜色谱法相比柱色谱法具有提供用于分离生物物质,尤其是生物分子的显著优点的潜能。在聚合物树脂广泛用于柱色谱法的情况下,还必须发生孔隙扩散以使靶标分子与其结合位点相互作用,从而显著增加分离操作所需的处理时间。然而,利用膜色谱法进行大规模纯化所带来的主要问题是缺乏官能化膜的良好技术且结合靶标物质的能力通常较低。因此,在本领域中需要用于微生物和其它生物物质的具有增强亲和力的聚合物基底,尤其是膜,以使得能从生物样品中将它们选择性除去。在本领域中还需要配体官能化基底,该基底可克服扩散和结合的限制,并且可以在高通过量和较低压降下操作。
发明内容
本公开涉及配体官能化聚合物、其制备方法以及具有配体官能化聚合物的接枝涂层的基底。更具体地讲,基底包括交联共聚物层,并且接枝有配体官能聚合物。接枝配体官能共聚物涂层包含以下的紫外线反应产物:
1)交联共聚物,该共聚物包含光引发剂官能单体单元,以及易于进行交联反应的单体单元(诸如,具有胺反应性官能团的单体单元);以及
2)包含配体官能单体单元的单体混合物。
配体接枝共聚物具有结合近中性或带电荷生物物质,诸如细胞、细胞碎片、细菌、孢子、病毒、核酸、多糖、脂质和蛋白质的必需亲和力。结合类型以及所结合的生物物质将根据配体官能单体上存在的配体的类型而改变。
“亲和力”是指通过任何手段,包括离子相互作用、共价相互作用、疏水相互作用以及生物亲和力(诸如抗体-抗原)相互作用结合生物物质的能力。
“烷基”是指具有一至约十二个碳原子的直链或支链、环状或无环的饱和单价烃基,例如甲基、乙基、1-丙基、2-丙基、戊基,等等。
“亚烷基”是指具有一至约十二个碳原子的直链饱和二价烃基或具有三至约十二个碳原子的支链饱和二价烃基,例如亚甲基、亚乙基、亚丙基、2-甲基亚丙基、亚戊基、亚己基,等等。
“烯基”是指具有二至约十二个碳原子的直链不饱和单价烃基或具有三至约十二个碳原子的支链不饱和烃基。
“芳基”是指单价芳族,诸如苯基、萘基,等等。
“亚芳基”是指多价芳族,诸如亚苯基、萘,等等。
“亚芳烷基”是指具有与亚烷基连接的芳基的以上定义的基团,例如苄基、1-萘乙基,等等。
“杂亚芳基”指为芳族和杂环的二价基团。即,杂亚芳基在5或6元的芳环中包含至少一个杂原子。合适的杂原子通常为氧、硫或氨基。所述基团可具有一至五个连接的、稠合的或它们的组合的环。至少一个环为芳杂环,且任何其它环可为芳环、非芳环、杂环、碳环或它们的组合。在一些实施例中,所述杂亚芳基具有至多5个环、至多4个环、至多3个环、至多2个环、或一个环。杂亚芳基基团的例子包括但不限于三嗪二基、吡啶二基、嘧啶二基、哒嗪二基,等等。
“烃基”包括芳基和烷基;
“(杂)烃基”包括烃基烷基和芳基基团,和杂烃基杂烷基和杂芳基基团,后者包含一个或多个链(链中)杂原子诸如醚或氨基基团。杂烃基可任选地包含一种或多种链中(链中的)官能团,所述官能团包括酯、酰胺、脲、氨基甲酸酯和碳酸酯官能团。除非另外指明,非聚合的(杂)烃基基团通常包含1至60个碳原子。除了以上对于“烷基”、“杂烷基”、“芳基”和“杂芳基”所述的那些外,如本文所用,此类杂烃基的一些例子包括但不限于甲氧基、乙氧基、丙氧基、4-二苯基氨基丁基、2-(2'-苯氧基乙氧基)乙基、3,6-二氧杂庚基、3,6-二氧杂己基-6-苯基。
“(杂)亚芳基”包括亚芳基和杂亚芳基。
具体实施方式
在本发明的制品和方法中,提供对生物物质,诸如蛋白质、DNA、RNA、多糖、脂质、病毒和其它微生物具有增强亲和力和/或能力的配体官能化基底。配体官能化基底使得配体基团能够选择性捕集或结合靶标生物物质,同时使缺少配体基团亲和力的其它材料通过。
共聚物包含接枝光引发剂单体的聚合的单体单元,接枝光引发剂单体包括烯键式不饱和可聚合基团(包括(甲基)丙烯酰基基团和烯基基团)以及α裂解型光引发剂基团,并且可由下式表示:
其中;
X1为-O-或-NR1,
R1独立地为H或C1-C4烷基;
R6为连接(甲基)丙烯酰基基团与光引发剂基团的二价(杂)烃基连接基团;并且
PI为由以下结构表示的α裂解型光引发剂基团:
其中Ar为具有6至12个碳原子的取代的芳烃,优选为苯三基;
R12为氢、C1至C12烷基基团、C1至C12烷氧基基团或苯基基团;并且
R13选自以下基团:
其中
R19为氢、C1至C12烷基基团、C1至C12烷氧基基团或苯基基团,
R16、R17和R18独立地为羟基基团、苯基基团、C1至C6烷基基团、C1至C6烷氧基基团或-NR19R20基团,其中R19和R20独立地为氢或C1至C12烷基基团,
条件是,当R13为-CR16R17R18时,以下中的一项必须是真实的:
(1)R16、R17和R18中的至少一个选自羟基、烷氧基和–NR19R20基团;
(2)R16、R17和R18中的任两个一起为-CtH2t-和-OCtH2tO-之一,其中t为2或3,使得它们与所连接的碳原子一起形成5元或6元环;并且
(3)R16、R17和R18中的任两个一起为羰基基团,前提条件是R16、R17和R18中的剩余一个选自羟基、烷氧基、-NR19R20和苯基基团。
在某些优选的实施例中,光引发剂单体可以为由以下通式表示的α裂解型:
X1为O或NR1;
p为0或1;
o为0或1至5的整数;
a、b和c独立地为0或1;
M1为CH2或Si(R1)2;
M2为C(R1)2或Si(R1)2;
M3为–O-、-NH-、-C(O)-、-C(O)O-、-C(O)NH-或-OC(O)NH-;
各R1独立地为H或C1至C4烷基基团;
G为共价键、-(CH2)d-或-(CH2)dO-,其中d为1至4的整数,优选为1至2的整数;
PI为α-裂解型光引发剂基团。
此类光引发剂单体例如在U.S.5,902,836(Bennett等人)和5,506,279(Babu等人)中描述,这些专利的公开内容以引用方式并入本文。可参照本文以及在引用的参考文献中的制备光引发剂接枝单体的方法找到关于该R6连接基团的更多细节。特别可用的可聚合光引发剂为2-乙烯基-4,4-二甲基吖内酯与IrgacureTM2959的1:1加合物,其如US 5,506,279(Babu等人)的实例1中所公开的那样进行制备,该专利以引用方式并入本文。
可通过使1)包含第一反应性官能团的丙烯酰基或烯基单体与2)包含辐射敏感性基团(光引发剂基团)和第二反应性官能团的化合物反应来制备多种光引发剂官能接枝单体,这两种官能团相互共反应。当这些第一和第二官能团反应时,它们形成共价键并连接这些共反应性化合物。
可用的反应性官能团的例子包括羟基、氨基、唑啉基、唑酮基、乙酰基、丙酮基、羧基、异氰酸基、环氧基、氮丙啶基、酰卤以及环酐基团。在该第一反应性官能团是异氰酸基官能团的情况下,该第二共反应性官能团优选包含氨基、羧基或羟基。在第一反应性官能团包含羟基的情况下,第二共反应性官能团优选包含羧基、异氰酸基、环氧基、酐、酰卤或唑啉基。在第一反应性官能团包含羧基的情况下,该第二共反应性官能团优选包含羟基、氨基、环氧基、乙烯氧基或唑啉基。
具有反应性官能团的丙烯酸酯化合物的代表性例子包括丙烯酸羟烷基酯,诸如丙烯酸2-羟基乙酯和丙烯酸2-(2-羟基乙氧基)乙酯;丙烯酸氨基烷基酯诸如丙烯酸3-氨基丙酯;唑酮基化合物诸如2-乙烯基-1,3-唑啉-5-酮和2-丙烯基-4,4-二甲基-1,3-唑啉-5-酮;羧基取代的化合物诸如丙烯酸和丙烯酸4-羧基苯甲基酯;异氰酸基取代的化合物诸如丙烯酸异氰酸基乙酯和丙烯酸4-异氰酸基环己酯;环氧基取代的化合物诸如丙烯酸缩水甘油酯;氮丙啶基取代的化合物诸如N-丙烯酰氮丙啶;以及丙烯酰卤化物。
