CN112955183B - 多糖和弹性蛋白-状多肽的生物共轭物及其用途 - Google Patents
多糖和弹性蛋白-状多肽的生物共轭物及其用途 Download PDFInfo
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Abstract
本发明涉及具有至少一个寡糖或多糖嵌段和至少一个弹性蛋白‑状多肽嵌段的嵌段共聚物,其中所述嵌段共聚物包括具有下式(I)的至少一个重复单元:
Description
本发明涉及多糖和弹性蛋白-状多肽的生物共轭物,其制备方法及其用途。
糖化学的最新进展导致了制备直链嵌段共聚物,其中多糖链与或者合成或者天然的第二嵌段结合。当碳水化合物链借助点击-化学与例如通过重组DNA技术获得的预定的肽序列共聚时,可获得高官能度,其中所述技术允许获得具有精确主结构的多肽。
这一方法允许设计具有确定官能度和可能地固有生物活性以及刺激响应的嵌段共聚物,这些性能可以整合在任何一个或两个嵌段中。通过设计,嵌段在水中的溶解度可以强烈地不同和/或对物理化学环境的变化做出应答,从而导致形成分隔的聚集体例如核-壳球形或圆柱形聚集体,或囊泡。
特别地,弹性蛋白-状多肽(ELP)作为温度响应型肽序列最近受到大的关注,这是因为在特定温度(转变温度,Tt)下它们经历从水合线圈到坍塌团聚体的相转变。可通过多肽的长度和主序列来控制与相图中最小温度对应的最低临界溶解温度(LCST),以便可视需要调节在特定浓度下的转变温度。
另外,由于它们具有天然的生物相容性和生物降解性,因此多糖和多肽基嵌段共聚物广泛应用于生物医疗和生物材料领域,用于组织工程或药物传输中。一些多糖识别特定受体(例如,半乳聚糖/半乳凝素,或透明质酸(hyaluronan)/CD44),从而表明对目标共聚物设计的巨大兴趣。
本发明的目的是提供具有温度-诱导的自-组装性能的新型嵌段共聚物。
本发明另一个目的是提供具有可调LCST,且取决于温度能形成纳米颗粒的嵌段共聚物。
本发明另一个目的是提供在高于特定和可调LCST下在水性条件下具有精确生物活性和刺激响应型自-组装性能的材料。
因此,本发明涉及具有至少一个寡糖或多糖嵌段和至少一个弹性蛋白-状多肽嵌段的嵌段共聚物,其中所述嵌段共聚物包括具有下式(I)的至少一个重复单元:
其中R′是除了脯氨酸及其衍生物以外的天然或合成氨基酸的侧链。
根据本发明的嵌段共聚物因此是含多糖(或寡糖)嵌段以及与式(I)的重复单元对应的弹性蛋白-状多肽(ELP)衍生物的共轭物。
ELP是[-Val-Pro-Gly-Xaa-Gly-]五肽的重复序列,客体残基Xaa是最初由弹性蛋白原的疏水区域激发(inspire)的除了脯氨酸以外的任何氨基酸(在根据本发明的式(I)的重复单元内,R′对应于所述Xaa氨基酸的侧链)。
ELP显示出与合成聚合物例如聚(N-异丙基丙烯酰胺)(pNIPAM)类似的最低临界溶解温度(LCST),也称为逆转温度转变(Tt)。ELP链在LCST以下完全可溶于水中,而在LCST以上则转变为不可溶状态。完全可逆的聚集受到不同参数例如在ELP重复部分内Xaa客体残基的性质,ELP的总分子量和摩尔浓度,以及溶液的离子强度影响(Meyer,D.E.;Chilkoti,A.Biomacromolecules 2004,5,846-851;McDaniel,J.R.;Radford,D.C.;Chilkoti,A.Biomacromolecules 2013,14(8),2866-2872)。这一溶解度的转变证明对于从细菌溶解产物中纯化重组ELP,以及对于单独ELP嵌段的受控自-组装来说是主要的优点。
根据本发明,措辞“脯氨酸和衍生物”是指脯氨酸以及任何环状α-氨基酸。
术语“脯氨酸衍生物”设计基于脯氨酸主链的任何非-标准氨基酸,即在α,β,γ或δ碳原子上具有取代基的脯氨酸,例如4-羟基脯氨酸或α-甲基脯氨酸。
优选,Xaa氨基酸是缬氨酸或蛋氨酸。
根据有利的实施方案,本发明的嵌段共聚物包括具有式(I)的至少一个重复单元,其中R′是-CH(CH3)2或-(CH2)2SCH3。
根据一个实施方案,在本发明的嵌段共聚物中,寡糖或多糖嵌段和弹性蛋白-状多肽嵌段通过连接基连接在一起,所述连接基包括通过点击化学可获得的基团Y。
通过点击化学反应如此获得基团Y。这些点击化学反应尤其包括不饱和化合物的环加成,在所述反应当中人们可引证二烯亲和物和二烯烃之间的Diels-Alder反应,和特别地叠氮化物-炔烃的1,3-偶极环加成,和优选铜-催化的叠氮化物-炔烃环加成(CuAAC)。
其他点击化学反应包括牵涉硫醇官能的反应例如由烯烃和混合二硫化物形成硫醚,以及牵涉非-羟醛型亲电羰基的反应,例如由羟胺形成肟膜,由肼形成腙或由硫代半卡巴嗪(thiosemicarbazine)形成缩氨基硫脲。
作为点击化学反应,人们也可引证牵涉硫代羧酸或硫酯导致硫酯和酰胺形成的反应,以及也可引证在叠氮化物和膦之间的反应(例如,Staudinger连接反应)。
优选,通过两个反应性官能团之间的反应而获得基团Y,所述反应选自由下述组成的组:
-叠氮化物和炔烃之间的反应,
-醛或酮和酰肼之间的反应,
-醛或酮和羟胺之间的反应,
