CN102458367B - 基于多氨基酸的聚(酯酰胺) - Google Patents
基于多氨基酸的聚(酯酰胺) Download PDFInfo
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- CN102458367B CN102458367B CN201080024674.5A CN201080024674A CN102458367B CN 102458367 B CN102458367 B CN 102458367B CN 201080024674 A CN201080024674 A CN 201080024674A CN 102458367 B CN102458367 B CN 102458367B
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Abstract
通过多氨基酸单体制得的可生物降解的饱和及不饱和聚酯酰胺(PEA),以及制备可生物降解的饱和及不饱和PEA的方法。
Description
技术领域
本发明涉及由多氨基酸单体制备得到的可生物降解的饱和及不饱和聚酯酰胺(PEA),以及制备可生物降解的饱和及不饱和PEA的方法。
背景技术
因为其具有生物相容性,生物可降解性以及机械性能,基于氨基酸的可生物降解的PEA已被研究了多年。PEA中存在的酰胺键和酯键使得PEA同时显示出聚酯和聚酰胺的典型性质。典型地,可生物降解的PEA可以通过α-氨基酸,脂肪族二羧酸(或二羧酸二氯化物)和二醇的溶液缩聚反应来合成(参见Guo等人,Synthesis,Characterization,andBiodegradationofCopolymersofUnsaturatedandSaturatedPoly(esteramide)s.JournalofPolymerScience,PartA:PolymerChemistry2007;45(9):1595-1606)。
PEA均聚物通常在PEA骨架主链上不存在官能团,也不以官能团作为侧基。然而,在PEA骨架上存在官能团或将其作为侧基会明显拓展PEA的应用。
例如,官能团将会使其可与多种药物,生物试剂和/或活性试剂相偶联,继而开辟作为功能性生物材料的新途径。在PEA的内部引入官能团也可以为改进PEA的性质提供有效的方法,例如PEA的亲水性、降解速率以及机械强度。
首个报道的功能性PEA的合成是基于共聚物途径。羧酸形式的游离官能团被引入到PEA共聚物的赖氨酸片段。(参见Jokhadze等人,SynthesisandCharacterizationofFunctionalElastomericPoly(esterAmideCo-polymers.JournalofBiomaterialsScience--PolymerEdition2007;18(4):411-438)。
在另一个方法中,碳-碳双键被引入到PEA骨架上从而为通过不饱和二酸或/和二醇将官能团引入到PEA这一方式提供反应位点。这些碳-碳双键的存在还使得可以通过光-胶凝化PEA前体这一方法来制造水凝胶,但是基于饱和二酸或/和二醇的PEA不能用于形成水凝胶(参见Guo等人,Synthesis,Characterization,andBiodegradationofCopolymersofUnsaturatedandSaturatedPoly(esteramide)s.JournalofPolymerScience,PartA:PolymerChemistry2007;45(9):1595-1606)。
本发明涉及一种高效的且经济的制备带有游离的侧基官能团的饱和及不饱和的PEA的方法。
发明简述
本发明涉及带有游离的侧基官能团的可生物降解的PEA的合成和表征。
第一实施例是式I所示的PEA:
其中m约为0.1-0.9;
n约为0.9至0.1;
R3是第一氨基酸的残基;
R4及R6是(C2-C20)亚烃基;以及
R5是具有选自由NH2、COOH和OH组成的组的侧基官能团的第二氨基酸的残基,以及
其中,所述侧基可以可选地被保护,以及
其中,所述PEA的Mn为1至500kg/mol。
第二实施例是制备第一实施例所述PEA的方法,通过将氨基酸二酯盐单体与氨基酸N-羧酸酐单体进行反应以获得反应产物(即衍生物单体),以及将该衍生物单体与硝基酚二酸单体进行反应以获得式I化合物。
第三实施例是式(X)所示的饱和聚合物:
其中m约为0.1-0.9;
n约为0.9至0.1;
R3是具有在肽合成过程中无需保护的取代基的第一氨基酸的残基;
R4及R6选自由下列基团组成的组:(C2-C28)烷氧基;(C2-C28)亚烃基;侧链被选自以下组中的基团取代的(C2-C28)烷氧基:(2-羧乙基)硫,(2-羟乙基)硫,(2氨乙基)硫及(2-氨乙基)硫盐酸盐;或者侧链被选自以下组成中的基团取代的(C2-C28)亚烃基:(2-羧乙基)硫,(2-羟乙基)硫,(2氨乙基)硫及(2-氨乙基)硫盐酸盐;以及
R5是具有选自由NH2、COOH和OH组成的组的侧基的第二氨基酸的残基,
其中,所述侧基可以可选地被保护,以及