共反应性化合物的代表性例子包括官能团取代的化合物,诸如1-(4-羟苯基)-2,2-二甲氧基乙酮、1-[4-(2-羟乙基)苯基]-2,2-二甲氧基乙酮、(4-异氰酸基苯基)-2,2-二甲氧基-2-苯乙酮、1-{4-[2-(2,3-环氧丙氧基)苯基]}-2,2-二甲基-2-羟基乙酮、1-[4-(2-氨基乙氧基)苯基]-2,2-二甲氧基乙酮和1-[4-(甲酯基)苯基]-2,2-二甲氧基乙酮。
相对于共聚物的单体的总重量,共聚物中式I或IV的光引发剂单体的重量百分比可以为至少约0.5%,并且通常小于约25%。并入到共聚物链中的那些光引发剂单体将在暴露于紫外线辐射时引发配体单体的自由基聚合并将这些配体单体作为接枝链并入到交联的共聚物上。
共聚物包含易于进行交联反应的单体单元——“可交联的单体单元”。包含此类单体使得能将包含共聚光引发剂单体的交联涂层应用到多种基底上。此类单体在本领域是已知的,并且包括诸如烯基和(甲基)丙烯酰基烷基硅烷、羟甲基和烷氧基甲基(甲基)丙烯酰胺的单体,以及包含胺反应性官能团的单体。后种单体是尤其优选的,因为它们允许在低温下,诸如室温下进行涂布和交联操作。
共聚物的可交联的单体具有可聚合烯键式不饱和基团以及能够交联的反应性官能团,其一些实施例由式V表示:
其中
X1为-O-或-NR1-,
R1为H或C1-C4烷基;
R2为单键或(杂)烃基连接基团,优选地为1至20个碳原子的二价亚烷基;
A为与交联化合物反应或自交联的反应性官能团,包括单、二或三烷氧基硅烷以及羟甲基或烷氧基甲基取代的氮;并且
x为0或1。
在一些实施例中,式V的化合物为(甲基)丙烯酰基化合物,而在其它实施例中为烯基化合物。优选地“A”为胺反应性官能团。优选地,R2为单键或烃基连接基团,其将烯键式不饱和可聚合基团(例如,烯基或(甲基)丙烯酰基基团)连接至反应性官能团A并且优选地为具有1至6个碳原子的亚烷基基团、具有5至10个碳原子的5或6元亚环烷基基团或具有6至16个碳原子的二价芳香族基团;并且A为能够与交联剂的胺基团反应的反应性官能团。
可用的胺反应性官能团“A”包括羧基、唑啉基、吖内酯、乙酰基、丙酮基、乙酰乙酰基、酯、异氰酸基、环氧基、氮丙啶基、酰卤和环酐基团。优选地,将胺反应性官能团A选择为在低于约50℃、优选低于25℃的温度下与交联剂的胺基团反应,使得反应在涂布和干燥操作过程中发生。
式V的代表性吖内酯基团取代的官能化合物包括:2-乙烯基-1,3-唑啉-5-酮;2-乙烯基-4-甲基-1,3-唑啉-5-酮;2-异丙烯基-1,3-唑啉-5-酮;2-异丙烯基-4-甲基-1,3-唑啉-5-酮;2-乙烯基-4,4-二甲基-1,3-唑啉-5-酮;2-异丙烯基-4,4-二甲基-1,3-唑啉-5-酮;2-乙烯基-4-甲基-4-乙基-1,3-唑啉-5-酮;2-异丙烯基-3-氧杂-1-氮杂[4.5]螺癸-1-烯-4-酮;2-乙烯基-5,6-二氢-4H-1,3-嗪-6-酮;2-乙烯基-4,5,6,7-四氢-1,3-氧氮杂卓-7-酮;2-异丙烯基-5,6-二氢-5,5-二(2-甲基苯基)-4H-1,3-嗪-6-酮;2-丙烯酰氧基-1,3-唑啉-5-酮;2-(2-丙烯酰氧基)乙基-4,4-二甲基-1,3-唑啉-5-酮;2-乙烯基-4,5-二氢-6H-1,3-嗪-6-酮;和2-乙烯基-4,5-二氢-4,4-二甲基-6H-1,3-嗪-6-酮。
式V的代表性乙酰乙酰基取代的官能化合物包括2-(乙酰乙酸基)甲基丙烯酸乙酯。
式V的代表性羧基基团取代的官能化合物包括(甲基)丙烯酸、3-(甲基)丙烯酰氧基-丙酸、4-(甲基)丙烯酰氧基-丁酸、2-(甲基)丙烯酰氧基-苯甲酸、3-(甲基)丙烯酰氧基-5-甲基苯甲酸、4-(甲基)丙烯酰氧基甲基-苯甲酸、邻苯二甲酸单-[2-(甲基)丙烯酰氧基-乙基]酯、2-丁炔酸和4-戊炔酸。
式V的代表性异氰酸酯基团取代的官能化合物包括(甲基)丙烯酸2-异氰酸基乙酯、(甲基)丙烯酸3-异氰酸基丙酯、(甲基)丙烯酸4-异氰酸基环己酯、4-异氰酸基苯乙烯、2-甲基-2-丙烯酰基异氰酸酯、4-(2-(甲基)丙烯酰氧基乙氧基羰基氨基)苯基异氰酸酯、烯丙基2-异氰酸基***和3-异氰酸基-1-丙烯。
式V的代表性环氧基团取代的官能化合物包括(甲基)丙烯酸缩水甘油酯、(甲基)丙烯酸硫代缩水甘油酯、(甲基)丙烯酸3-(2,3-环氧丙氧基)苯酯、2-[4-(2,3-环氧丙氧基)苯基]-2-(4-(甲基)丙烯酰氧基-苯基)丙烷、(甲基)丙烯酸4-(2,3-环氧丙氧基)环己酯、(甲基)丙烯酸2,3-环氧环己酯和(甲基)丙烯酸3,4-环氧环己酯。
式V的代表性酰卤基取代的官能化合物包括(甲基)丙烯酰氯、α-氯代(甲基)丙烯酰氯、(甲基)丙烯酰氧基乙酰氯、5-己烯酰氯、2-(丙烯酰氧基)丙酰氯、3-(丙烯酰硫)丙酰氯和3-(N-丙烯酰基-N-甲基氨基)丙酰氯。
其它可用的胺反应性单体包括酸酐基团取代的官能单体,包括马来酸酐、(甲基)丙烯酸酐、衣康酸酐、3-(甲基)丙烯酰氧基邻苯二甲酸酐和2-(甲基)丙烯酰氧基环己烷二羧酸酐。
交联的共聚物层可包含一种或多种亲水单体,这些亲水单体包含至少一个烯基基团(优选为(甲基)丙烯酰基基团)和亲水基团(包括聚(亚烷基氧)和离子基团),用于向基底提供亲水性,或用于在结合生物物质时向基底提供更强选择性。
亲水性基团可以是中性的、具有正电荷、负电荷,或者它们的组合。可用的中性亲水共聚单体包括二甲基丙烯酰胺、丙烯酰胺、甲基丙烯酰胺、(甲基)丙烯酸羟乙酯、(甲基)丙烯酸羟丙酯、N-乙烯基吡咯烷酮、N-乙烯基甲酰胺,或它们的组合。
在一些优选实施例中,亲水单体可具有丙烯酸酯基团,或其它烯键式不饱和基团和聚(亚烷基氧)基团;例如,单丙烯酸化的聚(亚烷基氧)化合物,其中末端是羟基或烷基醚基团。此类单体可由式VI表示:
CH2=CR1-C(O)-X1-(CH(R1)-CH2-O)n-R1, VI
其中各R1独立地为H或C1-C4烷基,
X1为-O-或-NR1-,并且
n为2至100。
其它包括聚醚胺的链烯吖内酯加合物(诸如基于聚醚胺结构的单胺)。这些化合物的一个实例是得自亨兹曼公司(Huntsman)(美国德克萨斯州伍德兰(The Woodlands,TX,USA))的系列。
相对于共聚物的100份总单体重量,此类亲水共聚单体以约35至约97.5重量份,优选60至约93重量份,最优选约70至约87重量份的量使用。然而,当离子单体用作亲水共聚单体组分的部分时,它以15重量份或更小的量使用,以便不降低接枝基底与带类似电荷的生物物质相互作用或捕集它们的能力。在这种情况下,亲水共聚单体组分的其余部分包含中性共聚单体。
任选地,可以在可交联的共聚物中包含低水平的其它共聚单体。这些其它共聚单体可以选自本领域熟知的单体并且是可商购获得的,诸如常见的(甲基)丙烯酸酯、苯乙烯、乙烯基醚和乙烯基酯。
具有光引发剂基团和可交联的单体基团的官能共聚物可以通过多种自由基聚合过程来制备,其中反应性单体与共聚单体共聚。典型的溶液聚合过程已在例如U.S.4,304,705(Heilmann等人)和U.S专利3,583,950(Kollinsky等人)中进行报导。使用自由基引发剂诸如热引发剂而不是光引发剂来制备共聚物从而不引发光引发剂单体。
在交联之前,共聚物具有式:
-(MPI)k-(M亲水)l-(MFG)m-(M其它)i-,其中
(MPI)k为具有“k”个聚合的单体单元的光引发剂官能单体单元,其中k为至少一,
(M亲水)l为具有“l”个聚合的单体单元的亲水单体单元,
(MFG)m为具有胺反应性官能团且具有“m”个聚合的单体单元的单体单元。
(M其它)表示具有“i”个聚合的单体单元的其它单体单元,其中“i”可为零。
参考单体的量:
k为0.5重量%至25重量%的单体单元;
l为35重量%至97.5重量%的单体单元;
