CN102395357B - 使用聚合的脂蛋白体的纳米结构的膜 - Google Patents
使用聚合的脂蛋白体的纳米结构的膜 Download PDFInfo
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- CN102395357B CN102395357B CN201080006576.9A CN201080006576A CN102395357B CN 102395357 B CN102395357 B CN 102395357B CN 201080006576 A CN201080006576 A CN 201080006576A CN 102395357 B CN102395357 B CN 102395357B
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- proteoliposome
- liposome
- protein
- polymerization
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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- A61K47/38—Cellulose; Derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F1/00—Treatment of water, waste water, or sewage
- C02F1/44—Treatment of water, waste water, or sewage by dialysis, osmosis or reverse osmosis
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Abstract
本发明一般性地涉及纳米结构的膜，其包含聚合的脂蛋白体。纳米结构的膜是一种生物-纳米融合的选择性膜，其中使用整合了蛋白质的uv可交联脂质体，该脂质体带有化学反应性的生物相容性间质基质。在本发明中，使用内部UV交联的整合了蛋白质的脂蛋白体，原因是由天然的脂质制成的脂蛋白体寿命短，对环境应力例如高和低的温度、压力、离子强度等的抵抗力弱。此外，由于聚合物不可避免的聚合差异化，由两亲性嵌段共聚物制成的蛋白质囊泡在批次间实现正确的功能中表现出较差的一致性。
Description
背景技术
本发明是一种纳米结构的膜，其包含聚合的脂蛋白体。在本发明的一个实施方式中，该膜是一种整合了蛋白质(protein-incorporated)的水选择性膜。
在美国专利6,878,278提供的传统反渗透膜中，在采用与多官能(multifunctional)胺单体和多官能(polumultifunctional)酰卤单体的Schotten-Baumann反应的多孔膜上有聚酰胺表面。但是，一些化学物质，例如均苯三甲酰氯(trimesoyl chloride,TMC)会破坏蛋白质的功能，原因是这些该化学物质具有非常高的水解性。这意味着难于，如果不是不可能的话，将整合了蛋白质的聚合脂质体原位整合到聚酰胺基质上，这对填充脂蛋白体的外部空间是必要的。
发明概述
本发明一般性地涉及纳米结构的膜(nanofabricated membrane)，其包含聚合的脂蛋白体。纳米结构的膜是一种生物-纳米融合的选择性膜，其使用整合了蛋白质的uv可交联脂质体，该脂质体带有化学反应性的生物相容性间隙基质(interstitial matrix)。在本发明中，使用内部UV交联的整合了蛋白质的脂蛋白体，原因是由天然的脂质制成的脂蛋白体寿命短，并且对环境应力，例如高和低的温度、压力、离子强度等的抵抗力弱。此外，由于聚合物不可避免的聚合差异性(polydiversity)，由两亲性嵌段共聚物制成的蛋白质囊泡(proteo-vesicle)在批次间实现正确的功能中表现出更小的一致性。
与两亲性三嵌段共聚物相比，合成的和UV介导的可聚合脂质体在疏水性区域有UV可交联的化学结构和更高的牢固性(consistency)以制造脂蛋白体。另外，聚合的脂蛋白体对物理性应力具有强的机械抗性。此外，脂质单体的亲水性区域的化学结构可以被修饰以与间隙基质连接或者通过各种导入的共价键修饰载体或者基底膜的表面。
在本发明的一个实施方式中，本发明设法完成以下内容：1)将脂质整合到传统的聚酰胺表面和2)生物相容性的聚酰胺基质，其用于利用同基双官能(homobifuntional)聚乙二醇(PEG)交联剂或者胺树枝状高分子(amine-dendrimers)的原位(in situ)脂蛋白体整合，3)将脂质整合到胺基修饰的纤维素纳米膜、混合纤维素酯纳米膜、玻璃表面，以及胺修饰的硅或者任何合适的可以被胺基修饰的材料中。
在本发明的一个实施方案中，所整合的蛋白质是蛋白质中水通道蛋白家族(Aquaporin family)的成员。但是，应当理解本发明不限于仅仅蛋白质的这个家族。所得到的膜具有通过水通道蛋白介导的水选择性转运的水通道以及在生物相容地重建的间隙基质中的聚合脂蛋白体中的空洞。由于水通道蛋白的功能，该膜能够显示高度的水选择性、透水性以及低的能量需求。
附图说明
本发明的特征和优点将从下列的优选实施方式的详细说明，及结合随后的附图的详细说明变得清楚，其中：
图1表示脂质体壁的放大图，其中UV可交联的官能团存在于脂质单体的疏水性部分；