其中,所述PEA的Mn为1至500kg/mol。
第四实施例涉及一种制备式(X)聚合物的方法。
第五实施例是一种含有由前四个实施例公开的或制备的PEA的组合物。例如,在该实施例的一个方面,该组合物可以是凝胶。
本发明所述的术语“卤素”是指氯,氟,溴或碘。
烷基,烯基,炔基等,均包含表示直链及支链的基团。
术语“烷基”用在本发明中是指,具有特定数目碳原子的直链和支链的饱和脂肪族烃基。烷基的实例包括,但不限于,甲基,乙基,正丙基,异丙基,正丁基,异丁基,叔丁基,正戊基,以及异戊基。
术语“亚烃基”在此是指,具有两个开放化合价以及特定数目的碳原子的支链或直链的饱和脂肪族烃基。亚烃基的实例包括,但不限于,亚甲基,次乙基,正甲基代乙撑,正次丁基,异次丁基,以及正次戊基。
“烷氧基”是指如上面所定义的烷基中指定数目的碳原子连接氧桥后的基团。烷氧基的实例包括,但不限于,甲氧基,乙氧基,正丙氧基,异丙氧基,正丁氧基,异丁氧基,叔丁氧基,正戊氧基,以及异戊氧基。
本发明所述“烯基”是指在链上任何稳定位点具有一或多个不饱和碳-碳键的直链或支链构型的烃链,比如乙烯基和丙烯基。
本发明所述“炔基”是指在链上任何稳定位点具有一个或多个碳-碳三键的直链或支链构型的烃链,比如乙炔和丙炔。
“芳基”是指苯基,或者具有约9-10个环原子且至少其中一个环是芳香环的单边稠二碳环基团。芳基的实例包括但不限于,苯基和萘基。
本发明所述“氨基酸”是指D或L构型的天然氨基酸残基(如丙氨酸,精氨酸,天冬酰胺,天冬氨酸,半胱氨酰,谷氨酸,谷氨酰胺,甘氨酸,组氨酸,羟赖氨酸,羟脯氨酸,异亮氨酸,亮氨酸,赖氨酸,甲硫氨酸,苯丙氨酸,脯氨酸,丝氨酸,苏氨酸,色氨酸,酪氨酸,以及缬氨酸),以及具有一或多个开放化合价的非天然氨基酸(如磷酸丝氨酸;磷酸苏氨酸;磷酸酪氨酸;羟脯氨酸;γ-羧基谷氨酸;苯甲酰甘氨酸;八氢吲哚-2-羧酸;他汀类;1,2,3,4,-四氢异喹啉-3-羧酸;青霉胺;鸟氨酸;瓜氨酸;α-甲基丙氨酸;对苯甲酰基苯丙氨酸;苯基甘氨酸;炔丙基甘氨酸;甲甘氨酸;以及叔丁基甘氨酸)残基。
术语“氨基酸”也包含具有氨基保护基(如乙酰基,酰基,三氟乙酰基,或苄氧羰基)的天然及非天然氨基酸,以及羧基位点被保护基(如(C1-C6)烷基苯基或苄酯或酰胺)保护的天然及非天然氨基酸。还包括现有技术已知的其他适宜的氨基和羧基保护基。(参见例如,参见Wuts等人,Greene′sProtectiveGroupsinOrganicSynthesis,第4版,2006;L.Stryer,Biochemistry,第3版,W.H.FreemanandCo.:NewYork,1975;J.March,AdvancedOrganicChemistry,Reactions,MechanismsandStructure,第2版,McGrawHill:NewYork,1977;F.CareyandR.Sundberg,AdvancedOrganicChemistry,PartB;ReactionsandSynthesis,第2版,Plenum:NewYork,1977;以及本发明所引用的文献)。
术语“氨基酸”还包括α氨基酸以及β氨基酸。α氨基酸包括单羧基单氨基酸,二羧基单氨基酸,聚氨基酸以及杂环氨基酸。单羧基单氨基酸的实例包括甘氨酸,α-苯基甘氨酸,α-丙氨酸,丝氨酸,缬氨酸,正缬氨酸,β-青霉胺,苏氨酸,半胱氨酸,亮氨酸,异亮氨酸,己氨酸,N-甲基亮氨酸,β-羟基亮氨酸,甲硫氨酸,苯丙氨酸,N-甲基-苯丙氨酸,哌可酸,肌氨酸,硒代半胱氨酸,酪氨酸,3,5-二碘酪氨酸,三碘甲状腺氨酸,以及甲状腺氨酸。
单氨基二羧酸及酰胺的实例包括,天门冬氨酸,β-甲基天门冬氨酸,谷氨酸,天门冬素,α-氨基己二酸,4-氧代-哌可酸,羊毛硫氨酸,以及谷氨酰胺。聚氨基酸的实例包括,鸟氨酸,赖氨酸,6-N-甲基赖氨酸,5-羟赖氨酸,锁链素,精氨酸和胱氨酸。杂环氨基酸的实例包括,脯氨酸,4-羟脯氨酸和组氨酸,以及色氨酸。其他α氨基酸的实例是,γ-羧基谷氨酸和瓜氨酸。β氨基酸包括,例如,β-丙氨酸。
本发明所使用的术语“可生物降解的”是指可被各种酶例如胰岛素、脂肪酶及溶酶体在功能正常的人体、活体(如细菌)和/或水环境中被分解。
本发明所使用的术语“生物材料”是指用于密切接触活组织的合成材料。
本发明所使用的术语“生物活性剂”是指递送至细胞、组织或器官以发挥营养或治疗作用的试剂。包括但不限于,营养素、药物制剂、药品、肽类以及寡核苷酸。
本发明所使用的术语“水凝胶”是指在水中显示溶胀性能并在非溶解状态下可以将大量水保留在结构中的聚合材料。
本发明所使用的术语“可生物降解水凝胶”是指可以被水和/或自然界中发现的酶降解的交联聚合物所形成的水凝胶。
本发明所使用的术语“水凝胶前体”是指可以在介质溶液中进行光交联以生成水凝胶的水溶性聚合物。
本发明所使用的术语“光交联”是指在辐射能作用下可以引起乙烯键断裂并形成交联。
术语“凝胶渗透层析法”(“GPC”)是指用于测定聚合物平均分子量(Mn)以及分子量分布(PDI=Mw/Mn)的分离方法。
本发明所述术语“PEA-COOH”是指具有游离羧基的PEA。