m为2重量%-40重量%的单体单元;
i为0重量%-20重量%的单体单元,
基于100重量%的总单体计。
一旦制备好适当的共聚物(具有可交联的官能团、光引发剂基团和亲水基团),则通过向该共聚物添加交联剂或催化剂来配制涂层混合物。这便利地在不与共聚物的官能团反应的适当有机溶剂中进行。在添加交联剂或催化剂之前,可以用溶剂将共聚物稀释至约5重量%或更小的浓度。在其它实施例中,在添加交联剂或催化剂之前可以用溶剂将共聚物稀释至约10重量%或约20重量%的浓度。用于稀释的溶剂可为其中制备共聚物的相同溶剂或者可以为一种或多种不同的溶剂。通过共聚物浓度和所添加的交联剂的量来便利地控制交联时间,从而获得用于涂布的足够时间,随后是快速固化时间以提供成品。一般来讲,共聚物浓度越低或者交联剂的量越低,发生交联所需的时间将越长。
在共聚物包含可交联的单体诸如烯基和(甲基)丙烯酰基烷基硅烷或羟甲基和烷氧基甲基(甲基)丙烯酰胺的实施例中,可通过本领域熟知的方法,诸如通过添加酸催化剂来完成交联。由于硅烷单体在硅上具有能水解基团,外来水或少量水的添加可有助于生成中间羟基硅烷,最终引起硅氧烷交联。羟甲基或烷氧基甲基丙烯酰胺单体单元的酸催化的缩合导致聚合物链之间的亚甲基交联。
在一些实施例中,用于共聚物的交联剂是具有至少一个伯胺基团和至少一个其它官能团的胺官能化合物,所述至少一个其它官能团为a)为对共聚物的胺反应性官能团有反应性的,或者b)为自交联的。此类化合物可由下式表示:
(HNR1)r-R4-(FG)q, XIII
其中R1为H或C1-C4烷基,
R4为(杂)烃基基团,优选地为1至20个碳原子的二价亚烷基基团或二价聚(亚烷基氧)基团;
FG是这样的官能团:a)为对共聚物的胺反应性官能团有反应性的,或者b)为自交联的,并且下标r和q为至少一。这些类型的交联剂详细描述在US 6,794,458(Haddad)中,该专利的公开内容并入本文中。
在优选的实施例中,交联剂为聚胺:FG由下式表示:
-NHR1,其中R1为H或C1-C4烷基以提供具有下式的交联化合物:
R4(NHR1)m,其中
R4为(杂)亚烷基基团;
R1为H或C1-C4烷基,并且至少一个R1为H,并且m为至少二。
出于本发明的目的可用的交联剂包括但不限于包含亲核基团的材料,这些亲核基团将与胺反应性官能团发生加成或取代反应。合适的交联剂包括伯聚胺,诸如乙二胺、1,3-丙二胺、1,3-二氨基-2-羟基丙烷、1,6-己二胺、三-(2-氨基乙基)胺,等等;以及聚醚聚胺,诸如4,7,10-三氧杂-1,13-十三烷二胺、3,6-二氧杂-1,8-辛二胺、胺封端的聚乙二醇和聚丙二醇均聚物和共聚物,等等。
另一类交联剂包括伯/仲(1°/2°)含胺化合物。在这些材料中,伯胺提供在室温下与共聚物上的吖内酯基团的快速反应,而仲胺反应相对缓慢。除去溶剂、提高涂布制品的温度,或两者允许仲胺反应从而形成交联涂层。合适的含伯胺/仲胺的化合物包括但不限于N-甲基-1,2-乙二胺、N-乙基-1,2-乙二胺、N-异丙基-1,2-乙二胺以及其它N-烷基二氨基链烷。增大N-烷基取代基的空间体积使得更大程度地阻碍仲胺基团的反应,从而需要更高的温度来产生交联。
出于本发明的目的可用的另一类交联剂包括氨基烷基烷氧基硅烷,诸如例如,3-氨基丙基三甲氧基硅烷、3-氨基丙基三乙氧基硅烷、N-[3-(三甲氧基甲硅烷基)丙基]乙二胺,或其它氨基烷基单、二和三烷氧基硅烷。氨基与共聚物的胺反应性官能团发生反应,从而在共聚物上提供侧链烷氧基硅烷基团。在干燥时,烷氧基基团可水解并且随后在聚合物链之间形成硅氧烷交联。根据基底的性质,可同时与基底表面上的官能团形成共价键(例如,如果基底是硅质的,可以形成与基底的硅氧烷键)。
交联剂的胺基团与共聚物的反应性官能团之间的化学计量可以小于1:1最高至1:1,优选0.1:1,更优选0.5:1至1:1因此,初始共聚物中的胺反应性官能团含量将提供可以添加至涂层制剂中的交联剂的量的上限。交联涂层的主要目的是为基底的表面提供可发生接枝聚合的光引发剂位点。在一些情况下,涂层的次要目的是使得基底表面更具亲水性,以便减少生物物质的非特异性结合。
出于本发明的目的可用的配体单体是包含可自由基聚合的烯基或(甲基)丙烯酰基基团和以下官能团的官能单体,该官能团是能够与生物物质相互作用的配体基团或是可用于经由适当化学反应连接配体基团的反应性基团。可用的配体单体是式VIIIa或b的官能单体。
Z1-Y2-X1-CO-CR1=CH2 (VIIIa),或
Z1-Y2-CR1=CH2 (VIIIb)
其中X1为-O-或-NR1-,并且R1为H或C1-C4烷基。
在式VIII中,基团Y2为选自以下的连接基团:单键或含有亚烷基、杂亚烷基、亚芳基或它们的组合的(杂)烃基二价基团。基团Y2还可含有起到连接两个或更多亚烷基、杂亚烷基、亚芳基或它们的组合的功能的其它任选的基团。任选的基团可包括例如羰基、羰氧基、羰硫基、羰基亚胺基、氧基、硫基、-NR1-(其中R1为H或C1-C4烷基),或它们的组合。基团Z1为选自以下的第一配体官能团:(1)酸性基团或其盐、(2)氨基基团或其盐,(3)胍或双胍基团或其盐、(4)吖内酯基团或吖内酯基团的前体、(5)缩水甘油基基团、(6)生物亲和力配体基团、(7)疏水相互作用基团、(8)异氰酸酯基团或(9)它们的组合。
式(VIII)的官能配体单体具有能够经历加上配体官能团Z1的自由基聚合反应的烯键式不饱和基团。式(VIII)的官能单体与PI官能化基底经历自由基聚合反应,从而导致形成包括从固体载体伸出的接枝链的接枝基底。在许多实施例中,固体载体具有多个接枝链。接枝链包括至少一个,优选两个或更多个式VIIIa和/或b的接枝单体单元。
式VIII的配体官能单体的基团Z1可以为酸性基团或其盐,并且可用于制备阳离子交换基底。官能单体可以为弱酸、弱酸盐、强酸、强酸盐或它们的组合。配体官能单体可为中性状态,但如果调节pH值,则其能够带负电。一些示例性配体官能单体是磺酸或其盐,例如(甲基)丙烯酰胺磺酸或其盐。更具体的(甲基)丙烯酰胺磺酸包括但不限于(甲基)丙烯酰胺甲磺酸、2-(甲基)丙烯酰胺乙磺酸和2-(甲基)丙烯酰胺-2-甲基丙磺酸。也可以使用这些酸性单体的盐。具有酸性基团或其盐的一些其它示例性官能单体包括其它磺酸,例如乙烯基磺酸、(甲基)丙烯酸-3-磺丙酯、(甲基)丙烯酸磺乙酯和4-苯乙烯磺酸。
其它示例性的具有酸性基团的官能单体包括但不限于膦酸或其盐或者羧酸或其盐。例如,官能单体可以是:(甲基)丙烯酰胺烷基膦酸,例如2-(甲基)丙烯酰胺乙基膦酸和3-(甲基)丙烯酰胺丙基膦酸;丙烯酸和甲基丙烯酸;和(甲基)丙烯酸羧烷酯,例如(甲基)丙烯酸-2-羧乙酯和(甲基)丙烯酸-3-羧丙酯。其它合适的单体包括(甲基)丙烯酰氨基酸,例如U.S.专利4,157,418(海尔曼)中所述的那些。示例性的(甲基)丙烯酰氨基酸包括但不限于N-(甲基)丙烯酰甘氨酸、N-(甲基)丙烯酰天冬氨酸、N-(甲基)丙烯酰基-β-丙氨酸和N-(甲基)丙烯酰基-2-甲基丙氨酸。也可使用这些酸性单体中任何一种的盐。如果官能单体为弱酸盐或强酸盐的形式,则这些盐的抗衡离子可以是(但不限于)碱金属离子、碱土金属离子、铵离子或季铵离子。
第二类式VIII的配体官能单体具有用于Z1的氨基基团或其盐,并且可用于制备阴离子交换基底。所述氨基基团或其盐可以是伯氨基基团、仲氨基基团、叔氨基基团或季铵基团。这类官能单体可以是弱碱、强碱、弱碱盐、强碱盐或它们的混合物。官能单体可以处于中性状态,但如果对pH值进行调节则其可以带正电荷。如果官能单体为盐的形式,则抗衡离子可以是(但不限于)卤离子(如氯离子)、羧酸根(如醋酸根或甲酸根)、硝酸根、磷酸根、硫酸根、硫酸氢根、甲基硫酸根或氢氧根。