图2表示按照本发明的一个实施方式的通过UV曝光重建聚合的脂蛋白体的方法；
图3表示按照本发明的一个实施方式的囊泡之间的化学交联；
图4表示按照本发明的一个实施方式的含胺的磷脂(例如乙醇胺磷脂)，其带有用于MCE(混合纤维素酯)和尼龙基底膜上的薄聚酰胺层的表面修饰的亲水性部分(头部基团)；
图5表示按照本发明的一个实施方式的、整合了脂质的基底膜与基底膜顶部的共价键基质上的聚合脂蛋白体连接；
图6表示用uv可交联的胺-PEG水凝胶、生物相容的间隙基质原位包埋聚合的脂蛋白体，其中：(a)在深度可调节的模中提供基底膜；(b)将聚合的脂蛋白体和uv可交联的PEG溶液上到(dope)基底膜上，如果需要的话可以在胺-PEG和磷酸化脂质之间进行EDC介导的交联；(c)UV固化以使膜硬化；(d)使所制得的膜从模中分离和(e)根据本发明的一个实施方式的、原位包埋膜的横截面示意图。基底膜将被胺基或者丙烯酸活化以诱导与脂质体和水凝胶的交联。原位包埋膜采用墨喷印刷技术。
图7表示一种没有基底膜的脱盐过滤器的制造，利用：(a)被聚合脂蛋白体包覆的线(thread)，用于织造方法，和(b)聚合脂蛋白体之间的抗水纤维结构，采用非织造方法。
发明内容
为了得到本发明的纳米结构的膜，首先通过将蛋白质(6)整合到UV可交联的脂质体(1)中来形成聚合的脂蛋白体。UV可交联的脂质体(1)是用模拟天然脂质结构的材料合成的。如图1所示，UV可交联的脂质体(1)(例如l-棕榈酰基-2-(10Z,12Z-二十三碳二炔酰基(tricosdiynoyl))-sn-丙三氧基(glycero)-3-胆碱磷酸、1-棕榈酰基-2-(10Z,12Z-二十三碳二炔酰基)-sn-丙三氧基-3-磷酸乙醇胺、l,2-双(10Z,12Z-二十三碳二炔酰基)-sn-丙三氧基-3-胆碱磷酸、1-2-(10Z,12Z-二十三碳二炔酰基)-sn-丙三氧基-3-磷酸乙醇胺)在疏水性区域(3)中具有UV可交联的化学结构(2)；10,12-二十五碳二炔酸(PCDA)和它的亲水性部分的功能性衍生物(荧光联乙炔单体)。可以理解地，UV可交联的化学结构可以包括在一个或两个疏水性尾部(5)中。UV可交联的脂质体也包含亲水性区域(4)。在一个实施方式中，UV可交联的化学结构(2)可以包含联乙炔用于内部交联。但是，本发明不限于该特定的UV可交联的化学结构(2)，本领域技术人员可以不偏离本发明的范围而选择其他的UV可交联的化学结构(2)。图1表示具有l-棕榈酰基2-(10Z,12Z-二十三碳二炔酰基)-sn-丙三氧基-3-磷酸乙醇胺(DiynePE)的示意结构作为疏水性区域(3)的本发明的一个实施方式。这种内部的UV交联提供对物理性应力具有强的机械抗性的脂质体。在UV可交联的脂质体形成之后，用已知的技术将蛋白质(6)整合到脂质体壁中。在本发明的一个实施方式中，用水通道蛋白作为被整合的蛋白质(6)。但是，可以理解的是本领域技术人员知道可以将其他的蛋白质(6)整合到UV可交联的脂质体(1)中。一旦蛋白质(6)被整合到UV可交联的脂质体(1)中，用UV曝光将脂蛋白体聚合以形成聚合的脂蛋白体(7)。图2表示UV交联前的脂蛋白体(7)。在将脂蛋白体暴露于UV辐射之后，通过脂质体(1)的疏水性部分(3)中的UV可交联的官能团(2)形成聚合的脂蛋白体(8)。
如图3所示，聚合的脂蛋白体(8)的头部基团或者亲水性区域(4)被化学修饰以通过外部交联增加脂蛋白体之间或者脂蛋白体与间隙基质之间的连接性(connectivity)。合成的脂质的亲水性区域(4)可以包含各种多官能的胺、羧酸酯和磷酸酯。头部基团可以用异基官能性(hetero functional)交联剂修饰，例如，N-羟基琥珀酰亚胺酯(NHS酯)-生物素或者亚氨酸酯-生物素能被用于生物素化。修饰是通过使用各种类型的化学共轭物(conjugate)(11)的共价交联进行的，所述化学共轭物(11)包括但不限于光敏性交联剂(photoreactive crosslinkers)、零长度交联剂(zero-length crosslinkers)、同基双官能交联剂(homobifunctionalcrosslinkers)、异基双官能交联剂(heterobifunctional crosslinkers)、三官能交联剂(trifunctional crosslinkers)、树枝状高分子(dendrimers)及其他已知的化学共轭方法。用于酰胺键的零长度交联中，可以使用碳化二亚胺类。在本发明的一个实施方式中，用EDC(1-乙基-3-(3-二甲基氨基丙基)碳化二亚胺盐酸盐作为交联剂。但是，在不脱离本发明范围的条件下也可以使用其他的碳化二亚胺类。2,2’(亚乙基二氧基)二(乙基胺)的胺基通过EDC活化可以用于脂蛋白体的羧酸酯或者磷酸酯基团的共价交联。聚合的脂蛋白体对溶剂及其他反应有很强的抵抗力。所以，聚合的脂蛋白体本身能在可聚合的脂蛋白体和聚酰胺薄层之间用作优良的连接剂(linker)，同样地可以用在肌球蛋白和肌动蛋白纤丝之间的结构中。图4表示包含用于MCE(混合纤维素酯)和尼龙基底膜(12)上的薄聚酰胺层的表面修饰的亲水部分(4)的胺磷脂(例如乙醇胺磷脂)。为了在聚酰胺薄层中植入脂质体(1)，可以使用含胺的天然脂质和UV可交联的脂质。使用一种或多种胺源来形成聚酰胺基质，该聚酰胺基质包含面向基质的疏水性部分(3)。图5表示UV曝光之前的脂蛋白体(7)和最终的UV交联的聚合脂蛋白体(8)，其包括脂质体(1)的内部和外部交联(9)和脂质体修饰的聚酰胺基质(12)。