本发明所述术语“PEA-NH2”是指具有游离氨基的PEA。
本发明所述术语“PEA-AANCA-#”是指具有受保护氨基酸的PEA。“#”表示受保护氨基酸在PEA中的比例/量。
本发明所述术语“De-PEA-AANCA-#”是指具有氨基酸单元脱保护后恢复成侧基官能团的PEA。“#”表示氨基酸在PEA中的比例/量。例如,术语“De-PEA-LysNCA-25”是指,具有提供侧基官能团(脱保护后)赖氨酸的PEA,其中m是75且n是25(参见式I化合物)。
本发明所述术语“TosOH”是指对甲苯磺酸单水合物。
本发明所述术语“NEt3”是指三乙胺。
本发明所述术语“EtAc“是指乙酸乙酯。
本发明所述术语“TFA”是指三氟乙酸。
本发明所述术语“DMA”是指N,N-二甲基乙酰胺。
附图简述
图1显示两种单体(a)Phe-6和(b)Z-Lys-Phe-6的1HNMR谱。
图2显示两种单体(a)Phe-6和(b)Z-Lys-Phe-6的13CNMR谱。
图3显示三种代表性PEA(a)PEA-Z-Lys-0,(b)PEA-Z-Lys-25,以及(c)PEA-Lys-NH2-25的FTIR光谱。
图4是三种代表性PEA(a)PEA-Z-Lys-0,(b)PEA-Z-Lys-25,以及(c)PEA-Lys-NH2-25的1HNMR谱。
图5显示三种代表性PEA(a)PEA-Z-Lys-0,(b)PEA-Z-Lys-25,以及(c)PEA-Lys-NH2-25的13CNMR谱。
图6显示PEA薄膜在玻璃盖玻片上的荧光显微镜图像(a)在玻璃盖玻片上的PEA-Lys-05-薄膜,以及(b)PEA-Lys-NH2-05。
图7显示三种代表性PEA(a)PEA-Z-Lys-0,(b)PEA-Z-Lys-25,以及(c)PEA-Lys-NH2-25的DSC迹线。
图8显示各组粘附内皮细胞的显微镜图像:(a)空白对照(未进行任何处理);(b)明胶包被;以及(c)PEA-Lys-NH2-25包被。
图9显示增殖分析的结果(a)空白对照(未进行任何处理);(b)明胶包被;以及(c)PEA-Lys-NH2-25包被。
图10显示PEA中游离氨基的存在降低聚合物链的塑性且提高玻璃转化温度。
发明详述
本发明涉及具有游离的侧基官能团的可生物降解PEA的合成及表征。该PEA通过多氨基酸单体制备得到,并在同样的单体或嵌段中具有至少一个官能团比如-NH2、-OH和-COOH作为另外的氨基酸。
在第一实施例中,PEA具有如下分子式:
其中m约为0.0-1.0,优选0.1-0.9,以及更优选0.25-0.75;
其中n约为1.0-0.0,优选0.9-0.1,以及更优选0.25-0.75;
R3是第一氨基酸的残基;
R4及R6是(C2-C20)亚烃基;以及
R5是具有选自由NH2、COOH和OH组成的组的侧基的第二氨基酸的残基,以及
其中所述侧基可以可选地被保护,以及
其中所述PEA的Mn为1至500kg/mol。
在本发明的一个方面,当n=m时形成PEA均聚物。当0<m<n时形成聚氨基酸PEA的随机共聚物。
对于R3,第一氨基酸的残基是PEA合成后出现在PEA中的氨基酸部分。在该实施例的一个方面,第一氨基酸是任何具有一个游离NH2基和一个游离COOH基的氨基酸。在该实施例的另一方面,第一氨基酸是在PEA合成过程中不需要保护基的氨基酸。
在本发明的一个方面,残基是氨基酸的侧链且氨基酸的α-碳、氨基和羧酸被移除。
在本发明的另一方面,第一氨基酸选自由以下基团组成的组:苯丙氨酸,精氨酸,缬氨酸,亮氨酸,异亮氨酸,正亮氨酸,甘氨酸,丙氨酸,或甲
硫氨酸。残基分别优选自由以下基团组成的组:CH(CH3)2,CH2CH(CH3)2,CH(CH3)CH2CH3,(CH2)3CH3,H,CH3,及(CH2)2SCH3组成的组。
对于R5,第二氨基酸残基是PEA合成后出现在PEA中的第二氨基酸部分。第二氨基酸可以与第一氨基酸相同或不同。
在该实施例的一个方面,第二氨基酸优选自由以下组成的组:苏氨酸,脯氨酸,色氨酸,半胱氨酸,赖氨酸,丝氨酸,天冬氨酸,以及谷氨酸。第二氨基酸优选是向PEA提供选自由NH2、OH及COOH组成的组的侧基官能团的氨基酸。例如,第二氨基酸可以是赖氨酸,丝氨酸,天冬氨酸,以及谷氨酸。
在本发明的一个方面,残基是氨基酸的侧链且氨基酸的α-碳、氨基和羧酸被移除。第二氨基酸残基分别优选为(CH2)4NH2,CH2OH,CH2COOH,以及(CH2)2COOH。赖氨酸提供游离NH2侧基。丝氨酸提供游离OH侧基。天冬氨酸以及谷氨酸提供游离COOH侧基。
第二氨基酸的游离侧基官能团可以可选地被选自以下组的基团保护:甲基,甲酰基,乙烷基,乙酰基,叔丁基,甲氧苯基,苄基,三氟乙酰基,N-羟基琥珀酰亚胺基,叔丁氧羟基,苯甲酰基,4-甲苄基,thioanizyl,硫甲酚基,苯甲氧基甲基,4-硝基苯基,苄氧羰基,2-硝基苄基,2-硝基苯基硫苯基,4-甲苯磺酰,五氟苯基,二苯甲基(Dpm),2-氯苄氧羰基,2,4,5-三氯苯基,2-溴苄氧羰基,9-芴甲氧羰基,三苯甲基,以及2,2,5,7,8-五甲基-色满-6-磺酰(参见Wuts等人,Greene′sProtectiveGroupsinOrganicSynthesis,第4版,2006,其全部内容通过引用方式并入到本申请)。在该实施例的一个方面,保护基是苄氧羰基(Z)保护基。