具有氨基基团或其盐的一些示例性官能单体包括如下式VIIIc所示的氨基(甲基)丙烯酸酯或氨基(甲基)丙烯酰胺(以及它们的季铵盐):
N(R5)u-Y2-X1-(CO)-CR1=CH2 VIIIc
其中X1为-O-或-NR1-,并且R1为H或C1-C4烷基;
各R5独立地为氢、烷基、羟烷基(即被羟基取代的烷基)、氨基烷基(即被氨基取代的烷基)、芳基或芳烷基。对于伯、仲或叔氨基基团,下标u等于2,对于季氨基基团,下标u等于3。当u等于3时,三个R5基团独立地选自烷基、羟烷基、氨烷基、芳基或芳基烷基。也就是说,当变量u等于3时,R5通常不等于氢。
当下标u等于2时,式VIIIc中的R5基团与它们所连接的氮原子一起可以形成芳族的、部分不饱和(即,不饱和但非芳族的)或饱和的杂环基团。这种杂环基团可任选稠合至为芳族的第二环(例如苯)、部分不饱和的第二环(例如环己烯)或饱和的第二环(例如环己烷)。季铵盐的抗衡离子通常是卤离子、硫酸根、磷酸根、硝酸根,等等。
在其中变量u等于2的式VIIIc的一些实施例中,两个R5基团为氢。在其中变量u等于2的其它实施例中,一个R5基团是氢,另外一个是具有1至10、1至6或1至4个碳原子的烷基。在其中变量u等于2的其它实施例中,至少一个R5基团是具有2至10、2至6或2至4个碳原子的羟烷基或氨烷基,其中羟基或氨基位于烷基中除了第一个碳原子外的任意碳原子上。在其中变量u等于2的其它实施例中,R5基团中的至少一个是具有5或6个碳原子的芳基;或其中烷基具有1至10个碳原子且芳基具有5或6个碳原子的芳烷基。在其它实施例中,两个R5基团与它们所连接的氮原子组合而形成杂环基团。杂环基团包含至少一个氮原子,并且可含有其它杂原子,例如氧或硫。示例性的杂环基团包括但不限于咪唑基、哌嗪基和吗啉基。杂环基团可稠合至另外的环,诸如苯、环己烯或环己烷。稠合至另外环的示例性杂环基团包括但不限于苯并咪唑基。
其中X1是氧基的式VIIIc的示例性氨基(甲基)丙烯酸酯包括但不限于(甲基)丙烯酸-N,N-二烷氨基烷基酯,诸如例如(甲基)丙烯酸-N,N-二甲氨基乙酯、(甲基)丙烯酸-N,N-二乙氨基乙酯、(甲基)丙烯酸-N,N-二甲氨基丙酯、(甲基)丙烯酸-N-叔丁基氨基丙酯,等等。
其中X1是–NR1-的式VIIIc的示例性氨基(甲基)丙烯酰胺包括但不限于N-(3-氨丙基)(甲基)丙烯酰胺、N-[3-(二甲氨基)丙基](甲基)丙烯酰胺、N-(3-咪唑基丙基)(甲基)丙烯酰胺、N-(2-咪唑基乙基)(甲基)丙烯酰胺、N-(1,1-二甲基-3-咪唑基丙基)(甲基)丙烯酰胺和N-(3-苯并咪唑基丙基)(甲基)丙烯酰胺。
式VIIIc的官能单体的示例性季盐包括但不限于(甲基)丙烯酰胺基烷基三甲基铵盐,诸如(甲基)丙烯酰胺基丙基三甲基氯化铵;和(甲基)丙烯酰氧基烷基三甲基铵盐,诸如2-(甲基)丙烯酰氧基乙基三甲基氯化铵和2-(甲基)丙烯酰氧基乙基三甲基甲基硫酸铵。
第三类式VIIIa、b的官能单体具有胍或双胍或其盐,并且可用于制备在高离子强度条件下有用的阴离子交换载体。
第四类式VIIIa、b的官能单体具有吖内酯Z1基团。具有吖内酯基团的示例性官能单体包括但不限于乙烯基烷基吖内酯,诸如2-乙烯基-4,4-二甲基吖内酯(也称为2-乙烯基-4,4-二甲基-2-唑啉-5-酮)、2-(4-乙烯基苯基)-4,4-二甲基吖内酯、2-异丙烯基-4,4-二甲基吖内酯、2-乙烯基-4-乙基-4-甲基-2-唑啉-5-酮和2-乙烯基-4,4-二甲基-1,3-嗪-6-酮。第四类官能单体的另一个实施例具有作为Z1基团的吖内酯基团的前体基团。前体基团可经受闭环反应而形成吖内酯基团。可提供这种前体基团的示例性官能单体包括但不限于N-丙烯酰基甲基丙氨酸。
第五类式VIIIa、b的官能单体具有作为Z1基团的缩水甘油基。具有缩水甘油基的示例性单体包括但不限于(甲基)丙烯酸缩水甘油酯。
第四类和第五类官能单体以及具有异氰酸酯基团诸如(甲基)丙烯酸2-异氰酸基乙酯的单体由于其反应性官能团而可用于制备其它类型的载体,包括固定化酶载体、离子交换载体、疏水相互作用载体和生物亲和力分离载体。
第六类式VIIIa、b的官能单体具有疏水Z1基团,可用于制备疏水相互作用载体。
其它官能单体具有两种或更多种Z1官能团的组合,这些Z1官能团选自(1)酸性基团或其盐、(2)氨基基团或其盐、(3)羟基基团、(4)吖内酯基团或(5)缩水甘油基基团。具有多个且不同类型的官能团的示例性官能单体是3-(甲基)丙烯酰氧基-2-羟丙基三甲基氯化铵和2-(甲基)丙烯酰胺基乙醇酸。
在一些优选实施例中,基底的表面上的交联共聚物包含下式的聚合胍基配体官能单体单元:
其中
R1为H或C1-C4烷基;
R2为(杂)烃基基团,优选地为具有1至20个碳原子的二价亚烷基;
各R3独立地为H或C1-C4烷基;
R4为H、C1-C12烷基或–N(R3)2;
R7为H或烃基,优选地为C1-C12烷基或芳基;
X1为-O-或-NR3-,
e为0或1,并且
d为1或2。
此类式IXa和b的配体单体可通过烯基或烯酰基化合物(通常为(甲基)丙烯酰卤、(甲基)丙烯酰基异氰酸酯或烯基吖内酯)与式Xa或Xb的化合物的缩合来制备:
其中X1、R2至R4以及d如先前所定义。
其它配体单体可通过含羰基单体(诸如丙烯醛、丁烯酮、双丙酮丙烯酰胺或乙酰乙酰氧基乙基甲基丙烯酸酯)任选在还原剂的存在下与式Xa或Xb的化合物缩合来制备。
配体单体将通过光引发剂的残基接枝到交联共聚物,使得共聚物将具有连接其上的具有下式的配体基团(得自式VIIIa、b或IXa、b的单体):
其中
R1为H或C1-C4烷基;
R2为(杂)烃基基团,优选地为具有1至20个碳原子的二价亚烷基;
各R3独立地为H或C1-C4烷基;
R4为H、C1-C12烷基或–N(R3)2;
R7为H或烃基,优选地为C1-C12烷基或芳基;
X1为-O-或-NR3-,
Y2为选自单键或(杂)烃基二价基团的连接基团;
并且
PI*是接枝到基底表面上的光引发剂的残基。
参考PI*基团,接枝光引发剂单体诸如2-丙酰氨基-2,2-二甲基乙酸、2-(4-(2-羟基-2甲基丙酰)苯氧基)乙酯可并入交联共聚物中。在存在紫外线时,光引发剂基团经历α裂解变为两个自由基。在存在配体单体或其它单体时,自由基可以加入烯键式不饱和基团(诸如所描述的丙烯酰基基团)中,以通过如式XI所示并且以下方案I所示的光引发剂的残基引发配体单体的聚合。还应当理解,配体单体的自由基加成产物可进一步与另外的配体单体和其它任选的单体共聚,以产生具有其上悬垂的配体基团的接枝聚合物。
方案I
还应当理解,这种接枝方法将产生自由基物质,该自由基物质在式I的配体单体的羰基的α碳上具有自由基,它可进一步与一种或多种另外的配体单体、一种或多种亲水单体和/或一种或多种交联或“其它”单体聚合,从而得到具有以下简单说明的从该交联聚合物链上悬垂的这些基团的接枝聚合物。接枝聚合物链的形成显著提高了所需配体基团的密度以及结合的效率。
所得制品包含基底,以及该基底表面上的交联共聚物,该共聚物具有接枝聚合的配体单体,该制品并且可由下式表示:
其中
MPI*表示具有“f”个聚合的单体单元的MPI单体单元的残基,其中f为至少一,
M交联表示衍生自MFG单体单元(其随后已用氨基官能交联剂官能化)且具有“g”个聚合的单体单元的单体单元,其中g为至少一;
M亲水表示具有“h”个聚合的单体单元的亲水单体单元,其中h为至少一;
M配体表示具有“j”个聚合的单体单元的配体单体单元,其中j为至少1;
M其它表示具有“i”个聚合的单体单元的其它单体单元,其中“i”可为零。