为了将聚合的脂蛋白体(8)包封到基质中，脂蛋白体(7)与基质同时整合到基底膜(12)上。这个过程在这里被称作“原位整合(in situ incorporation)”。图6表示水凝胶-脂蛋白体的制造方法。该方法包括以下步骤：(a)在深度可调节的模(14)中提供基底膜(13)；(b)将聚合的脂蛋白体(8)和uv可交联的PEG溶液(15)上到基底膜(13)上，如果需要的话，可以在胺-PEG和磷酸化脂质之间进行EDC介导的交联，并且用-NHS-丙烯酸活化的聚合脂蛋白体可用于连接uv可交联的PEG；(c)UV固化以使膜硬化；和(d)使所制得的膜从模中分离。图6(e)表示根据本发明的一个实施方式的、原位包埋的膜的横截面示意图。
为了聚合的脂蛋白体技术的进一步应用，可以形成如图7所示的被聚合的脂蛋白体包覆的水解尼龙线。水解尼龙线(16)在其表面上包含用于与聚合的脂蛋白体共价交联的羧基和胺基。图7表示没有基底膜的脱盐过滤器的制造，利用：(a)被聚合脂蛋白体包覆的线(16)，用于织造方法(17)；和(b)聚合的脂蛋白体之间的抗水纤维结构，采用非织造方法，例如将它们暴露在UV交联光下。
在本发明的另一个方面中，包含被整合到脂质体壁中的水通道蛋白家族的蛋白质的聚合脂蛋白体可形成膜，包括织造结构和非织造结构，条件是得到仅通过水的稳定的膜，因此通过透析促进水的净化、脱盐和分子浓缩。水通道蛋白切断所有污染物的通路，包括细菌、病毒、矿物质、蛋白质、DNA、盐类、洗涤剂、溶解的气体，甚至包括水溶液中的质子；但是由于它们的结构，水通道蛋白分子能转运水。由于液压或者渗透压，水以特定的方向穿过膜。水的净化/脱盐作用可以通过在中心被刚性膜隔开的双室装置实现，该膜用水通道蛋白充满。膜本身是不透水的，并在室中将污水从净化水中分离。仅纯水能在双室之间流动。因此，当在膜一侧的海水或者其他的污水被施加适当的压力时，纯水自然地流入另一个室中。因此，可以从不能饮用的水源中获得净化水，或者，如果水源含有感兴趣的化学物质，水可以被选择性地除去，在输入室中留下高浓度的想要的化学物质。
但是，重要的是，水通道蛋白由于它们对水专有的选择性以外的原因也适用于本发明。蛋白质家族的许多成员(例如AquaporinZ(AqpZ))是极其粗糙(rugged)的，可以经得起污染水源的苛刻条件而不丧失功能。AqpZ抵制因暴露在酸、电压、洗涤剂和加热下引起的变性或者拆分(unraveling)。所以，本装置可用于纯化被可能污染或者破坏另外的膜的材料污染的水源，并且它可被用于一直经历高温的地区。AqpZ也是易变的。因为这种蛋白质是在宿主细菌中根据影响它的最终形态与功能的遗传序列而特定地表达的，技术人员可以容易地改变它的遗传密码以改变蛋白质的特征。所以，这种蛋白质可以被设计以满足所需的应用，该应用可以不同于蛋白质的原始功能。例如，通过简单地将临近水通道中心的特定氨基酸残基变成半胱氨酸，所生产的水通道蛋白会结合溶液中的任何游离汞并由于堵塞而停止转运水。因此，当有毒物质的浓度升得过高时，膜装置中使用的这些突变蛋白质可以通过简单地停止流动来检测水样中的汞污染。
因此，已经公开了利用生物组分以实现从污染的、含盐的或其他污水中高效地生产完全纯的水的方法和装置。本发明论证了水转运生物蛋白质和外部装置的一体化，并指出能大规模生产水净化装置的制造途径的方向。
题目为“Biomimetic membranes”的美国专利7,208,089的内容在本文中特别地引用作为参考。题目为“Biomimetic Polymer Membrane that Prevents IonLeakage”的国际专利申请PCT/US08/74163在本文中特别地引用作为参考。题目为“Making Functional Protein-Incorporated Polymersomes”的国际专利申请PCT/US08/74165在本文中特别地引用作为参考。题目为“Protein Self-ProducingArtificial Cell”的美国临时申请61/055,207在本文中特别地引用作为参考。
实施例
以下是本发明的一个实施方式的实施例。可以理解的是该实施例可以在不脱离本发明的范围的条件下进行各种修改。
1.聚合的脂蛋白体
将在疏水性区域具有UV交联的化学基团(例如，聚乙炔)的UV活性可聚合的脂质(例如，16:0-23:2 Diyne PC-Avanti cat#790146或者23:2 Diyne PC-Avaanticat#870016或者10-12-二十五碳二炔酸，聚联乙炔等)以5mg/ml的浓度溶于氯仿或者叔丁醇中。可以用2种方法生产膜：
a.将溶解的脂质溶液转移到完全干燥的玻璃真空瓶中。为了在玻璃器具内部形成膜，将溶液轻轻地摇动的同时在重气体(氩或者氮气)喷射下干燥。为了完全地除去溶剂，干燥的膜被净化4小时或以上。
b.将装在圆底烧瓶中的叔丁醇中溶解脂质的溶液装在旋转蒸发仪上，并在～40℃到70℃下减压除去溶剂。将膜干燥约60分钟或者更久以达到完全干燥的效果。膜可以立即使用或者储存在-80℃的惰性气氛中。
随后，将缓冲液-水通道蛋白混合物(缓冲液所需的浓度(100mM MOPS-Na，pH 7.5或者20mM PBS pH 7.5)洗涤剂(辛基葡糖苷，triton X-100，十二烷基麦芽糖苷等)和蛋白质)加入到形成有膜的玻璃器具中。