-叠氮化物和膦之间的反应,
-烯烃和四嗪之间的反应,
-异腈和四嗪之间的反应,和
-硫醇和烯烃之间的反应(硫醇-烯反应)。
根据一个实施方案,本发明的嵌段共聚物具有下式(II):
其中:
-R是(C1-C6)烷基;
-X是寡糖或多糖;
-X′是(C1-C6)亚烷基,
-Y是选自下述基团中的基团:
R1和R2是H或与携带它们的碳原子一起形成环己基;
R3和R4是H或与携带它们的碳原子一起形成环己基;和
R5是H或烷基;
-i是1至6的整数,
-X1是共价键或者下式的基团:
-X2是共价键或式-(AA)j-的基团,其中j是包括在1至6之间的整数,和AA独立地为天然或合成氨基酸,
X2优选是下式的基团:
-n是1至200的整数,
-R′如上式(I)中定义,且优选独立地为-CH(CH3)2或-(CH2)2SCH3。
根据本发明,措辞“(Ct-Cz)烷基”是指可具有t至z个碳原子的烷基。
在本申请内,术语“烷基”是指直链或支链,饱和或不饱和的烃-基脂族基团,除了另外提及以外,其包括1至6,优选1至4个碳原子。作为实例,可提及甲基,乙基,正丙基,异丙基,丁基,异丁基,叔丁基或戊基。
本文中所使用的术语“亚烷基”(或“烷叉基”)是指含1至6,优选1至4个碳原子的二价基团。当所述基团是直链时,它可用式(CH2)i表示,其中i是从1变化至6的整数。下述亚烷基可以引证作为实例:亚甲基,亚乙基,亚丙基,亚丁基,亚戊基或亚己基。
根据一个实施方案,通过下述获得以上定义的基团Y:
-叠氮化物和炔烃之间的反应,尤其通过铜-催化的叠氮化物和炔烃的Huisgen 1,3-偶极环加成(CuAAc);优选,这一基团具有以上提及的式(A);
-叠氮化物和环辛炔之间的反应,尤其通过张力-促进的无铜叠氮化物-炔烃[3+2]环加成(SPAAc);优选,这一基团具有以上提及的式(B);或
-四嗪和反式环辛炔之间的反应,尤其通过逆转电子需求的Diels-Alder环加成(iEDDA);优选,这一基团具有以上提及的式(C)。
更优选,Y选自三唑基团,和最优选具有式(A)。
根据一个实施方案,本发明的嵌段共聚物具有下式(III):
其中:
-k是1至6的整数,和
-i,n,X,X1,X2,R和R′如上式(II)中定义。
根据一个实施方案,本发明的嵌段共聚物具有下式(III-1):
其中:
-k是1至6的整数,和
-n,X,R和R′如上式(II)中定义。
优选,在本发明的嵌段共聚物中,尤其在式(II),(III)或(III-1)中,X是选自半乳聚糖,糖胺聚糖,纤维素,壳聚糖,岩藻聚糖(fucoidan)及其衍生物中的寡糖或多糖。
更优选,所述寡糖或多糖是透明质酸,昆布六糖(laminarihexaose),葡聚糖或半乳聚糖,和最优选是透明质酸,昆布六糖,或半乳聚糖。
根据一个实施方案,根据本发明的嵌段共聚物具有下式之一:
本发明还涉及以上定义的嵌段共聚物的制备方法,该方法包括使携带寡糖或多糖和官能团G1的化合物(1)与携带至少一个弹性蛋白-状多肽嵌段和官能团G2的化合物(2)反应,其中官能团G1和G2一起反应以便通过点击化学形成连接基。
更优选,本发明涉及以上定义且优选具有式(II)的嵌段共聚物的制备方法,该方法包括使具有式(IV)的化合物与具有式(V)的叠氮化物化合物反应:
其中i,X1,X2和R′如上式(II)中定义,
X,R,和X′如上式(II)中定义。
根据一个优选的实施方案,通过使具有下式(VI)的化合物与具有下式(VII)的化合物反应而获得式(IV)的化合物:
其中X1,X2,和R′如上式(II)中定义,
其中:
-i如上式(II)中定义,和
-R″是离去基团。
在上式(VII)中,R″代表本领域公知的任何离去基团。优选,这一基团选自下述基团:
-衍生于N-羟基琥珀酰亚胺(NHS)的基团,例如下述基团:
-或者衍生于五氟苯酚的基团,例如下述基团:
其他离去基团还包括氯原子或基团-OC(=O)-OAlk,其中Alk代表烷基。
本发明还涉及以上定义的,尤其具有式(II),(III)或(III-1)中之一的嵌段共聚物用于制备颗粒,例如纳米颗粒或微米颗粒的用途。
优选,所述颗粒的平均直径包括在10nm至10μm之间,和更优选50nm至500nm,这通过散射(光,中子)或显微技术(AFM,Cryo-TEM)来测量。
本发明还涉及以上定义的嵌段共聚物的(纳米)颗粒的制备方法,该方法包括在其转变温度以上加热该嵌段共聚物的步骤。
如此获得的颗粒,尤其微米颗粒或纳米颗粒是尤其有利的在于它们可在各种领域中使用,例如用于稳定乳液,而且用于个人护理或者在健康护理中用作纳米载体。它们也可在化妆品领域中使用。
根据一个实施方案,与所述嵌段共聚物的可溶形式相比由以上定义的嵌段共聚物制造的这些纳米颗粒具有增强的凝集素-结合亲合力。
附图
图1和2代表Dex-ELP(125μm)在水中组装的动态光散射分析。(图1)当快速加热时散射强度作为温度的函数。(图2)在各种温度(30℃,40℃,45℃,55℃和60℃)下强度中的尺寸分布。
图3代表当Dex-ELP(125μM)在DLS上在水中反复快速加热(45℃)和冷却(25℃)时Z-均尺寸和多分散性作为时间的函数。图4代表在45℃,90°下,对于在水中的Dex-ELP(125μM)来说,DLS自相关函数(g2(t)-1)和松弛-时间分布(A(q,t))。