应当理解,下标值将对应于如上文提出的每种单体单元的重量百分比。还应当理解,所描述的共聚物还可以具有未被M配体单体单元取代的MPI*单体单元,并且还可以具有未取代的MFG单体单元。
应当理解,关于以上式,共聚物可以是随机的或无规的,并且侧链配体单体单元可还包含另外的共聚单体单元,包括亲水单体单元、“其它”单体单元以及交联单体单元。
可以使用几个工序的组合来制备配体官能化基底。该方法可以包括:
1)提供基础基底,优选地多孔基础基底;
2)提供包含一种或多种具有光引发剂基团的单体、一种或多种具有胺反应性官能团的单体、一种或多种亲水单体、一种或多种“其它”单体以及胺官能交联剂的共聚物的涂料溶液;
3)用涂料溶液涂布基底;
4)使基底表面上的涂层与胺官能交联化合物交联以产生交联的共聚物;
5)干燥涂布基底;
6)用包含以下的溶液或悬浮液使具有交联的共聚物的基底吸液:(a)一种或多种配体官能单体、(b)任选地一种或多种亲水单体;以及任选地c)一种或多种“其它”单体;
7)将吸液的基础基底暴露于紫外线辐射以便由共聚物的光引发剂基团生成自由基;以及
将单体的烯键式不饱和的可自由基聚合的基团接枝聚合到基础基底的表面上。
在一些实施例中,吸液溶液仅包含配体官能单体和溶剂。在其它实施例中,吸液溶液包含一种或多种“其它”单体。这些其它单体包括对于交联的共聚物描述的相同共聚单体,包括亲水共聚单体;也包括多官能(甲基)丙烯酰基单体,包括(甲基)丙烯酸酯和(甲基)丙烯酰胺单体。可包括后面的这些共聚单体以向接枝配体官能聚合物链提供支化或低程度的交联。可用的多官能(甲基)丙烯酸酯的实例包括但不限于二(甲基)丙烯酸酯、三(甲基)丙烯酸酯和四(甲基)丙烯酸酯,诸如乙烯乙二醇二(甲基)丙烯酸酯、1,6-己二醇二(甲基)丙烯酸酯、聚(乙二醇)二(甲基)丙烯酸酯、聚丁二烯二(甲基)丙烯酸酯、聚氨酯二(甲基)丙烯酸酯和丙氧基化的甘油三(甲基)丙烯酸酯、亚甲基双丙烯酰胺、亚乙基双丙烯酰胺、六亚甲基双丙烯酰胺、二丙烯酰基哌嗪以及它们的混合物。
吸液溶液的溶剂可为可用于进行自由基聚合过程的任何溶剂。在多个实施例中,溶剂为水或水/可与水混溶的有机溶剂的混合物。根据单体的溶解度,水与有机溶剂的比率可以有很大变化。在一些单体的情况下,水与有机溶剂通常为大于1:1(v/v),优选大于5:1,并且更优选大于7:1。在其它单体的情况下,更高比例的有机溶剂(在一些醇类的情况下),甚至最高至100%,可能是优选的。
任何此类可与水混溶的有机溶剂优选地不具有将延迟聚合反应的基团。在一些实施例中,可与水混溶的溶剂是含有质子基团的有机液体,诸如具有1至4个碳原子的低级醇、具有2至6个碳原子的低级二醇以及具有3至6个碳原子和1至2个醚键的低级二醇醚。在一些实施例中,可以使用高级二醇,诸如聚(乙二醇)。具体实例是甲醇、乙醇、异丙醇、正丁醇、叔丁醇、乙二醇、甲氧基乙醇、乙氧基乙醇、丙氧基乙醇、丁氧基乙醇、甲基卡必醇、乙基卡必醇以及它们的混合物。
在其它实施例中,也可使用非质子的有机溶剂,诸如脂肪族酯和酮和亚砜、乙酸乙酯、乙酸甲氧基乙酯、乙酸乙氧基乙酯、乙酸丙氧基乙酯、乙酸丁氧基乙酯、磷酸三乙酯、丙酮、甲基乙基酮、甲基丙基酮和二甲基亚砜。
吸液溶液中每一种组分的浓度可以根据多种因素改变,这些因素包括但不限于吸液溶液中的一种或多种接枝单体、所需接枝程度、接枝单体的反应性和所用溶剂。通常,基于吸液溶液的总重量计,吸收溶液中的单体总浓度的范围是从约0.1重量%至约60重量%、有利地从约1重量%至约35重量%、更有利地从约5重量%至约25重量%。在接枝、洗涤和干燥后,基底的典型总重量增加在约5%至约30%的范围内,在约10%至约25%的范围内,或在约12%至约20%的范围内。
紫外光源可以是光强较低的光源,诸如黑光,其通常可提供280至400纳米波长范围内10mW/cm2或更小的强度(按美国国家标准技术协会批准的程序测量,例如用电子仪器与技术公司(Electronic Instrumentation&Technology,Inc.)(维吉尼亚州斯特灵(Sterling,VA))制造的UVIMAPTMUM 365L-S辐射计测量),以及光强较高的光源,诸如中压汞灯,其通常提供大于10mW/cm2(优选15和450mW/cm2之间)的强度。当紫外线辐射用于使组合物全部或部分聚合时,优选为中等光强和较长的暴露时间。例如,可以成功使用约10至50mW/cm2的光强和约1至5秒的暴露时间。另选地,可以使用最高至约30分钟的暴露时间。优选的紫外光源是得自昆腾公司(Quantum Technologies)(加利福尼亚州尔湾(Irvine,CA))的Quant 48TM紫外线固化***。
接枝步骤之后,可使接枝基底经受任选的洗涤/漂洗步骤,其中将官能化基底在漂洗室中洗涤或漂洗一次或多次以从官能化基底中除去任何未反应的单体、溶剂或其它反应副产物。通常,使用水漂洗、盐水漂洗,以及任选地醇漂洗、水漂洗和醇漂洗的组合和/或溶剂漂洗(例如丙酮、MEK等)对官能化基底洗涤或漂洗最多四遍。当使用醇漂洗时,漂洗液可以包含一种或多种醇,这些醇包括但不限于异丙醇、甲醇、乙醇、或实际可用的任何其它醇以及用于任何残余单体的有效溶剂。在每一个漂洗步骤中,官能化基底都可以经过漂洗浴或漂洗喷雾。
在任选的干燥步骤中,干燥官能化基底以从官能化基底除去任何漂洗溶剂。通常,官能化基底在具有较低的烘箱温度的烘箱中干燥所需的一段时间(本文称为“烘箱停留时间”)。烘箱温度通常在约30℃至约120℃的范围内,而烘箱停留时间通常在约120至约600秒的范围内。任何常规烘箱都可以用于该任选的干燥步骤。合适的烘箱包括但不限于对流烘箱和再循环空气烘箱。
在制造官能化基底的上述方法中,任何以上提及的多孔基础基底、接枝单体以及反应物可用于形成给定的官能化基底。多孔基础基底经常为多孔膜(诸如微孔膜)、非织造幅材或多孔纤维的形式。在一些实施例中,多孔基础基底包括通过溶剂诱导的相分离(SIPS)方法形成的微孔膜。
在一个实施例中,这些方法提供一种制品,该制品具有共价接枝到其表面上的配体官能化的涂层,该配体官能化的涂层包含一种或多种配体单体、一种或多种亲水单体以及一种或多种任选的“其它单体”的紫外线聚合反应产物,自由基聚合产物是由基底表面上的接枝的光引发剂单体单元引发的自由基聚合的结果。
这种制备配体官能化基底的方法改变了多孔基础基底的最初性质,因为这些接枝的和紫外线聚合的物质包括配体基团。该方法使得能够形成配体官能化的基底,这些基底具有多孔基础基底的许多优点(例如,机械和热稳定性、多孔性),还对生物分子诸如酶、蛋白质、碳水化合物、脂质、核酸、宿主细胞蛋白质、内毒素和微生物具有增强的亲和力,这来源于用于形成给定的官能化基底的单体和步骤。
具有配体官能化的聚合物涂层的多孔基底特别适合作为过滤介质用于选择性结合和移除靶标生物物质,包括来源于生物样品的蛋白质、细胞、细胞碎片、微生物、核酸和/或病毒。如本文所述,本发明还提供了通过使样品与配体聚合物官能化的基底接触从生物样品中除去靶标生物物质的方法。如本文所用的,“靶标生物物质”可以包括所关注的污染物或物质。
对于生物样品或包含生物来源物质(生物物质)的其它流体样品的纯化来说,配体官能化基底是有用的。生物物质包括但不限于细胞、细胞碎片、蛋白质、核酸、内毒素和病毒。
在一些实施例中,从流体中除去的生物物质是纯化的目标。诸如,重组的蛋白质或酶可在细胞培养物中制备或通过发酵制备,并且作为纯化过程中的第一步骤,可使用基底来捕集蛋白质或酶。又如,作为浓缩、计数和/或辨识微生物的过程中的第一步骤,可使用基底来从流体中捕集微生物。
在其它实施例中,从流体中除去的生物物质是必须在针对流体的其它处理步骤之前除去的污染物。