连续地，将带有膜的混合物在重气体的喷射下超声处理直到溶液变成透明。然后，将溶液用分析缓冲液(50mM MOPS-Na，150mM N-甲基-D-葡糖胺，1mM叠氮化钠，pH 7.5或者20mM PBS缓冲液，pH 7.5)透析2天，至少换3次新鲜的缓冲液。透析之后，将透析过的溶液用分析缓冲液稀释两次，并用0.22um的一次性针筒式过滤器过滤。在UV聚合之前，用截流光散射(stop flow lightscattering,SFLS)测定整合了水通道蛋白的脂蛋白体的功能。一直到这个步骤，整个过程应在暗室中完成。为了计算脂蛋白体的通透性，动态光散射(DLS)对测量该脂质体的大小是必需的。
为制造聚合的脂蛋白体，脂蛋白体在波长254nm的UV下曝光10分钟进行聚合。
2.修饰脂质单体的头部基团以通过外部交联增加脂蛋白体之间或者脂蛋白体和间隙基质之间的连接性。
为建立共价化学交联，使用各种类型的化学共轭物，例如光敏性交联剂、零长度交联剂、同基双官能交联剂、异基双官能交联、三官能交联剂、四官能交联剂、树枝状高分子等。在光敏性交联剂中，有丙烯酸衍生物和丙烯基叠氮化物衍生物，例如NHS-丙烯酸和NHS-ASA(NHS-4-叠氮基水杨酸)，和双-[β-(4-叠氮基水杨酰氨基)乙基]二硫化物(BASED)。在用于酰胺键的零长度交联剂中，有碳化二亚胺类，例如EDC(1-乙基-3-(3-二甲基氨基丙基)碳化二亚胺盐酸盐、含磺基-NHS(N-羟基磺基琥珀亚胺)的EDC、CMS(l-环己基-3-(2-吗啉代乙基)碳化二亚胺)、DCC(二环己基碳化二亚胺)、DIC(二异丙基碳化二亚胺)、Woodward's试剂K(N-乙基-3-苯基异唑-3-磺酸盐)、CDI(N,N’-羰基二咪唑)。在传统的蛋白共轭方法中，EDC是一种用于制造肽键(酰胺键)的生物相容的介质。对于这个反应，对于通过被EDC活化的羧酸酯基团或者磷酸酯基团的共价交联(肽键)，胺基是必需的。在同基官能性交联剂中，有同基官能性NHS酯；二硫代双(琥珀酰亚氨基丙酸酯)(DSP)、3,3’-二硫代双(磺基琥珀酰亚氨基丙酸酯)(DTSSP)、双琥珀酰亚氨基辛二酸酯(DSS)、二(磺基琥珀酰亚氨基)辛二酸酯(BS3)、双琥珀酰亚氨基酒石酸酯(DST)、双磺基琥珀酰亚氨基酒石酸酯(磺基-DST)、二[2-(琥珀酰亚氨基氧基羰氧基)乙基]砜BSOCOES、二[2-(磺基琥珀酰亚氨基氧基羰氧基)乙基]砜(磺基-BSOCOES)、乙二醇双(琥珀酰亚氨基丁二酸酯)(EGS)、乙二醇双(磺基琥珀酰亚氨基丁二酸酯)(磺基-EGS)、双琥珀酰亚氨基葡糖酸酯(DSG)、N,N’-双琥珀酰亚氨基碳酸酯(DSC)、和双NHS(PEG)n。以及同基官能性亚氨酸酯，例如二亚胺代己二酸二甲酯(DMA)、二亚胺代庚二酸二甲酯(DMP)、二亚胺代辛二酸二甲酯(DMS)、二亚胺代3,3-二硫基丙二酸二甲酯(DTBP)。在异基官能性交联剂中，有NHS-肼moiet(SANH)、NHS-adldyde moiet(SFB)等。在三官能交联剂中，有4-叠氮基-2-硝基苯基生物胞素-4-硝基苯基酯(ABNP)、磺基琥珀酰亚氨基-2–[6-(生物素氨基(biotinamido))-2-(对-叠氮基苯甲酰氨基)己酰氨基]乙基-1,39-二硫代丙酸酯(dithopropinate)(磺基SBED)。
在四官能性交联剂中，有抗生物素蛋白、链霉抗生物素和中性抗生物素(neutravidin)，其可以与4个生物素反应。
各种多官能的胺类、生物素类、羧酸酯和磷酸酯可以加入到合成脂质的亲水性区域。另外，光敏性交联剂例如丙烯酸类、联乙炔、甲基丙烯酸被用于通过在聚合的脂蛋白体或者间隙基质之间的交联诱导膜硬化。
3.将脂质整合到聚酰胺基质中
聚合的脂蛋白体对溶解溶剂及其他反应有很强的抵抗力。所以，确定UV可交联的脂质(或者脂质体，在下文中仅以脂质为例)本身能被用作可聚合的脂蛋白体和聚酰胺薄层之间的优良的连接剂(linker)，同样地可以用在肌球蛋白和肌动蛋白纤丝之间的结构中。为了将UV可交联的脂质植入聚酰胺薄层中，我们使用包含乙醇胺的天然脂质和UV可交联的脂质。乙醇胺基团用作另一个胺源以形成聚酰胺基质，预期疏水性的部分在该基质上面朝上。为了实施该方法，将MCE(混合纤维素酯)和尼龙多孔膜(也可以使用其他的膜例如durapore和isopore膜)浸渍在脂质溶剂溶液中。随后，蒸发溶剂并在二胺类化学物质例如间苯二胺或者任何其他的多官能胺中温育。除去并干燥过量胺源之后，用多官能酰卤例如均苯三甲酰氯(TMC)(或者任何其他的可以形成酰胺键的酰基衍生物)处理，该多官能酰卤溶解在非极性有机溶剂例如己烷中。反应在几秒钟之后结束，在去离子水中完全冲洗掉过量的TMC。预期到如图4所示的结构。水滴接触角观测表明，正如对脂质体的亲水性部分所预期的那样，疏水性提高。此反应后，我们断定包含脂质的基质的疏水性增加。这意味着亲水性区域如所预期地面朝向。
4.原位整合到生物相容的基质例如包含PEG的水凝胶或者胺树枝状高分子中
对于间隙基质中的聚合脂蛋白体的原位整合，一些生物相容的材料是必需的。聚乙二醇(PEG)和胺树枝状高分子是这一目的的优良候选物。
聚乙二醇(PEG)由于它的水溶性和生物相容性已经被用来共轭生物分子。PEG是一种显示出低聚合差异性的聚合物，其有能力整合活性基团，例如UV可交联的试剂、金属螯合剂、荧光剂、配体等。另外，PEG可以带有羧酸基团以能引起与胺基团的EDC介导的生物相容性交联反应。PEG聚合物能通过连接甲基丙烯酸UV可交联的化学物质形成水凝胶。在以前的研究中这种PEG水凝胶方法被用于脂质平面膜的硬化。在这个实施例中，使用羧酸化的或者连有胺的PEG水凝胶作为聚合的脂蛋白体之间的纳米级别的交联间隔物。