图5代表Hex-ELP(125μM)在水中组装的动态光散射分析。(A)当快速加热时散射强度作为温度的函数。(B)在各种温度(30℃,33℃,37℃,42℃,50℃和60℃)下强度中的尺寸分布。
图6代表在(A)35℃或(B)65℃下在云母基底上Dex-ELP(50μM在水中)的液体AFM图像,和在(C)30℃或(D)55℃下在HOPG基底上Hex-ELP(50μM在水中)的液体AFM图像。刻度条表示1μm。
图7,8和9代表对于Hex-ELP来说,在90°,(图7)33℃,(图8)37℃,和(图9)45℃下,DLS自相关函数(g2(t)-1)和松弛-时间分布(A(q,t))。
图10和11代表在HA-ELP(150μM)水中组装的动态光散射分析。(图10)当快速加热时散射强度作为温度的函数。(图11)在各种温度(25℃,35℃,48℃,和60℃)下强度中的尺寸分布。
图12表示代表当HA-ELP(125μM)在DLS上在水中反复快速加热(48℃)和冷却(25℃)时,Z-均尺寸和多分散性作为时间的函数。图13代表在50℃,90°下,对于在水中的HA-ELP(125μM)来说,DLS自相关函数(g2(t)-1)和松弛-时间分布(A(q,t))。
图14代表在(A)25℃,(B)52℃或(C)55℃下,在云母基底上HA-ELP(150μM在水中)的液体AFM图像。刻度条表示1μm。
实施例
材料
丙烯醛(95%),叠氮化钠(NaN3,99.5%),醋酸(AcOH,99.8%),甲氧基胺盐酸盐(98%),氰基硼氢化钠(NaBH3CN,95%),盐酸(HCl,37%),4-戊炔酸(97%),N,N'-二环己基碳二酰亚胺(DCC,99%),N-氰基琥珀酰亚胺(NHS,98%),三甲胺(TEA,99%),五水合硫酸铜(II)(CuSO4,99%),二氯甲烷(DCM,99.9%),N,N-二甲基甲酰胺(DMF,99.8%),二甲亚砜(DMSO,99.7%),甲醇(MeOH,99.8%),二乙醚(99.9%)和无水硫酸镁(MgSO4,99.5%)购自Sigma-Aldrich。N,N-二异丙基乙胺(DIPEA,99%),醋酸钠(AcONa,99%)和抗坏血酸钠(NaAsc,99%)获自Alfa Aesar。甲氧基聚乙二醇(mPEG),三(苄基三唑基甲基)胺(TBTA,97%)和4-甲苯磺酰氯(TsCl,99%)购自TCI。购自Seachem。葡聚糖(Dex,T10)购自pharmacosmos。昆布六糖(Hex)购自Megazyme。透明质酸钠(HA)购自LifecoreBiomedical。使用ELGA PURELAB Classic体系纯化水。使用来自Innovative Technology的PureSolv MD-5溶剂纯化体系纯化溶剂。使用/>透析膜进行透析。
式(V)化合物的制备
叠氮化物连接基的制备
N-(3-叠氮基丙基)-O-甲基羟胺(叠氮化物-连接基)。在圆底烧瓶内将醋酸(4mL)冷却到-20℃并添加丙烯醛(1.84mL,27.4mmol),接着滴加叠氮化钠(2.38g,41.2mmol)在H2O(10.4mL)中的溶液。在-20℃下继续搅拌该混合物1.5h。通过添加饱和碳酸氢钠溶液(饱和NaHCO3水溶液80mL)猝灭它并用DCM(2×100mL)萃取所得混合物。用饱和NaHCO3水溶液(150mL)洗涤合并的有机萃取物,在无水MgSO4上干燥,过滤并真空浓缩到100mL。向在DCM内的溶液中添加甲氧基胺盐酸盐(2.68g,31.68mmol)和醋酸钠(4.42g,54mmol),并在室温下搅拌该混合物过夜。添加饱和NaHCO3水溶液(150mL)猝灭该反应,然后用DCM(2×100mL)萃取所得混合物。用饱和NaHCO3水溶液(150mL)洗涤合并的有机萃取物,在无水MgSO4上干燥,过滤并真空浓缩到100mL。向在DCM内的溶液中添加NaBH3CN(2g,32mmol),接着滴加1M乙醇HCl(32mL,通过添加乙酰氯到乙醇中新鲜制备)。在室温下搅拌所得混合物1.5h。之后通过蒸发器去除溶剂,并将所得白色固体悬浮在饱和NaHCO3水溶液(150mL)中并用DCM(2×100mL)萃取。用饱和NaHCO3水溶液(150mL)洗涤合并的有机萃取物,在无水MgSO4上干燥,过滤并真空浓缩以得到黄色油状物形式的粗N-(3-叠氮基丙基)-O-甲基羟胺。通过硅胶柱色谱法(1-3%MeOH在DCM内)纯化该粗产物,得到无色油状物形式的N-(3-叠氮基丙基)-O-甲基羟胺(叠氮化物-连接基,1.1g,三步产率62%)。
1H NMR(400MHz,CDCl3):δ3.55(s,3H,CH3O),3.41(t,2H,CH2N3),3.00(t,2H,NHCH2),1.83(p,2H,CH2CH2CH2)。
13C NMR(101MHz,CDCl3):δ62.01(CH3O),49.44(CH2N3),48.94(NHCH2),26.87(CH2CH2CH2)。
1.合成葡聚糖-叠氮化物