所制PEA中的保护基被完全脱除以生成具有选自由NH2、COOH以及OH组成的组的游离侧基官能团的PEA。
在该实施例的另一方面,PEA含有来自至少三种不同氨基酸的残基。第三氨基酸残基是PEA合成后出现在PEA中的第三氨基酸部分。第三氨基酸优选是具有至少一个游离NH2基以及至少一个游离COOH基的氨基酸。第三氨基酸的实例包括,丙氨酸,精氨酸,天门冬酰胺,天冬氨酸,半胱氨酸,谷氨酸,谷氨酰胺,甘氨酸,组氨酸,羟赖氨酸,羟脯氨酸,异亮氨酸,亮氨酸,甲硫氨酸,苯丙氨酸,脯氨酸,丝氨酸,苏氨酸,色氨酸,酪氨酸以及缬氨酸。
在本发明的一个方面,残基是氨基酸的侧链且氨基酸的α-碳、氨基和羧酸被移除。另一方面,第三氨基酸残基分别优选自由以下基团组成的组:(CH2)4NH2,CH2OH,CH2COOH,(CH2)2COOH,CH(CH3)2,CH2CH(CH3)2,CH(CH3)CH2CH3,(CH2)3CH3,H,CH3,以及(CH2)2SCH3。第三氨基酸可以向也可以不向PEA提供选自由NH2、OH以及COOH组成的组的侧基官能团。
第三氨基酸以第二m或n单体的形式存在于PEA中。例如,PEA具有包含m1,m2及n1单体的至少三种氨基酸,其中m1和m2单体各自具有不同的氨基酸残基。或者,PEA由m1,n1及n2单体组成,其中n1和n2单体各自具有不同的氨基酸残基。例如,所制PEA包含m1,其中m1的R3是m1的R5是(CH2)4NH2,以及m2的R3是
在聚合物骨架上具有游离侧基的可生物降解PEA被制备得到。该PEA具有至少两个氨基酸残基,在单个单元中所述残基被肽键分隔开来。换而言之,该PEA具有两个不需要借助间隔物或酯基的邻近氨基酸。其中至少一个氨基酸残基提供游离的侧基官能团。游离的侧基官能团的存在使得PEA可与生物或化学活性试剂比如药物以及其他化合物相结合。
在该实施例的另一方面,单体的末端基团可以变化。例如,当亲电单体过量时,末端基团可以是如图所示的对硝基苯基(羧基衍生物):
当亲核单体过量时,末端基团可以是如图所示的氨基:
当单体摩尔比相同时,一个末端基团是对硝基苯基,另一个末端基团是氨基,如图所示:
我们现在转向第二实施例。
第一实施例所述PEA是通过氨基酸二酯盐单体与氨基酸N-羧酸酐单体反应获得反应产物而制得的。氨基酸N-羧酸酐单体可以可选地存在保护基。如果存在的话,该保护基出现在制备全过程中并在式I化合物中保留。反应产物是含有氨基酸N-羧酸酐单体氨基酸残基以及氨基酸二酯盐单体氨基酸残基,以及保护基(如果存在的话)的衍生物单体。该制备方法与下述方法一致:Knobler等人ReactionofN-carboxy-alpha-aminoacidanhydrideswithhydrochloridesofhydroxylamine,O-alkylhydroxylamines,andamines;synthesesofaminohydroxamicacids,amidooxypeptides,andalpha-aminoacidamides.JournaloftheChemicalSociety1964(Oct.):3941-3951;以及Knobler等人,α-AminoacylderivativesofaminobenzoicacidandofaminooxyacidsbyreactionoftheirhydrochlorideswithaminoacidN-carboxyanhydrides.JournaloftheChemicalSociety[Section]C:Organic1969(14):1821-1824。
在随后的步骤中,衍生物单体继续和二酸单体反应以获得式I化合物。在该实施例的一个方面,采用反应产物与二酸单体的溶液缩聚反应获得式I化合物。如果存在保护基的话,采用脱保护步骤以脱除保护基。保护基的脱除可以使PEA中出现游离的侧基官能团。
该PEA可以可选地进行纯化。例如,将PEA置于三氟乙酸和甲磺酸的混合溶液中。采用沉淀剂,比如二乙醚使PEA从混合溶液中沉淀出来。然后将沉淀的PEA溶于有机溶剂,比如DMF中。该溶剂可以可选地被溶液例如三乙胺中和,然后采用含水溶液比如水进行沉淀。
引入到PEA中的单体量取决于最终PEA聚合物中的预期氨基量,其可以通过改变所加单体的摩尔比而加以控制。例如,在制备PEA过程中,可通过调节起始原料的投料摩尔比使PEA中m和n值发生改变。在一个实例中,氨基酸二酯、氨基酸N-羧酸酐单体和二酸单体的量比为0.1-20.0∶0.1-1.0∶0.1-20.0,且优选为2.0∶1.0∶2.0。
氨基酸二酯单体通过氨基酸和二醇在含有有机溶剂(如甲苯)和酸(如对甲苯磺酸单水化物)的溶液中反应制得。例如,通过缩合氨基酸和二醇(如OH-(CH2)nOH,其中n是1-8),氨基酸可转变成二-(α-氨基酸)二酯单体。结果形成酯键。