另外，包含纤维素的支撑膜可以被3-氨基丙基三乙氧基硅烷(APTES)活化，APTES可以提供伯胺官能团用于与各种类型的胺介导交联剂进行原位交联。此外，UV交联基团与它一起使用。图6表示水凝胶-脂蛋白体的制造过程。聚合的脂蛋白体溶液和UV可交联的PEG水凝胶溶液是水基溶液。将溶液混合在一起并上到在深度可调节的模中的基底膜上。用UV固化之后，形成一种非常结实和硬的膜。
树枝状高分子通常用作通过1,2-乙二胺(EDA)和丙烯酸甲酯(emthylacrylate)预构建得到的多价生物共轭支架(scaffold)。树枝状高分子的尺寸可以通过化学合成阶段在纳米水平上调节，为G-0(1.4nm，3个胺表面基团)～G-4(4.4nm，48个胺表面基团)。那些树枝状高分子具有多官能胺附着结构，能通过EDC介导的酰胺键形成来交联UV可交联的脂质体的亲水性区域(头部基团)中的磷酸酯或者羧酸酯基团而用作生物相容的间隙基质。
此外，另一个利用聚-L-赖氨酸的对蛋白无毒的方法可以用于通过EDC介导的反应与胺基团形成酰胺键，其中所述聚-L-赖氨酸是一种含SMCC的天然的异基双官能性胺。来自两种材料的基质都是已知的生物相容的材料，其可以制造软垫层以固定聚合的脂蛋白体。
5.没有基底膜的反渗透膜的制造
为聚合的脂蛋白体技术的进一步应用，可以生产被聚合的脂蛋白体包覆的水解尼龙线。水解尼龙线在高温(80℃)下在它表面上包含羧基和胺基。上面提到的零长度交联方法也同样，聚合的脂蛋白体可以通过EDC介导的酰胺键形成共价交联到已被活化的线上，如图7(a)所示。或者可以使用被APTES活化并与胺交联剂相互作用过的纤维线。
此外，已有报道采用CO2喷雾非织造纤维样品可以形成高密度聚乙烯(Ind.Eng.Chem.Res.，1997，36(5)，pp 1586-1597)。本发明的聚合的脂蛋白体可以与这些的高密度聚乙烯材料一起使用，原因是该聚合的脂蛋白体对外部环境具有高抵抗力。
虽然本发明已经以优选的实施方式公开，可以理解的是在不偏离本发明范围的条件下可以做许多其他的修饰和变更。
Claims (11)
1.一种包含脂质体(1)的膜，所述脂质体具有被整合到所述脂质体壁中的蛋白质(6)，其中脂质体具有UV可交联的化学结构联乙炔，蛋白质是水通道蛋白，将蛋白质(6)整合到UV可交联的脂质体(1)中来形成聚合的脂蛋白体(8)，修饰脂质单体的头部基团，再将脂质整合到聚酰胺基质中或原位整合到生物相容的基质，且其中在脂蛋白体之间或者脂蛋白体与间隙基质之间存在外部交联，所述外部交联通过聚合的脂蛋白体(8)的头部基团或亲水性区域(4)进行。
2.按照权利要求1的膜，其中所述脂质体(1)包含具有两个疏水性尾部(5)的脂质，且内部UV交联包含在一个或两个疏水性尾部(5)中。
3.按照权利要求1-2中任一项的膜，其中亲水性区域(4)包含各种多官能胺、羧酸酯和/或磷酸酯。
4.按照权利要求1-2中任一项的膜，其中亲水性区域(4)中包含用于零长度交联酰胺键的碳化二亚胺类。
5.按照权利要求1-2中任一项的膜，其中用EDC(1-乙基-3-(3-二甲基氨基丙基)碳化二亚胺盐酸盐和/或胺交联剂作为交联剂。
6.按照权利要求1-2中任一项的膜，其包含基底膜(12)。
7.按照权利要求6的膜，其中所述基底膜(12)是混合纤维素酯、纤维素膜和/或尼龙基底膜。
8.按照权利要求7的膜，其中所述基底膜(12)包含薄的聚酰胺层(9)，该薄的聚酰胺层(9)包含带有被修饰的亲水性部分(4)的脂质体(1)。
9.按照权利要求1-2中任一项的膜，其中脂蛋白体(8)包覆在其表面含有羧基或胺基以用于共价交联的水解尼龙线。
10.按照权利要求1-2中任一项的膜，其中蛋白质的水通道蛋白家族的蛋白质(6)被整合到脂质体(1)中，所述膜成为水滤过膜。
11.用聚合的脂蛋白体(8)形成膜的方法，该方法包括以下步骤：
(a)提供被官能团活化的基底膜(13)，其中所述官能团为胺或者羧基；
(b)提供如权利要求1所述的聚合的脂蛋白体(8)和将UV可交联的PEG溶液上到基底膜(13)上，如果需要的话，然后进行EDC介导的交联和/或胺-PEG与磷酸化脂质之间的直接交联，
(c)UV固化以使膜硬化；和
(d)使所制得的膜从模中分离。
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| US8505743B2 (en) * | 2009-04-08 | 2013-08-13 | Michigan Molecular Institute | Surface modification of polyamide reverse osmosis membranes |
| KR20170024129A (ko) * | 2009-06-26 | 2017-03-06 | 카톨리에케 유니버시테이트 루벤 | 항균제 |
| US8647853B2 (en) | 2009-12-15 | 2014-02-11 | Ensovi, Llc | Foam microreactor for multi-phase shear-sensitive reactions |
| DK177307B1 (en) * | 2010-12-17 | 2012-11-12 | Aquaporin As | A liquid membrane |
| CN104144737B (zh) * | 2011-09-21 | 2017-03-29 | 南洋理工大学 | 基于水通道蛋白的薄膜复合膜 |