葡聚糖-叠氮化物(Dex-叠氮化物)。向葡聚糖(MW 8000)(1g,0.125mmol)在醋酸盐缓冲液(AcOH/AcONa,2M,pH 4.6,4.2mL)内的溶液中添加叠氮化物-连接基(380mg,2.9mmol),并在热混合器上在40℃下摇动该反应混合物9天(每天涡流3次)。然后通过用透析袋(MWCO 1000)对着纯水透析24h(每天换水3次)纯化该混合物。通过冻干法获得最终产物(白色粉末,805mg,79%产率)。
1H NMR(400MHz,D2O):δ4.98(d,H-1),4.18(d,CHN(OCH3)CH2),4.04-3.97(m,H-6),3.95-3.89(m,H-5),3.69-3.80(br m,H-6′,H-3),3.61-3.37(br m,H-2,H-4,CH2N3),3.20-3.13(dt,CHN(OCH3)CH2),3.01-2.93(dt,CHN(OCH3)CH2′),1.92-1.88(m,CH2CH2CH2)。
FT-IR(ATR):3368,2906,2106(υ叠氮化物),1351,1148,1164,1007,915,846,763,545,429cm-1。
2.合成昆布六糖-叠氮化物
昆布六糖-叠氮化物(Hex-叠氮化物)。向昆布六糖(500mg,0.5mmol)在醋酸盐缓冲液(AcOH/AcONa,2M,pH 4.6,5mL)内的溶液中添加叠氮化物-连接基(900mg,6.9mmol),并在热混合器上在40℃下摇动该反应混合物8天(每天涡流3次)。然后冻干该混合物并在水5mL中再溶解,通过用透析袋(MWCO 100)对着纯水透析36h(每天换水3次)来纯化。通过冻干法获得最终产物(白色粉末,302mg,54%产率)。
1H NMR(400MHz,D2O):δ4.81(d,H-1),4.23(m,CHN(OCH3)CH2),3.97-3.88(m,H-6),3.86-3.68(br m,H-6′,H-3),3.67-3.33(br m,H-2,H-4,H-5,CH2N3),3.22-3.13(m,CHN(OCH3)CH2′),3.03-2.95(m,CHN(OCH3)CH2),1.91(m,CH2CH2CH2)。
FT-IR(ATR):3434,3151,2890,2100(υ叠氮化物),1568,1403,1308,1159,1072,1022,896,557cm-1。
3.合成透明质酸-叠氮化物
透明质酸-叠氮化物(HA-叠氮化物)。向透明质酸钠(MW 7000)(1g,0.14mmol)在醋酸盐缓冲液(AcOH/AcONa,2M,pH 5.5,5mL)内的溶液中添加叠氮化物-连接基(520mg,4mmol)和氰基硼氢化钠(65mg,1mmol),并在热混合器上在50℃下摇动该反应混合物5天(每天涡流3次)。然后用水5mL稀释该混合物,接着用透析袋(MWCO1000)对着纯水透析24h(每天换水3次)。通过冻干法获得最终产物(白色粉末,610mg,60%产率)。
1H NMR(400MHz,D2O):δ4.56(d,GlcNAc H-1),4.48(d,GlcUA H-1),3.99-3.67(brm,GlcNAc H-6,H-2,H-3,H-5,GlcUA H-4),3.66-3.41(br m,GlcNAc H-4,GlcUA H-3,H-5,CH2N3),3.35(t,GlcUA H-2),2.94-2.86(m,CH2N(OCH3)CH2),2.03(s,GlcNAc COCH3),1.87(m,CH2CH2CH2)。
FT-IR(ATR):3323,2892,2107(υ叠氮化物),1729,1642,1555,1376,1315,1152,1042,610cm-1。
制备式(IV)的化合物
1.合成戊炔酸NHS-酯
戊炔酸NHS-酯。向戊炔酸(210mg,2.14mmol)在DCM(8mL)内的溶液中添加N,N′-二环己基碳二酰亚胺(480mg,2.3mmol)。搅拌所得混合物5min和然后添加N-羟基琥珀酰亚胺(260mg,2.3mmol)。在室温下连续搅拌该反应3h。之后用Celite过滤沉淀的二环己基脲,并用冷DCM(2×10mL)洗涤滤饼。收集滤液,并真空去除DCM。将产物再溶解在EtOAc(10mL)中,并在冰箱内在0℃下冷却20min。再次用Celite过滤掉沉淀物,并用饱和NaHCO3(2×50mL)和盐水(2×50mL)洗涤滤液,在无水MgSO4上干燥,过滤并真空浓缩以得到无色油状物形式的粗产物。通过硅胶柱色谱法(石油醚:EtOAc=2:1)纯化残渣得到白色固体形式的戊炔酸NHS-酯(300mg,72%产率)。
1H NMR(400MHz,CDCl3):δ2.90-2.82(m,6H,COCH2CH2CO,OCOCH2CH2),2.62(ddd,2H,CH2C≡CH),2.05(t,1H,C≡CH)。
13C NMR(101MHz,CDCl3):δ168.89(COCH2CH2CO),167.02(OCOCH2),80.84(CH2C≡CH),70.04(CH2C≡CH),30.31(OCOCH2),25.57(COCH2CH2CO),14.09(CH2C≡CH)。
2.合成炔烃-ELP