在该实施例的一个方面,基于氨基酸的二酯单体是二(α-氨基酸)α,ω-亚烃基二酯的二-对甲苯磺酸盐。二-氨基酸酯的二-对甲苯磺酸盐可采用U.S.专利6,503,538描述的方法制得。例如,基于氨基酸的二酯单体可以是如下所示的二-(1-α-氨基酸)-α,ω-亚烃基二酯的二-对甲苯磺酸盐:
其中
R3是独立的异丁基或苄基;以及
R4是(CH2)4,(CH2)6,或(CH2)12。
在另一实例中,可以用在该实施例中的特定的L-赖氨酸芳烃基酯的二-对甲苯磺酸盐是:
其中R2是苄基仲苯乙基,或甲苄基。更特别地,R2可以是苄基。
氨基酸N-羧酸酐单体通过氨基酸与碳酰氯化合物(如三光气)反应制得。
该实施例的一个方面是氨基酸N-羧酸酐单体中的氨基酸与第一实施例中的第二氨基酸一致。
氨基酸N-羧酸酐可以可选地具有保护基。在该实施例的一个方面,保护基是苄氧羰基(Z)保护基。
二酸单体可通过多种方法制得,包括将二酰氯(如癸二酰氯)与酚(如对硝基酚)进行反应。二酸单体也可以采用美国专利号6,503,538公开的方法进行制备。
例如,二酸单体可以是式IV化合物:
其中
R1是(CH2)4,(CH2),或(CH2)12,以及
R5是对硝基苯基。
在另一个实例中,化合物是式V化合物:
其中
R5是对硝基苯基;以及
R6是(CH2)3或(CH2)2-O-(CH2)2。
在该实施例的一个优选方案中,二酸单体选自由二-对硝基苯基己二酸盐,二-对硝基苯基癸二酸酯,二-对硝基苯基癸二酸盐以及二-对硝基苯基十二烷基二羧酸盐组成的组。
在该实施例的另一方面,制得含有来自至少三种不同氨基酸残基的PEA。除了第三氨基酸以第二m或n单体的形式引入到PEA外,该PEA采用的制备方法与第一及第二实施例相一致。例如,含有至少三种氨基酸的PEA可包含m1,m2及n1单体,其中m1和m2单体各自具有不同的氨基酸残基。
或者,PEA由m1,n1及n2单体组成,其中n1和n2单体各自具有不同的氨基酸残基。例如,所制PEA包含m1,其中m1的R3是m1的R5是(CH2)4NH2,以及m2的R3是
第三实施例是式(X)所示的PEA:
其中m约为0.1-0.9;
n约为0.9至0.1;
R3是具有在肽合成过程中无需保护的取代基的第一氨基酸的残基;
R4及R6选自由下列基团组成的组:(C2-C28)烷氧基;(C2-C28)亚烃基;侧链被选自以下组中的基团取代的(C2-C28)烷氧基:(2-羧乙基)硫,(2-羟乙基)硫,(2氨乙基)硫及(2-氨乙基)硫盐酸盐;或者侧链被选自以下组中的基团取代的(C2-C28)亚烃基:(2-羧乙基)硫,(2-羟乙基)硫,(2氨乙基)硫及(2-氨乙基)硫盐酸盐;以及
R5是具有选自由NH2、COOH和OH组成的组的侧基的第二氨基酸的残基,
所述侧基可以可选地被保护,以及
所述PEA的Mn为1至500kg/mol。
在该实施例的一个方面,R4及R6提供不饱和碳碳键。
第一及第二氨基酸的残基与在第一和第二实施例中讨论过的残基一致。
单体末端基团也与之前讨论过的一致。
我们现在转向第四实施例。
不饱和PEA(UPEA)可通过(1)二(α-氨基酸)不饱和二醇二酯的二-对甲苯磺酸盐和饱和二羧酸的二-对硝基苯基酯或(2)二(α-氨基酸)饱和二醇二酯的二-对甲苯磺酸盐和不饱和二羧酸的二-对硝基苯基酯或(3)二(α-氨基酸)不饱和二醇二酯的二-对甲苯磺酸盐和不饱和二羧酸的二-对硝基苯基酯的溶液缩聚反应制得。
已知对甲苯磺酸盐可用于合成含有氨基酸残基的聚合物。该芳基苯磺酸盐用于替代游离碱,因为二(α-氨基酸)二酯的芳基苯磺酸盐易于通过重结晶进行纯化并可使氨基生成为惰性氨基苯磺酸盐。
不饱和二羧酸的二-对硝基苯基酯可由对硝基苯酚和不饱和羧酸酰氯合成,如通过将三乙胺和对硝基苯酚溶于丙酮并在-78℃搅拌条件下滴加不饱和羧酸酰氯并倾入水中沉淀得到产物。适宜的酰氯是二羧酸酰氯,包括,例如反丁烯二酸,马来酸,甲基富马酸,顺甲基丁烯二酸,戊烯二酸,衣康酸,乙烯基-丁烷二酸以及2-丙烯基-丁二酸酰氯。
二(α-氨基酸)不饱和二醇二酯的二-对甲苯磺酸盐可通过在甲苯中混合氨基酸、芳基磺酸(如对甲苯磺酸单水化物)和不饱和二醇,加热至回流温度,直至水量变到最少,然后进行冷却而制备得到。不饱和二醇包括,例如,2-丁烯-1,4-二醇和1,18-十八-9-碳烯-二醇。
饱和二羧酸的二-对硝基苯基酯以及二(α-氨基酸)饱和二醇二酯的二-对甲苯磺酸盐可通过U.S.专利6,503,538B1描述的方法制得。
该实施例的这一方面也被Guo,K.,等人,JournalofPolymerScience,PartA:PolymerChemistry43(7),1463-1477(2005年2月15日)的实验及结论所支持,其全部内容通过引用方式并入到本申请中。
可以通过基于巯基的化合物和聚合物的反应而将UPEA功能化。该基于巯基的化合物含有巯基和另一官能团。在该实施例的一个方面,该基于巯基的化合物选自由3-巯基丙酸,巯乙胺,2-巯基乙醇,钠-3巯基1-丙烷-磺酸盐,以及2-氨基乙硫醇盐酸盐组成的组。在另一方面,官能团选自由NH2,NH2HCl,COOH,磺基及OH组成的组。基于巯基的化合物的巯基通过UPEA中的碳碳双键与之相结合,分别生成聚合物骨架上的游离的侧基官能团。