| EP2859938B1 (en) * | 2012-05-31 | 2020-03-25 | LG Chem, Ltd. | Highly permeable carbodiimide comprising reverse osmosis membrane and method for preparing same |
| US20150136690A1 (en) * | 2012-06-01 | 2015-05-21 | National Unibersity of Singapore | Method of making a membrane and a membrane for water filtration |
| KR101949125B1 (ko) * | 2012-07-04 | 2019-02-18 | 고려대학교 산학협력단 | ｐＨ 민감성 형광 발광의 폴리디아세틸렌 리포좀 및 이를 포함하는 약물 전달체 |
| GB201300465D0 (en) | 2013-01-11 | 2013-02-27 | Aquaporin As | A hollow fiber module having tfc-aquaporin modified membranes |
| DK177696B1 (en) * | 2013-02-25 | 2014-03-17 | Aquaporin As | Systems for water extraction |
| DK179128B1 (en) * | 2014-02-24 | 2017-11-20 | Aquaporin As | Systems for utilizing the water content in fluid from a renal replacement therapy process |
| GB201405390D0 (en) | 2014-03-26 | 2014-05-07 | Applied Biomimetic As | Process for making membranes |
| GB201405391D0 (en) | 2014-03-26 | 2014-05-07 | Applied Biomimetic As | Novel polymers and process for making membranes |
| DK3191709T3 (da) | 2014-09-08 | 2023-05-22 | Applied Biomimetic As | Fremgangsmåde til produktion af elektricitet |
| US20190076789A1 (en) * | 2016-02-08 | 2019-03-14 | Aquaporin A/S | Self-assembled nanostructures and separation membranes comprising aquaporin water channels and methods of making and using them |
| GB201605070D0 (en) | 2016-03-24 | 2016-05-11 | Applied Biomimetic As | Power generation process |
| GB201605068D0 (en) | 2016-03-24 | 2016-05-11 | Applied Biomimetic As | Electricity generation process |
| EP3219381A1 (de) * | 2016-03-16 | 2017-09-20 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. | Poröse dünnschichtmembran, verfahren zu ihrer herstellung sowie verwendungsmöglichkeiten |
| WO2018035411A1 (en) * | 2016-08-18 | 2018-02-22 | The Board Of Trustees Of The Leland Stanford Junior University | Production and use of phosphoethanolamine cellulose and derivatives |
| US10842746B1 (en) | 2016-08-25 | 2020-11-24 | Verily Life Sciences Llc | Bi-directionally crosslinked liposomes and method of making same |
| EP3538252A1 (en) * | 2016-11-11 | 2019-09-18 | Aquaporin A/S | Self-assembled polymeric vesicular structures with functional molecules |
| KR102038282B1 (ko) * | 2016-12-29 | 2019-11-26 | 인하대학교 산학협력단 | 다공성 구조체 및 이의 제조방법 |
| CN106928324A (zh) * | 2017-01-20 | 2017-07-07 | 宁波日新恒力科技有限公司 | 一种提高囊泡中水通道蛋白表达活性的方法及反渗透膜 |