炔烃-ELP(Alk-ELP)。向ELP(225mg,13.2μmol)在无水DMSO(18mL)内的溶液中添加戊炔酸NHS-酯(92mg,0.47mmol)和N,N-二异丙基乙胺(1.7mg,13.2μmol)。在室温下搅拌该反应72h。然后用水(20mL)稀释该混合物,并在透析袋(MWCO 15000)内对着纯水透析所得溶液2天(每天换水3次)。通过冻干法获得最终产物(白色粉末,210mg,93%产率)。
1H NMR(400MHz,D2O):δ7.63-7.09(br,吲哚H Trp),4.57(m,CHαMet),4.45(m,CHαVal,Pro),4.19(d,CHαVal Xaa),4.06-3.89(br m,CH2αGly,CH2δPro),3.75(m,CH2’δPro),2.69-2.46(br m,CH2γMet,CH2CH2C≡CH),2.33(m,CH2βPro),2.18-1.91(m,CH2βMet,CH2’βPro CH2γPro,CHβVal,CH3εMet,CH2C≡CH),1.05-0.91(m,CH3γVal)。
MALDI-TOF:理论MW=17115Da,实验[M+H]+=17120.5Da。
制备式(II)的嵌段共聚物
1.合成葡聚糖-b-ELP
葡聚糖-b-ELP(Dex-ELP)。在氩气氛围下将炔烃-ELP(65mg,3.8μmol),葡聚糖-叠氮化物(46mg,5.7μmol),硫酸铜(6mg,22.8μmol),抗坏血酸钠(10mg,45.6μmol)和TBTA(12mg,22.8μmol)溶解在无水DMSO(8mL)中。在室温下搅拌该混合物3天。然后用冷水(20mL)稀释该混合物,并在冰箱中在4℃下冷却20min。将TBTA沉淀并通过离心机去除。添加Cuprisorb(120mg)到上清液中,并在室温下摇动所得溶液过夜,以去除铜。通过离心,去除Cuprisorb,并在透析袋(MWCO 15000)内对着纯水透析该上清液5天(每天换水3次)。通过冻干法获得最终产物(白色粉末,92mg,90%产率)。
1H NMR(400MHz,D2O):δ7.75(s,三唑H),7.63-7.09(br,吲哚HTrp),4.99(d,Dex H-1),4.55(m,CHαMet),4.44(m,CHαVal,Pro),4.17(d,CHαValXaa),4.06-3.87(br m,CH2αGly,CH2δPro,Dex H-6,H-5),3.82-3.67(m,CH2’δPro,Dex H-6’,H-3),3.62-3.49(Dex H-2,H-4),2.69-2.48(br m,CH2γMet),2.31(m,CH2βPro),2.18-1.89(m,CH2βMet,CH2’βPro CH2γPro,CHβVal,CH3εMet),1.03-0.88(m,CH3γVal)。
FT-IR(ATR):3332,2929,1653,1527,1443,1342,1152,1106,1017,917,547cm-1。
2.合成昆布六糖-b-ELP
昆布六糖-b-ELP(Hex-ELP)。在氩气氛围下将炔烃-ELP(62mg,3.6μmol),昆布六糖-叠氮化物(20mg,18.1μmol),硫酸铜(5.5mg,22μmol)和抗坏血酸钠(9mg,45.4μmol)溶解在无水DMSO(8mL)中。在室温下搅拌该反应3天。然后用冷水(20mL)稀释该混合物。添加Cuprisorb(110mg)到该混合物中,并在室温下摇动所得溶液过夜以去除铜。通过离心,去除Cuprisorb,并在透析袋(MWCO 15000)内对着纯水透析该上清液5天(每天换水3次)。通过冻干法获得最终产物(白色粉末,60mg,93%产率)。
1H NMR(400MHz,D2O):δ7.74(s,三唑H),7.60-7.09(br,吲哚HTrp),4.80(m,HexH-1),4.55(m,CHαMet),4.43(m,CHαVal,Pro),4.17(d,CHαValXaa),4.05-3.85(br m,CH2αGly,CH2δPro,Hex H-6),3.82-3.66(m,CH2’δPro,Hex H-6’,H-3),3.62-3.34(Hex H-2,H-4,H-5),2.69-2.48(br m,CH2γMet),2.41-2.24(m,CH2βPro),2.19-1.88(m,CH2βMet,CH2′βProCH2γPro,CHβVal,CH3εMet),1.05-0.85(m,CH3γVal)。
FT-IR(ATR):3322,2917,1654,1522,1440,1221,1105,1063,1027,562cm-1。
3.合成透明质酸-b-ELP