将UPEA与基于巯基的化合物及有机溶剂例如DMA、DMSO、DMF或其组合进行混合以形成混合物。加热该混合物以制得预期的聚合物。该混合物优选加热温度是50℃至120℃,优选60℃至80℃,更优选70℃;加热时间为12-36小时,优选24小时。
在该实施例的另一方面,反应中使用引发剂。例如,巯基基团和非共轭C=C双键生成硫醚的巯基-烯烃反应是可在自由基引发剂存在的情况下推动进行的反应。UPEA(或UPEEA)聚合物在聚合物骨架上具有双键,该双键可用于自由基加成各种巯基以提供各种不同的侧基官能团,该侧基可进一步用作生物活性试剂或药物的活性共价连接位点。例如,化合物双键上的巯基自由基加成反应可在DMF中使用AIBN作为自由基引发剂的情况下,在50-100℃条件下进行。
该反应可以使得生成被例如(2羧乙基)硫、(2-羟乙基)硫、(2-氨乙基)硫以及(2-氨乙基)硫盐酸盐侧链取代的UPEA。
本发明第五实施例是含有第一实施例PEA的组合物。可利用第一实施例所述PEA制备多种不同组合物,包括薄膜,凝胶,水凝胶,凝血产品,伤口愈合产品,骨再生材料,组织工程支架,隐形眼镜,牙科设备,种子涂层,化肥,农药控释成分,膳食食品添加剂,防腐剂,抗菌无纺织物,污水处理材料,化妆品,乳液,增湿剂。
为制备该组合物,PEA上的官能团直接或通过连接物间接地被生物活性和/或活性物质取代。当PEA具有COOH或OH侧基时,COOH及OH基团被带正电荷的活性物质所取代。当PEA具有游离NH2侧基时,NH2基团被带负电荷的活性物质所取代。
生物活性和/或活性物质选自由下列物质组成的组中的一种或多种的组合:肽,抗生素,药物,多肽,抗炎剂,抗血小板剂,抗凝血剂,免疫抑制剂,一氧化氮衍生物,抗微生物剂,生长因子,聚合物,荧光化合物(如荧光素),形成水凝胶的聚合物,形成凝胶的聚合物及其组合。
本发明所用的术语“肽”是2至25个氨基酸(例如,如上定义的氨基酸)的序列或具有一个或多个开放化合价的肽残基的序列。序列可以是直链的或环状的。例如,环肽可通过序列中的两个半胱氨酸残基形成二硫键而制备或形成。肽可以通过羧基端、氨基端或通过任何其他适宜的结合位点例如通过半胱氨酸的二硫键而进行连接。肽衍生物可通过U.S.专利4,612,302;4,853,371;以及4,684,620公开的方法制备。特别地,本发明所述肽序列书写方式为氨基端在左边,羧基端在右边。一个优选的肽是GRGD。
一种或多种抗生素和/或药物可直接或间接连接于PEA的官能团上。适宜的抗生素包括β-内酰胺类抗生素(如青霉素衍生物,头孢菌素,单环β-内酰胺类,碳青霉烯类和β-内酰胺酶抑制剂),阿霉素PFS/RDF(法玛西亚&普强),博来霉素(百时-美施贵宝肿瘤/免疫学),柔红霉素(贝德福德),更生霉素(默克),枸橼酸柔红霉素脂质体(星特朗),盐酸多柔比星脂质体(塞奎斯),盐酸阿霉素(阿斯特拉),伊达比星(PFS法玛西亚&普强),光辉霉素(拜耳),丝裂霉素(施贵宝肿瘤/免疫学),Nipen(超基因),米托蒽醌(免疫公司)和盐酸阿霉素(百时美施贵宝肿瘤/免疫学)。适宜的抗代谢药物包括Cytostar-U(法玛西亚&普强),氟达拉滨(Berlex),无菌5-氟脱氧尿苷(罗氏实验室),克拉立平(奥托生物技术),甲氨蝶呤(免疫公司),Parinethol(葛兰素威康),硫鸟嘌呤(葛兰素威康)和希罗达(罗氏实验室)。
药物是治疗剂或诊断试剂,并包括除食物外的任何用于预防、诊断、减轻、治疗或治愈疾病的物质。参见Stedman′sMedicalDictionary第25版,(1990)第486页。该物质的摄入方式可为经口;肌肉注射,皮肤注射,血管注射,或身体腔道注射;或局部给药。Mosby′sMedical,Nursing&AlliedHealthDictionary,第5版,(1998)第516页。药物可包括公开物质中的至少一种:TheMerckIndex,第12版(1996);ConciseDictionaryofBiomedicineandMolecularBiology.Pei-ShowJuo,(1996);U.S.PharmacopeiaDictionary2000版;以及Physician′sDeskReference,2001版。更特别地,药物可以包括但不限于,一种或多种以下物质:多肽,治疗性抗体阿昔单抗,抗炎剂,血液改进剂,抗血小板剂,抗凝剂,免疫抑制剂,抗细胞增殖剂,以及一氧化氮释放剂。在该实施例的一个方面,抗生素和/或药物是β-内酰胺类化合物,如青霉素(如青霉素V,青霉素G,普鲁卡因青霉素,苄星青霉素)。
青霉素与PEA的接合如下所示:
多肽可具有任何适宜的长度。特别地,多肽长度可为约2至约5000个氨基酸;约2至约2000个氨基酸;约2至约1000个氨基酸;或约2至约100个氨基酸。
多肽也可包括“肽模拟物”。肽类似物作为与模板肽具有相似性质的非肽药物广泛应用于制药行业。这些类型的非肽化合物被称为“肽模拟物”。Fauchere,J.(1986)Adv.DrugRes.15:29;Veber以及Freidinger(1985)TINS第392页;以及Evans等人(1987)J.Med.Chem.,30:1229;且在计算机分子药物设计的帮助下得到发展。