| GB201711238D0 (en) | 2017-07-12 | 2017-08-23 | Saltkraft Aps | Power generation process |
| GB201711240D0 (en) | 2017-07-12 | 2017-08-23 | Saltkraft Aps | Power generation process |
| ES2907844T3 (es) * | 2017-10-25 | 2022-04-26 | Aquaporin As | Vesícula que incorpora una proteína transmembrana |
| US20200405857A1 (en) * | 2018-02-19 | 2020-12-31 | Boise State University | Radiation-triggered liposomes |
| WO2019187870A1 (ja) * | 2018-03-29 | 2019-10-03 | 栗田工業株式会社 | 選択性透過膜、その製造方法及び水処理方法 |
| JP6939742B2 (ja) * | 2018-03-29 | 2021-09-22 | 栗田工業株式会社 | 選択性透過膜、その製造方法及び水処理方法 |
| SE544407C2 (en) * | 2019-02-27 | 2022-05-10 | Aquammodate Ab | Stabilized filtration device |
| CN112973467B (zh) * | 2019-12-02 | 2022-12-13 | 欧美新材料(浙江)有限公司 | 一种复合纳滤膜的制备方法及复合纳滤膜 |
| CN111151137B (zh) * | 2020-01-03 | 2022-03-15 | 浙江工业大学 | 一种高通量高截盐反渗透复合膜及其制备方法 |
| WO2023187112A1 (en) * | 2022-03-31 | 2023-10-05 | Illumina Cambridge Limited | Amphiphilic block-co-polymers cross-linked with different cross-linkers consecutively forming a cross-linking hierarchy |
| US20240076322A1 (en) * | 2022-03-31 | 2024-03-07 | Illumina Cambridge Limited | Barriers including cross-linked amphiphilic molecules, and methods of making the same |
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| US4931498A (en) * | 1988-02-25 | 1990-06-05 | Purdue Research Foundation | Immobilized artificial membranes |
| US4927879A (en) | 1988-02-25 | 1990-05-22 | Purdue Research Foundation | Method for solid phase membrane mimetics |
| US5288517A (en) | 1988-08-26 | 1994-02-22 | Canon Kabushiki Kaisha | Method of forming planar membrane |
| JP2632956B2 (ja) * | 1988-08-26 | 1997-07-23 | キヤノン株式会社 | 平面膜の形成方法 |
| JPH06234626A (ja) * | 1993-02-09 | 1994-08-23 | Canon Inc | 重合性プロテオリポソーム |
| JPH0731871A (ja) * | 1993-05-18 | 1995-02-03 | Canon Inc | 膜構造物 |
| EP0902681B1 (en) | 1996-03-01 | 2002-05-22 | The Regents of the University of California | Inhibition of selectin binding |
| WO2001049265A1 (en) | 1999-12-30 | 2001-07-12 | Dana-Farber Cancer Institute, Inc. | Proteoliposomes containing an integral membrane protein having one or more transmembrane domains |
| US6337018B1 (en) | 2000-04-17 | 2002-01-08 | The Dow Chemical Company | Composite membrane and method for making the same |
| WO2004036172A2 (en) * | 2002-05-09 | 2004-04-29 | Dennis Farwell | Bioweapon-detecting fibrous-network products and methods for making same |