显著地,这些配体官能化基底中的一些在高盐浓度或高离子强度的条件下是有用的,即,它们是“盐耐受的”。含胍或双胍的配体由于它们在这些高离子强度条件下保持离子相互作用的能力而为尤其优选的。
基底可为任何形式,诸如粒子、纤维、薄膜或薄片。合适的粒子包括但不限于有机粒子、无机粒子以及多孔的和无孔的粒子。优选基础基底为多孔的。合适的多孔基础基底包括但不限于多孔粒子、多孔膜、多孔非织造幅材和多孔纤维。
基底可由任何合适的热塑性聚合物材料形成。合适的聚合物材料包括但不限于聚烯烃、聚(异戊二烯)、聚(丁二烯)、氟化聚合物、氯化聚合物、聚酰胺、聚酰亚胺、聚醚、聚(醚砜)、聚(砜)、聚(乙酸乙烯酯)、聚酯诸如聚(乳酸)、乙酸乙烯酯的共聚物,诸如聚(乙烯)-共-聚(乙烯醇)、聚(磷腈)、聚(乙烯基酯)、聚(乙烯基醚)、聚(乙烯醇)以及聚(碳酸酯)。
在一些实施例中,热塑性聚合物可被表面处理(诸如通过等离子体放电)以将合适的官能度提供给基底表面。表面处理提供可通过涂层或任选的底漆溶液改善润湿的官能团,例如羟基。一种这样的可用等离子体处理在U.S.7,125,603(David等人)中描述。
合适的聚烯烃包括(但不限于):聚(乙烯)、聚(丙烯)、聚(1-丁烯)、乙烯和丙烯的共聚物、α烯烃共聚物(诸如乙烯或丙烯与1-丁烯、1-己烯、1-辛烯、和1-癸烯的共聚物)、聚(乙烯-co-1-丁烯)以及聚(乙烯-co-1-丁烯-co-1-己烯)。
合适的氟化聚合物包括(但不限于)聚(氟乙烯)、聚(偏二氟乙烯)、偏二氟乙烯的共聚物(诸如聚(偏二氟乙烯-co-六氟丙烯))和三氟氯乙烯的共聚物(诸如聚(乙烯-co-三氟氯乙烯))。
合适的聚酰胺包括但不限于聚(亚氨基己二酰亚氨基六亚甲基)、聚(亚氨基己二酰亚氨基十亚甲基)以及聚己内酰胺。合适的聚酰亚胺包括但不限于聚(苯均四酸二酰亚胺)。
合适的聚(醚砜)包括(但不限于)聚(二苯醚砜)和聚(二苯基砜-co-二苯并呋喃砜)(poly(diphenylsulfone-co-diphenylene oxide sulfone))。
合适的乙酸乙烯酯的共聚物包括(但不限于)聚(乙烯-co-乙酸乙烯酯)以及其中乙酸酯基团中的至少一些已被水解以提供各种聚(乙烯醇)的此类共聚物。
基底可以为任何形式,诸如薄膜或薄片。优选基础基底为多孔的。合适的多孔基础基底包括但不限于多孔膜、多孔织造和非织造幅材和多孔纤维。
优选的基底为多孔基底,其为微孔膜,诸如溶剂诱导的相分离(SIPS)膜。在该实施例中,多孔基础基底包含尼龙微孔薄膜或薄片,诸如在U.S.专利6,056,529(Meyering等人)、6,267,916(Meyering等人)、6,413,070(Meyering等人)、6,776,940(Meyering等人)、3,876,738(Marinacchio等人)、3,928,517、4,707,265(Knight等人)和5,458,782(Hou等人)中描述的那些。
在另一个实施例中,多孔基底为热致相分离(TIPS)膜。常通过形成热塑性材料和具有超出该热塑性材料的熔点的第二材料的溶液来制备这些膜。在冷却时,所述热塑性材料结晶并且与第二材料实现相分离。结晶材料通常为拉伸的。第二材料可选地在拉伸之前或之后被除去。微孔膜进一步公开于U.S.4,529,256(Shipman)、U.S.4,726,989(Mrozinski)、U.S.4,867,881(Kinzer)、U.S.5,120,594(Mrozinski)、U.S.5,260,360(Mrozinski)和U.S.5,962,544(Waller,Jr.)中。一些示例性的TIPS膜包括聚(偏二氟乙烯)(PVDF)、聚烯烃如聚乙烯或聚丙烯、含乙烯基的聚合物或共聚物如乙烯-乙烯醇共聚物,以及含丁二烯的聚合物或共聚物,和含丙烯酸酯的聚合物或共聚物。对于一些应用,包含PVDF的TIPS膜尤其可取。包含PVDF的TIPS膜进一步描述于U.S.7,338,692(Smith等人)。
在许多实施例中,基础基底具有通常大于约0.2微米的平均孔径以使体积排阻分离最小化、使扩散限制最小化以及使基于靶标分子结合的表面积和分离最大化。一般来讲,当用于结合生物物质时,孔径在0.1至10微米的范围内,优选0.5至3微米,最优选0.8至2微米。结合其它靶标分子的效率可导致不同的最佳范围。
在其它实施例中,多孔基础基底是非织造幅材,其可包括由任何通常已知的制造非织造幅材的工艺制造的非织造幅材。如本文所用,术语“非织造幅材”是指这样的织物,该织物具有以毡状方式随机和/或单向***的单纤维或细丝的结构。
诸如,可通过湿法成网技术、梳理成网技术、气纺技术、射流喷网技术、纺粘技术或熔喷技术或它们的组合制备该纤维非织造幅材。纺丝成网纤维通常为小直径纤维,它们是通过从喷丝头的多个细小的、通常为圆形的毛细管将熔融的热塑性聚合物以细丝形式挤出而形成的,其中挤出的纤维的直径迅速减小。熔喷纤维通常通过多个细小的通常圆形的模塑毛细管将熔融的热塑性材料以熔融的线或细丝挤出到高速的通常被加热的气体(诸如空气)气流中而形成的,该气流使熔融的热塑性材料的细丝细化以减小它们的直径。此后,熔喷纤维由高速气流运送并沉积在收集面上,以形成随机分散的熔喷纤维幅材。非织造幅材中的任何一者均可由单一类型的纤维或在热塑性聚合物的类型和/或厚度方面不同的两种或更多种纤维制成。
关于本发明的非织造幅材的制备方法的更多细节可见于Wente,SuperfineThermoplastic Fibers,48INDUS.Eng.Chem.1342(1956)或Wente等人,Manufacture OfSuperfine Organic Fibers,(Naval Research Laboratories Report No.4364,1954)中。
如果需要,可通过使用多个堆叠的配体官能化多孔膜作为过滤元件来改善结合和捕集的效率。因此本发明提供一种过滤元件,该过滤元件包括一层或多层多孔配体官能化基底。各个层可以相同或不同,并且可具有不同孔隙度和上述接枝单体的接枝度的层。过滤元件还可包括上游预过滤层和下游支承层。根据需要,各个过滤元件可以是平面的或折叠的。
合适的预过滤器和支承层材料的实例包括聚丙烯、聚酯、聚酰胺、树脂粘合的或无粘合剂的纤维(诸如玻璃纤维)以及其它合成材料(织造或非织造羊毛结构)的任何合适的多孔膜;烧结的材料,诸如聚烯烃、金属和陶瓷;纱线;专用滤纸(诸如纤维、纤维素、聚烯烃和粘合剂的混合物);聚合物膜;等。
在另一个实施例中,提供一种滤筒,该滤筒包括上述过滤元件。在另一个实施例中,提供一种过滤组件,该过滤组件包括过滤元件和过滤壳体。在另一个实施例中,本发明涉及生物物质捕集方法,该方法包括以下步骤:
a)提供过滤元件,该过滤元件包括一层或多层本发明的配体官能化基础基底,以及
b)使含有靶标生物物质的移动生物溶液喷射到过滤元件的上游表面上足够的时间,以实现靶标物质的结合。
上文描述了本公开,下面以举例的方式进一步说明本发明,这些实例不应当以任何方式被解释为对本发明的范围的强制限制。相反,应当清楚地理解,可以采用多种其它实施例、修改形式及其等同物。在阅读了本说明书之后,在不脱离本发明的实质和/或所附的权利要求书的范围的情况下,这些实施例、修改形式及其等同物对本领域内的技术人员将是显而易见的。
实例
测试方法
用于官能化基底的静态BSA容量方法