通常,肽模拟物与典型多肽(如具有生物化学性质或药理学活性的多肽)结构类似,但有一个或多个肽键任选地被选自由-CH2NH-,-CH2S-,-CH2-CH2-,-CH=CH-(顺式及反式),-COCH2-,-CH(OH)CH2-,以及-CH2SO-组成的组的连接键通过现有技术已知的并在如下参考文献中进一步描述的方法所取代:Spatola,A.F.于“ChemistryandBiochemistryofAminoAcids,Peptides,andProteins,”B.Weinstein,eds.,MarcelDekker,NewYork,第267页(1983);Spatola,AF.,VegaData(1983年3月),Vol.1,Issue3,;“PeptideBackboneModifications”(综述);Morley,J.S.,Trends.Pharm.Sci.,(1980)第463-468页(综述);Hudson,D.等人,IntJ.Pept.Prot.Res.,(1979)14:177-185(-CH2NH-,-CH2CH2-);Spatola,A.F.等人,LifeSci.(1986)38:1243-1249(-CH2-S-);Hann,M.M.,J.Chem.Soc.PerkinTransI(1982)307-314(-CH=CH-,顺式及反式);Almquist,R.G.等人,J.Med.Chem.,(1980)23:1392-1398(-COCH2-);Jennings-White,C.等人,TetrahedronLett.,(1982)23:2533(-COCH2-)Szelke,M.等人,欧洲专利申请EP45665(1982)CA:97:39405(1982)(-CH(OH)CH2-);Holladay,M.W.等人,TetrahedronLett.,(1983)24:4401-4404(-CH(OH)CH2-);以及Hruby,V.J.,LifeSci.,(1982)31:189-199(-CH2-S-)。
与多肽实施例相比,这些肽模拟物可能具有显著的优势,包括,例如:更经济的合成过程,更稳定的化学性质,增强的药理学性质(半衰期,吸收,效价,效能等),改变的特异性(如生物活性的广谱性),减少的抗原性,以及其他优势。
此外,在多肽中用相同类型的D-氨基酸取代一或多个氨基酸(如D-赖氨酸取代L-赖氨酸)可以用于生成更稳定的多肽以及耐内源性酶的多肽。
一方面,多肽可以是抗体。此种抗体的实例包括单链抗体,嵌合抗体,单克隆抗体,多克隆抗体,抗体片段,Fab片段,IgA,IgG,IgM,IgD,IgE和人源化抗体。在一个实施例中,该抗体可以与细胞粘附分子相结合,如钙粘蛋白,整合素或选择蛋白。在另一种情况中,该抗体可以与分子相结合,如胶原蛋白,弹性蛋白,纤维连接蛋白或层粘连蛋白。
在该实施例的另一方面,抗体可以与受体,如肾上腺素受体,B-细胞受体,补体受体,胆碱能受体,雌激素受体,胰岛素受体,低密度脂蛋白受体,生长因子受体或T-细胞受体相结合。本发明抗体还可以与血小板聚集因子(例如,纤维蛋白原),细胞增殖因子(如生长因子和细胞因子),以及血液凝固因子(例如,纤维蛋白原)相结合。
在另一种情况中,抗体可与活性试剂例如毒素相偶联。例如,抗体可以是阿昔单抗(ReoPro(R))。阿昔单抗是与β(3)整合素相结合的嵌合抗体的Fab片段。阿昔单抗对于例如血液细胞中的血小板糖蛋白IIb/IIIa受体具有特异性。人主动脉平滑肌细胞在其表面表达α(V)β(3)整合素。采用表达平滑肌细胞的β(3)进行处理可能会抑制其他细胞的粘附并减少细胞的迁移或增殖,从而减少经皮冠状动脉介入(CPI)例如,狭窄、血管成形术,支架置入术后的血管再狭窄。阿昔单抗也能抑制血小板聚集。
在一种情况中,肽可以是糖肽。“糖肽”是指具有可选地被糖基取代的多环肽核的寡肽(如七肽)抗生素,如万古霉素。包含在该定义范围内的糖肽实例可见“GlycopeptidesClassification,Occurrence,andDiscovery”,byRaymondC.RaoandLouiseW.Crandall,(“DrugsandthePharmaceuticalSciences”Volume63,editedbyRamakrishnanNagarajan,publishedbyMarcalDekker,Inc.)。更多糖肽实例公开于U.S.专利4,639,433;4,643,987;4,497,802;4,698,327;5,591,714;5,840,684;以及5,843,889;EP0802199;EP0801075;EP0667353;WO97/28812;WO97/38702;WO98/52589;WO98/52592;以及J.Amer.Chem.Soc.,1996,118,13107-13108;J.Amer.Chem.Soc.,1997,119,12041-12047;以及J.Amer.Chem.Soc.,1994,116,4573-4590。