| KR100803845B1 (ko) * | 2002-07-29 | 2008-02-14 | 엠티 테크날러지스, 인코포레이션 | 생체유사 막 |
| US20040242770A1 (en) | 2003-04-16 | 2004-12-02 | Feldstein Mikhail M. | Covalent and non-covalent crosslinking of hydrophilic polymers and adhesive compositions prepared therewith |
| CA2428677A1 (en) | 2003-05-15 | 2004-11-15 | Fisenko Anatoliy | A method of induced froth (foam) formation process and natural purification |
| EP1845943A2 (en) * | 2005-01-03 | 2007-10-24 | Ben Gurion University of the Negev Research and Development Autority | Nano- and mesosized particles comprising an inorganic core, process and applications thereof |
| US20060183166A1 (en) | 2005-02-11 | 2006-08-17 | Michael Mayer | Arrays of supported biomembranes and uses thereof |
| EP1885477B1 (en) * | 2005-05-20 | 2010-02-17 | Aquaporin APS | Membrane for filtering of water |
| AT502713B1 (de) | 2005-10-19 | 2008-08-15 | Univ Wien Bodenkultur | Verfahren zur herstellung von lipid-membranen |
| ES2641272T3 (es) | 2006-04-28 | 2017-11-08 | Children's Hospital Medical Center | Composiciones que comprenden proteínas o polipéptidos fusogénicos derivados de la prosaposina para aplicación en sistemas de suministro de fármacos transmembrana |
| WO2008154500A1 (en) * | 2007-06-08 | 2008-12-18 | Northwestern University | Compositions and methods for polymer-caged liposomes |
| DK2344269T3 (da) | 2008-10-07 | 2019-12-02 | Applied Biomimetic As | Biomimetisk membran dannet af tråde med vedhæftede vesikler |
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| AU2010210664B2 (en) | 2013-10-10 |
| EP2393481B1 (en) | 2019-04-17 |
| JP2012516776A (ja) | 2012-07-26 |
| CN102395357A (zh) | 2012-03-28 |
| EP2393481A4 (en) | 2016-12-07 |
| US20120043275A1 (en) | 2012-02-23 |
| IL214395A0 (en) | 2011-09-27 |
| WO2010091078A3 (en) | 2011-07-07 |
| WO2010091078A2 (en) | 2010-08-12 |
| CA2751331A1 (en) | 2010-08-12 |
| DK2393481T3 (da) | 2019-07-15 |
| KR101367437B1 (ko) | 2014-02-26 |
| EP2393481A2 (en) | 2011-12-14 |
| KR20110117696A (ko) | 2011-10-27 |
| US9359230B2 (en) | 2016-06-07 |
| MA33094B1 (fr) | 2012-03-01 |
| IL214395A (en) | 2016-02-29 |
| MX2011008050A (es) | 2011-09-09 |
| JP5654493B2 (ja) | 2015-01-14 |
| SG173165A1 (en) | 2011-08-29 |
| CA2751331C (en) | 2016-04-26 |
| AU2010210664A1 (en) | 2011-08-25 |
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