通过在测试分析物溶液中振动一个基底盘过夜来分析官能化基底的静态结合容量。通过从基底薄片模冲切24-mm直径的盘来制作该盘。将每个盘放置在5mL离心管中,该离心管具有4.5mL的BSA(牛血清白蛋白)测试用溶液(目录#A-7906;西格玛奥德里奇公司(Sigma Aldrich);密苏里州圣路易斯(St.Louis MO)),该测试用溶液在25毫摩尔每升的TRIS(三(羟甲基)甲胺)缓冲液(pH 8.0)中浓度为约3.0mg/ml。将管封端,并且在旋转混合器上翻转过夜(通常为14小时)。使用UV-VIS光度计在279nm下分析上清液溶液(采用325nm下应用的背景校正)。通过与起始的BSA溶液的吸收进行比较而确定每个基底的静态结合容量,并将结果以mg/mL记录为三次重复测量的平均值。
用于官能化基底的动态BSA容量方法
通过使测试分析物溶液流过6层基底叠堆来分析官能化基底的蛋白质动态结合。通过从基底薄片模冲切25-mm直径的盘来制作该叠堆并且将该叠堆放置在附接到AKTA色谱***(通用医疗(GE Healthcare),纽约州(NY))的25mm直径的夹持器中。在包含50毫摩尔每升NaCl的25毫摩尔每升TRIS缓冲液(pH8.0)中以1mg/ml的浓度制备BSA。以1mL/min的流速将BSA测试用溶液泵送通过基底叠堆,随后在280nm的波长处监控流出物的紫外吸光度。使用标准色谱技术评估基底的动态结合容量,并且在10%穿透处以mg/mL记录。
用于官能化基底的静态IgG容量方法
通过在测试分析物溶液中摇动一个基底盘过夜来分析官能化基底的静态结合容量。通过从基底薄片模冲切24-mm直径的盘来制作该盘。将每个盘放置在具有4.5mL的IgG测试用溶液(艾美杰科技有限公司(Equitech Bio),德克萨斯州克尔维尔(Equitech Bio,Kerrville,TX))的5mL离心管中,该测试用溶液在具有40mM NaCl的50mM乙酸盐缓冲液(pH4.5)中浓度为约4.0mg/mL。将管封端,并且在旋转混合器上翻转过夜(通常为14小时)。使用UV-VIS光度计在280nm下分析上清液溶液(采用325nm下应用的背景校正)。通过与起始的IgG溶液的吸收进行比较而确定每个基底的静态结合容量,并将结果以mg/mL记录为三次重复测量的平均值。
材料
DMA–二甲基丙烯酰胺,威斯康星州密尔沃基的西格玛奥德里奇公司(Sigma-Aldrich,Milwaukee,WI)
VDM–乙烯基二甲基吖内酯,新泽西州普林斯顿的SNPE公司(SNPE,Inc,Princeton,NJ)
VAZPIA–光引发剂单体,VDM和Irgacure 2959(瑞士巴泽尔的汽巴公司(CIBA,Basil,Switzerland))的加合物,如US 5,506,279的实例1所述那样制备
甲苯,宾夕法尼亚州西切斯特的VWR公司(VWR,West Chester,PA)
VAZO 67,威斯康星州密尔沃基的西格玛奥德里奇公司
乙二胺,威斯康星州密尔沃基的西格玛奥德里奇公司
IEM-AGM–甲基丙烯酸异氰酸基乙酯和硫酸胍丁胺的加合物,经NMR测定标称90%纯,如共同未决的U.S.13/353413的实例99所述那样制备。
MBA–亚甲基双丙烯酰胺,威斯康星州密尔沃基的西格玛奥德里奇公司
异丙醇,宾夕法尼亚州西切斯特的VWR公司
IPA/DI水–异丙醇与水的体积比为1:1
PEG-MA–PEG(400)单甲基丙烯酸酯,宾夕法尼亚州瓦里顿市的聚合科学有限公司(Polysciences,Inc.,Warrington,PA)
尼龙66膜–(单增强层尼龙三区膜,标称孔径1.8μm,#080ZN,来自康涅狄格州梅里登的3M纯化公司(3M Purification,Inc.,Meridan,CT)
DAAm–双丙酮丙烯酰胺,马萨诸塞州沃德希尔的阿法埃莎公司(Alfa Aesar,WardHill,MA)
AG–硫酸氨基胍,马萨诸塞州沃德希尔的阿法埃莎公司
MAPTAC-[3-(甲基丙烯酰氨基)丙基]-三甲基氯化铵,50重量%水性溶液,威斯康星州密尔沃基的西格玛奥德里奇公司
PEI–聚氮丙啶,MW 70,000,30重量%水性溶液,Cat#00618,宾夕法尼亚州瓦里顿市的聚合科学有限公司(Polysciences,Inc.,Warrington,PA)
BUDGE–丁二醇二缩水甘油醚,威斯康星州密尔沃基的西格玛奥德里奇公司
DADMAC–二烯丙基二甲基氯化铵,威斯康星州密尔沃基的西格玛奥德里奇公司
AMPS-Na–2-丙烯酰胺基-2-甲基-2-丙烷磺酸的钠盐,来自俄亥俄州威克利夫的路博润公司(Lubrizol,Wickliffe,OH)
实例1–5:可交联聚合物光引发剂的制备
通过在16盎司玻璃瓶中以表1所示的量将DMA、VDM、VAZPIA与甲苯(120克)和VAZO67(2克)混合来制备可交联聚合物光引发剂组合物。各混合物用缓慢氮气流吹扫15分钟,并且将瓶密封并在水浴中翻转且平衡至60℃保持24小时,以使单体转换为聚合物。通过添加异丙醇(200克)将所得聚合物溶液稀释至20%。IR和1H-NMR分析证实,实例1的聚合物形成为聚(DMA/VDM/VAZPIA,比率为78:20:2w/w)。
表1.
实例6-10:涂底漆膜
对于实例6-10,分别通过将乙二胺(25.7微升)在异丙醇(102克)中的溶液与实例1-5的各聚合物溶液(5克)混合来制备底漆溶液。通过将尼龙66膜(约10cm×10cm)浸渍到底漆溶液中并且用#14绕线涂布棒除去过量溶液来制备涂底漆膜。使涂底漆膜在环境温度下风干至少15分钟。
实例11–18:接枝膜
通过将IEM-AGM(13.33克)和MBA(0.12克)溶解在IPA/DI水的溶液(46.55克)中来制备20%固体w/w接枝溶液。将此溶液(17.81克)与PEG-MA(1.43克)和IPA/DI水(5.76克)混合以提供14.25%固体涂料溶液。将实例6或9的涂底漆膜放置在聚酯薄膜薄片上。将约4.5mL的接枝溶液移取到膜的顶表面上,并使之浸泡2分钟。将第二个聚酯薄膜薄片放置在膜的顶部并且使用#14绕线涂布棒除去过量的接枝溶液。使用黑光紫外线源对夹心的两侧持续表2所示的时间进行辐照。然后将各个接枝的膜放置在500mL聚乙烯瓶中,用去离子水填充这些瓶并且摇动30分钟以洗掉残余单体或未接枝的聚合物。用50毫摩尔每升乙酸钠(pH 4.5)代替水并且洗涤30分钟,随后用去离子水再洗涤30分钟。将膜从瓶中取出并且使之干燥。实例11-15用14.25%涂料溶液接枝,而实例16–18用20%固体溶液接枝。辐照时间、涂底漆聚合物以及静态BSA结合容量在表2中列出。
表2.
实例19-23
如实例11-18所述,在IPA/DI水中制备含MBA的IEM-AGMA的20%固体溶液。通过将不同量的此溶液与PEG(400)MA和IPA/DI水混合来制备涂料溶液,如表3所示。将来自实例6的涂底漆膜如实例11-15所述进行涂布并且通过每侧暴露于紫外线辐射15分钟来接枝。如上所述洗涤接枝膜、干燥并且评估静态和动态BSA结合容量两者,结果在表3中示出。
表3.
实例24-28
如实例19-23那样制备膜,不同的是接枝溶液在IEM-AGM溶液中不包含MBA。BSA容量在表4中示出。
表4.
实例29-36
如实例11-18所述制备涂料溶液,不同的是使用DAAm、MBA和IPA/去离子水组合物以及实例6和9的涂布的涂底漆膜,如表5所示。如上所述,将膜的每侧暴露于紫外线辐射15分钟。将接枝膜放置在500mL聚乙烯瓶中。将通过将AG(49.2克)溶解在去离子水(100mL)中并添加0.2mL浓盐酸制备的2.0摩尔氨基胍(AG)溶液添加到每个瓶中。使膜与AG溶液反应3小时,然后倒掉过量的溶液。用去离子水填充瓶,并且摇动30分钟以洗掉残余单体或未接枝的聚合物。用50毫摩尔每升乙酸钠(pH 4.5)代替水并且洗涤30分钟,接着用去离子水再洗涤30分钟,然后使其干燥。静态BSA容量在表5中列出。
表5.