透明质酸-b-ELP(HA-ELP)。通过添加HCl水溶液,首先酸化透明质酸-叠氮化物,以便在DMSO内完全可溶。在氩气氛围下将炔烃-ELP(60mg,3.5μmol),硫酸铜(9mg,36μmol),抗坏血酸钠(18mg,90μmol)和三(苄基三唑基甲基)胺(TBTA,22mg,41μmol)溶解在无水DMSO(4mL)中。添加在无水DMSO(2mL)中完全可溶的透明质酸-叠氮化物(18mg,3.5μmol)溶液。在40℃下搅拌该反应4天。然后用冷水(20mL)稀释该混合物,并在冰箱内在4℃下冷却20min。将TBTA沉淀并通过离心机去除。添加Cuprisorb(180mg)到该上清液中并在室温下摇动所得溶液过夜以去除铜。通过离心去除Cuprisorb并在透析袋(MWCO 15000)内对着纯水透析该上清液5天(每天换水3次)。通过冻干法获得粗产物(白色粉末,53mg)。添加去离子水(5.3mL)并加热该溶液到40℃且保持1h。通过离心机在40℃下去除不可溶的未反应的ELP并冻干该上清液以得到最终产物(白色粉末,42mg,54%产率)。
1H NMR(400MHz,D2O):δ7.75(s,三唑H),7.60-7.09(br,吲哚HTrp),4.62-4.37(br,CHαMet,Val,Pro,GlcUA H-1,GlcNAc H-1),4.17(d,CHαValXaa),4.04-3.66(br,CH2αGly,CH2δPro,CH2’δPro,GlcUA H-4,GlcNAc H-2,H-3,H-5,H-6),3.65-3.42(GlcUA H-3,H-5),3.41-3.30(t,GlcUA H-2),2.69-2.48(br m,CH2γMet),2.41-2.25(m,CH2βPro),2.20-1.89(m,CH2βMet,CH2’βPro CH2γPro,CHβVal,CH3εMet),1.06*0.88(m,CH3γVal)。
FT-IR(ATR):3298,2964,1631,1528,1440,1232,1153,1044,541cm-1。
制备颗粒
温度-诱导的自-组装研究
借助动态光散射(DLS),静态光散射(SLS)和液体原子力显微术(液体AFM)研究多糖-ELP生物共轭物(对应于根据本发明的嵌段共聚物)的温度-诱导的自-组装。
实验方法
动态光散射测量(DLS)
在NanoZS仪器(Malvern,U.K.)上在90°的角度下在恒定位置在小玻璃管(恒定散射体积)内进行动态光散射测量。推导出的计数率(DCR)定义为通过衰减因子归一化的平均散射强度。DCR对温度作图和Tt定义为与其中在这一图表内DCR开始增加的点相对应的温度。
静态光散射(SLS)
使用具有全数字相关器结合Spectra Physics激光器(在λ=632.8nm处发出垂直偏振光)和恒温浴控制器(范围从20至50℃)的ALV/CG6-8F角度计,进行静态光散射测量。采用ALV相关器软件获得数据,在递增10,范围从30°至150°的每一不同的散射角处,计数时间典型地为15秒。由表观扩散系数和Stokes-Einstein方程式,测定水力半径(Rh)。由根据在同一角度处平均散射强度的测量获得的Guinier图表,测定回转半径(Rg)。
温度-控制的液体原子力显微术(液体AFM)
使用Dimension FastScan Bruker AFM体系,进行温度-控制的液体原子力显微测量。在峰值力轻敲模式中,使用具有5nm的典型尖头半径的Silicon悬臂(ScanAsyst-Fluid+,Bruker),获得生物共轭物的形貌图像。悬臂共振为150kHz,和弹簧常数为0.7N/m。基底购自Agar Scientific。通过在直接用于成像的新鲜解离的云母或HOPG表面上下落流延50μM(150μM,对于HA-ELP来说)生物共轭物的水溶液,制备样品。在液体环境中,在特定温度下进行AFM成像过程。利用外部加热段(Bruker),实现在基底表面上的目标温度。
实验结果
Dex-ELP的自-组装研究
一旦在DLS上快速加热猛升温,发现Dex-ELP(125μM,在水中)的转变温度(Tt)在约40℃处,这高于ELP和物理混合物的Tt。诚然,亲水嵌段共轭到ELP上导致Tt的增加。
在比Dex-ELP的Tt低的低温下,采用非常低散射强度(30℃),观察到小的物体和几个聚集体。在转变温度(约40℃)处散射强度锐增,并触发自-组装,形成水力直径(Dh)为约165nm的结构。一旦在45℃以上加热Dex-ELP,则该纳米颗粒的直径显示出很小的变化,其中Dh为约290nm(图1-2)。
通过进行各种加热方法,研究在转变温度以上Dex-ELP组装体的稳定性。全部加热方式在30min内达到约300-330nm的Dh,且在PDI上没有显示出显著差别。DLS冷却猛降温显示出Dex-ELP缓慢的解组装行为。在Dex-ELP溶液上进行反复加热和冷却DLS的测量,以测试温度响应型体系的可逆性(图3-4)。开始时,在45℃下,Dex-ELP快速组装成纳米颗粒并在5min后稳定且平均直径为约250nm。之后,冷却Dex-ELP纳米颗粒到25℃并保持10-15min,以便完全解组装该组装体。在25℃下观察到平均直径低于25nm的小物体和高PDI。再次反复加热和冷却显示出类似行为,这表明这一温度-响应型行为是完全可逆的,这提供控制ELP温度转变的简单方法。
随后,在45℃下,通过SLS分析Dex-ELP组装体,测定回转半径(Rg)和水力半径(Rh)。Rg/Rh之比计算为0.72,从而表明是胶束结构。