实例37–39
通过将MAPTAC溶解在去离子水中来制备涂料溶液以在表6所示实例中所制备的涂底漆膜上产生%固体接枝溶液。将这些溶液涂布到涂底漆膜上并且每侧暴露于紫外线辐射15分钟以便将MAPTAC接枝到膜上。将接枝膜放置在500mL聚乙烯瓶中,用去离子水填充这些瓶并且摇动30分钟以洗掉残余单体或未接枝的聚合物。用50毫摩尔每升乙酸钠(pH 4.5)代替水并且洗涤30分钟。取代乙酸钠,用去离子水再洗涤30分钟,然后使其干燥。涂底漆膜、涂料溶液的%固体以及静态BSA容量在表6中示出。
表6.MAPTAC接枝膜的静态BSA容量(mg/mL)
实例43–44
将PEI用异丙醇稀释至1.0%固体。将50克部分此溶液与足够的BUDGE一起配制以便与PEI聚合物的5%胺基团反应。如实例6-10所述由尼龙66膜制备涂底漆膜。然后将涂底漆膜浸入实例5的进一步用异丙醇稀释至1%的聚合物溶液中,使其浸泡5分钟,然后取出并用新的异丙醇漂洗并使其风干。如实例37所述,将这些膜用5%和10%的MAPTAC的溶液涂布、接枝、洗涤并干燥。静态BSA容量在表7中列出。
表7.MAPTAC接枝膜的静态BSA容量(mg/mL)
实例45–47
如实例43所述用PEI制备涂底漆膜,不同的是将它们浸入聚合物4在异丙醇中的1%固体溶液,使其浸泡5分钟,取出并用新的异丙醇漂洗,并使其干燥。如实例37所述,将这些膜用MAPTAC溶液涂布、接枝、洗涤并干燥。BSA容量在表8中列出。
表8.MAPTAC接枝膜的静态BSA容量(mg/mL)
实例48–53
将如实例10所述制备的涂底漆尼龙膜(约10cm×10cm)用DADMAC在去离子水中的水性溶液(添加或未添加MBA(基于DADMAC的量为1重量%))涂布,如表9所示。如实例37中所述,对涂布膜进行接枝、洗涤和干燥。静态BSA容量在表9中列出。
表9.DADMAC接枝膜的BSA静态容量(mg/mL)
实例54
如实例37所述,将如实例10所述制备的涂底漆尼龙膜用AMPS-Na在去离子水中的15%固体水性溶液涂布、接枝、洗涤并干燥。测试该膜对IgG的静态结合容量,并且发现具有102mg/mL的容量。
Claims (16)
1.一种用于制备配体官能化基底的方法,包括:
a)提供基础基底;
b)提供包含具有光引发剂基团的单体单元、具有可交联的官能团的单体单元、亲水单体单元、以及任选地“其它”单体单元的共聚物的涂料溶液;
c)用所述涂料溶液涂布所述基础基底,从而提供具有涂层的基底;
d)使所述涂层交联以产生交联的共聚物;
e)用包含以下物质的溶液或悬浮液使具有所述交联的共聚物的所述基底吸液:(a)一种或多种配体官能单体、(b)任选地一种或多种亲水单体;以及任选地c)一种或多种“其它”单体;
f)将所吸液的基础基底暴露于紫外线辐射以便由所述共聚物的所述光引发剂基团生成自由基;以及
g)将步骤e)所述单体的烯键式不饱和的可自由基聚合的基团接枝聚合到所述基础基底的表面上。
2.根据权利要求1所述的方法,其中所述共聚物的所述亲水单体单元包含聚丙烯酰基单体单元、聚甲基丙烯酰基单体单元、聚亚烷基氧丙烯酰基单体单元、聚亚烷基氧甲基丙烯酰基单体单元、丙烯酰胺单体单元、甲基丙烯酰胺单体单元、乙烯基酰胺单体单元、羟烷基丙烯酰基单体单元以及羟烷基甲基丙烯酰基单体单元中的一种或多种。
3.根据权利要求1所述的方法,其中具有可交联的官能团的所述单体单元具有式:
其中
X1为-O-或-NR1-,
R1为H或C1-C4烷基;
R2为单键或烃基或杂烃基连接基团;
A为与交联化合物反应或为自交联的反应性官能团;并且
x为0或1。
4.根据权利要求3所述的方法,其中A为胺反应性官能团并选自羧基、唑啉基、吖内酯基、乙酰基、丙酮基、乙酰乙酰基、酯基、异氰酸基、环氧基、氮丙啶基、酰卤基和环酐基团。
5.根据权利要求1所述的方法,其中具有可交联的官能团的所述单体单元为可自交联的并选自烯基硅烷单体单元、丙烯酰基硅烷单体单元、甲基丙烯酰基硅烷单体单元、羟甲基丙烯酰胺单体单元、羟甲基甲基丙烯酰胺单体单元、烷氧基甲基丙烯酰胺单体单元、和烷氧基甲基甲基丙烯酰胺单体单元。
6.根据权利要求4所述的方法,其中所述涂料溶液还包含胺官能交联化合物。
7.根据权利要求6所述的方法,其中所述胺官能交联化合物具有式:
(HNR1)r-R4-(FG)q,
其中R1为H或C1-C4烷基,
R4为杂烃基或烃基基团;
FG为这样的官能团:a)对所述共聚物的所述官能团为反应性的,或b)自交联的,并且下标r和q为至少一。
8.根据权利要求7所述的方法,其中FG为-NHR1,其中R1为H或C1-C4烷基。
9.根据权利要求8所述的方法,其中所述交联化合物为具有下式的聚胺:
R4(NHR1)m,
R4为杂亚烷基或亚烷基基团;
R1为H或C1-C4烷基,并且至少一个R1为H,并且m为至少二。
10.根据权利要求1所述的方法,其中所述配体官能单体具有式:
Z1-Y2-X1-CO-CR1=CH2,或
Z1-Y2-CR1=CH2
其中X1为-O-或-NR1-,
R1为H或C1-C4烷基,
Y2为选自单键或杂烃基或烃基二价基团的连接基团;
Z1为通过离子相互作用、共价相互作用、疏水相互作用、以及生物亲和力相互作用结合生物物质的配体官能团。
11.根据权利要求1所述的方法,其中所述配体官能单体具有式:
其中
R1为H或C1-C4烷基;
R2为杂烃基或烃基基团;
各R3独立地为H或C1-C4烷基;
R4为H、C1-C12烷基或-N(R3)2;
R7为H或烃基;
X1为-O-或-NR3-,
e为0或1,并且
d为1或2。
12.根据权利要求1所述的方法,其中所述共聚物在交联之前具有式:
-(MPI)k-(M亲水)l-(MFG)m-(M其它)i-,其中
(MPI)k为具有“k”个聚合的单体单元的光引发剂官能单体单元,其中k为至少一,
(M亲水)l为具有“l”个聚合的单体单元的亲水单体单元,
(MFG)m为具有可交联的官能团且具有“m”个聚合的单体单元的单体单元,
(M其它)i为具有“i”个聚合的单体单元的其它单体单元,其中“i”可为零,
其中:
k为0.5重量%至25重量%的所述单体单元;
l为35重量%至97.5重量%的所述单体单元;
m为2重量%-40重量%的所述单体单元;
i为0重量%-20重量%的所述单体单元,
基于100重量%的总单体计。
13.根据权利要求6所述的方法,其中所述胺官能交联化合物的胺基团与所述共聚物的所述反应性官能团之间的化学计量为0.1:1至1:1。
14.一种配体官能基底,包含以下物质的自由基反应产物:
a)基底,所述基底在其上具有交联的共聚物涂层,所述共聚物包含光引发剂官能单体单元、亲水单体单元以及可交联的单体单元;以及
b)包含配体官能单体单元的单体混合物。
15.一种配体官能化基底,其由下式表示:
其中
(MPI*)f表示具有“f”个聚合的单体单元的MPI*单体单元的残基,其中f为至少一,其中MPI*是具有光引发剂基团的单体单元;
(M交联)g表示衍生自随后交联的MFG单体单元且具有“g”个聚合的单体单元的单体单元,其中g为至少一并且MFG为具有可交联的官能团的单体单元;
(M亲水)h表示具有“h”个聚合的单体单元的亲水单体单元,其中h可为零;
[M配体]j表示具有“j”个聚合的单体单元的配体单体单元,其中“j”为至少1;
(M其它)i表示其它单体单元,所述其它单体单元是甲基丙烯酰基单体单元或丙烯酰基单体单元,其中“i”可为零。
16.一种从生物样品中选择性结合并除去生物物质的方法,包括使生物样品与根据权利要求14所述的配体官能化基底接触的步骤。
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