进行液体原子力显微术,研究通过在Tt以下/以上ELP的转变形成的纳米结构的形貌。与DLS结果一致的是,在35℃下在Tt以下显示出非常小的物体,且在65℃下在Tt以上观察到平均直径为约280-300nm的球形颗粒(图6)。
Hex-ELP的自-组装研究
由于Hex-ELP的小的亲水部分,发现Hex-ELP的转变温度(Tt)为约33℃,这略高于ELP的Tt。在比Hex-ELP的Tt低的低温下,采用非常低散射强度(30℃)观察到小的物体和几个聚集体。在转变温度(约33℃)下散射强度锐增并触发自-组装,形成水力直径(Dh)为约210nm的结构。Hex-ELP的温度-响应行为是完全可逆的。当在45℃以上加热温度时,纳米颗粒显示出散射强度的很少变化,且显示出Dh具有约400-500nm的直径(图5)。
通过静态光散射,在室温(25℃),Tt(33℃),峰值温度(37℃)和高温(45℃)下进一步分析Hex-ELP组装体。与DLS一致的是,Hex-ELP组装体分别在Tt和45℃下显示出约250nm和500的Dh(图7-9)。在Tt和高温下,Rg和Rh是类似的,从而表明在高温下该组装体相对稳定。与SLS数据类似,对于Hex-ELP聚集体来说,液体AFM显示出大的直径(500-900)(图6)。
表-Hex-ELP(125μM,在水中)的Rg和Rh和Rg/Rh之比的数值
T(℃) | Rg(nm) | Rh(nm) | Rg/Rh |
25 | 36 | 24 | 1.5 |
33 | 100 | 130 | 0.77 |
37 | 140 | 259 | 0.54 |
45 | 128 | 252 | 0.51 |
HA-ELP的自-组装研究
与UV-vis测量类似,发现DLS加热猛升温时HA-ELP的Tt为约45℃。在比HA-ELP的Tt低的低温下,采用非常低散射强度(35℃),观察到小的物体。在转变温度处,散射强度锐增,并触发自-组装,在48-50℃下形成Dh为约300nm的结构(图10-11)。当在55℃以上加热HA-ELP时,纳米颗粒的直径变得不稳定并分成两个尺寸分布,这也通过液体AFM证实(图14C)。
通过在DLS上反复加热和冷却,研究在48℃下HA-ELP组装体的稳定性。这一温度-响应体系也是完全可逆的,以及在每一单独的加热时间上,在48℃下,在20min内HA-ELP显示出相对稳定,且平均直径为约280nm(图12)。在50℃下通过静态光散射进一步分析同样显示出在304nm处的Dh(图13)。Rg/Rh之比计算为0.79,从而表明可能是胶束结构。在同一浓度下,在50℃下,通过液体AFM,观察到平均直径为约220-280nm的纳米颗粒(图14B)。
总之,以上提及的生物共轭物能自-组装成不同尺寸的颗粒。在下表中概述了自-组装特征:
通过控制温度,自-组装工艺是完全可逆的,该方法允许在生物材料,药物传输和受体识别中使用这些多糖-ELP生物共轭物。
Claims (6)
1.一种嵌段共聚物,其具有至少一个寡糖或多糖嵌段和至少一个弹性蛋白-状多肽嵌段,且具有下式(III-1):
其中:
-k是1至6的整数,
-n是1至200的整数,
-R是(C1-C6)烷基,
-X是寡糖或多糖,其中寡糖或多糖是透明质酸、昆布六糖、葡聚糖或半乳聚糖,和
-R′是-CH(CH3)2或-(CH2)2SCH3。
2.根据权利要求1所述的嵌段共聚物,其具有下式之一:
R′是-CH(CH3)2或-(CH2)2SCH3。
3.制备根据权利要求1所述的嵌段共聚物的方法,该方法包括使式(IV)的化合物与式(V)的叠氮化物化合物反应:
其中i是1至6的整数,和R′是-CH(CH3)2或-(CH2)2SCH3,
X1是下式的基团:
X2是下式的基团:
X是寡糖或多糖,其中寡糖或多糖是透明质酸、昆布六糖、葡聚糖或半乳聚糖,
R是(C1-C6)烷基,
和X′是(CH2)k基团,k是1至6的整数。
4.根据权利要求3所述的方法,其中通过使具有下式(VI)的化合物与具有下式(VII)的化合物反应而获得式(IV)的化合物:
其中X1,X2和R′如权利要求3中定义,
其中:
-i是1至6的整数,和
-R″是离去基团。
5.根据权利要求1所述的嵌段共聚物用于制备纳米颗粒的用途。
6.制备根据权利要求1所述的嵌段共聚物的纳米颗粒的方法,该方法包括在所述嵌段共聚物转变温度以上加热嵌段共聚物的步骤。
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EP (2) | EP3628333A1 (zh) |
JP (1) | JP7431834B2 (zh) |
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EP1422242A1 (en) * | 2002-11-22 | 2004-05-26 | Emory University | Plastic and elastic protein copolymers |
JP2004231633A (ja) * | 2002-11-22 | 2004-08-19 | Emory Univ | 可塑性かつ弾性のタンパク質コポリマー |
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WO2007146228A2 (en) * | 2006-06-09 | 2007-12-21 | Abbott Cardiovascular Systems Inc. | Elastin-based copolymers |
JP2012506940A (ja) * | 2008-10-30 | 2012-03-22 | ユニベルシテ ボルドー アン | 多糖−及びポリペプチド−ベースのブロック共重合体、これらの共重合体により構成されるベシクル、及びその使用 |
CN106279439A (zh) * | 2016-08-26 | 2017-01-04 | 易金阳 | 一种含有穿膜肽的寡肽‑1融合蛋白及其制备方法 |
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2018
- 2018-09-25 EP EP18306238.9A patent/EP3628333A1/en active Pending
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2019
- 2019-09-25 US US17/279,653 patent/US12084488B2/en active Active
- 2019-09-25 EP EP19773093.0A patent/EP3856259B1/en active Active
- 2019-09-25 WO PCT/EP2019/075865 patent/WO2020064836A1/en unknown
- 2019-09-25 ES ES19773093T patent/ES2973460T3/es active Active
- 2019-09-25 JP JP2021541316A patent/JP7431834B2/ja active Active
- 2019-09-25 CN CN201980069697.9A patent/CN112955183B/zh active Active
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EP1422242A1 (en) * | 2002-11-22 | 2004-05-26 | Emory University | Plastic and elastic protein copolymers |
JP2004231633A (ja) * | 2002-11-22 | 2004-08-19 | Emory Univ | 可塑性かつ弾性のタンパク質コポリマー |
WO2006001806A2 (en) * | 2004-06-15 | 2006-01-05 | Duke University | Method for non-invasive thermometry using elastin-like polypeptide conjugates |
WO2007146228A2 (en) * | 2006-06-09 | 2007-12-21 | Abbott Cardiovascular Systems Inc. | Elastin-based copolymers |
JP2012506940A (ja) * | 2008-10-30 | 2012-03-22 | ユニベルシテ ボルドー アン | 多糖−及びポリペプチド−ベースのブロック共重合体、これらの共重合体により構成されるベシクル、及びその使用 |
CN106279439A (zh) * | 2016-08-26 | 2017-01-04 | 易金阳 | 一种含有穿膜肽的寡肽‑1融合蛋白及其制备方法 |
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Publication number | Publication date |
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ES2973460T3 (es) | 2024-06-20 |
EP3628333A1 (en) | 2020-04-01 |
JP2022502559A (ja) | 2022-01-11 |
WO2020064836A1 (en) | 2020-04-02 |
EP3856259A1 (en) | 2021-08-04 |
US20210388056A1 (en) | 2021-12-16 |
EP3856259C0 (en) | 2024-02-07 |
CN112955183A (zh) | 2021-06-11 |
EP3856259B1 (en) | 2024-02-07 |
JP7431834B2 (ja) | 2024-02-15 |
US12084488B2 (en) | 2024-09-10 |
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