代表性的糖肽包括A477,A35512,A40926,A41030,A42867,A47934,A80407,A82846,A83850,A84575,AB65,阿克他宁,类放线菌素,阿达星,阿伏霉素,远青霉素,Balhimycin,Chloroorientiein,氯多孢菌素(Chloropolysporin),Decaplanin,去甲万古霉素,Bremomycin,Galacardin,Helvecardin,伊肽菌素(Izupeptin),凯勃孢囊菌素(Kibdelin),LL-AM374,甘露糖肽素,MM45289,MM47756,MM47761,MM49721,MM47766,MM55260,MM55266,MM55270,MM56597,MMS6598,OA-7653,Orenticin,寡子菌素(Parvodicin),利托菌素,瑞斯托霉素,顺氯海因,替考拉宁,UK-68597,UK-69542,UK-72051,万古霉素,及其类似物。本发明所使用的术语“糖肽”或“糖肽抗生素”还包括上述公开的一般糖肽缺失糖基团后的分子,例如糖肽的苷元。例如,通过温和水解移除万古霉素中连接在苯酚上的二糖基团以获得万古霉素苷元。上述公开的一般糖肽类的合成衍生物,包括烷基化和酰化衍生物也包含在术语“糖肽抗生素”的范围内。此外,该术语的范围还进一步包括额外连接有二糖残基的糖肽类,特别是与万古胺类似的氨基糖苷类。
在一个方面中,肽是脂糖肽。术语“脂糖肽”尤其是指,通过合成修饰从而含有脂质取代基的糖肽抗生素。如本发明所述,术语“脂质取代基”是指含有5个或多个碳原子,更优选地,10至40个碳原子的任何取代基。该脂质取代基可以可选地含有1至6个选自卤素,氧,氮,硫及磷的杂原子。脂糖肽抗生素已在现有技术中被熟知。参见,例如,在U.S.专利5,840,684,5,843,889,5,916,873,5,919,756,5,952,310,5,977,062,5,977,063,EP667,353,WO98/52589,WO99/56760,WO00/04044,WO00/39156中,其公开的全部内容通过引用方式并入到本申请中。
抗炎剂包括,例如,镇痛剂(如NSAIDS和水杨酸),抗风湿药,消化系统药物,痛风剂,激素(糖皮质激素),鼻用制剂,眼用制剂,耳用制剂(如抗生素和甾体激素的组合),呼吸系统药物,皮肤和粘膜剂。参见,Physician′sDeskReference,2001版。具体而言,抗炎剂可包括地塞米松,其化学名为(11β,16α)-9-氟-11,17,21-三羟基-16-1-甲孕4二烯-3,20-二酮。另外,抗炎剂可包括西罗莫司(雷帕霉素),一种从吸水链霉菌中分离出的三烯大环内酯类抗生素。
抗血小板和抗凝药物包括,例如,香豆素(杜邦),法安明(法玛西亚&普强),肝素(惠氏),依诺肝素阿地肝素钠达那肝素钠(欧加农),Aggrastat(默克),阿那格雷(罗伯茨),阿司匹林(SmithklineBeechamn),佛罗兰(葛兰素威康),Halfprin(克莱默),依替巴肽(COR治疗),依替巴肽(Key),潘生丁(勃林格殷格翰),波立维(布里斯托尔-百时美施贵宝),阿昔单抗(Centecor),抵克立得(罗氏),雅激酶(雅培),Activase(基因泰克),依米那酶(罗伯茨),以及Strepase(阿斯特拉)。参见,Physician′sDeskReference,2001版。具体而言,抗血小板和抗凝药物可以包括曲匹地尔(avantrin),西洛他唑,肝素,水蛭素,或伊洛前列素。
曲匹地尔的化学名为N,N-二甲基-5-甲基-[1,2,4]三唑并[1-5-A]嘧啶4-胺。西洛他唑的化学名为6-[4-(1-环己基-1H-四唑5-基)丁氧基]-3,4-二氢-2(1H)-喹啉。
肝素是一种具有抗凝血活性的氨基葡聚糖;一种由D-葡萄糖胺和L-艾杜糖醛酸或D-葡萄糖醛酸重复单元构成的可变磺化多糖链异构混合物。水蛭素是从水蛭例如医用水蛭中提取的抗凝蛋白。伊洛前列素的化学名5-[六氢-5-羟基-4-(3-羟基-4-甲基-1-辛烯-6-炔基)-2(1H)-亚戊搭烯基]戊酸。
免疫抑制剂可包括,例如,硫唑嘌呤(罗克珊),BayRho-D(拜耳生物),骁悉(罗氏实验室),依木兰(葛兰素威康),MiCRhoGAM(Ortho-临床诊断),Neoran(诺华),OrthocloneOKT3(奥托生物技术),普乐(藤泽),PhoGAM(Ortho-临床诊断),山地明(诺华),舒莱(诺华),赛尼哌(罗氏实验室)。具体而言,免疫抑制剂可包括雷帕霉素或沙利度胺。雷帕霉素是一种从吸水链霉菌中分离得到的三烯大环内酯。
沙利度胺的化学名为2-(2,6-二氧-3-哌啶基)-1H-异-吲哚-1,3(2H)-二酮。
在一种情况中,治疗有效量的一氧化氮(NO)衍生化合物与PEA中功能性酸相结合。此类化合物的实例是2,2,5,5-四甲基吡咯烷-1-氧,碘化物(CAT16);4-三甲基铵-2,2,6,6-四甲基吡咯烷-1-氧,碘化物(CAT1);3-氨基-2,2,5,5-四甲基吡咯烷-1-氧;N-(3-(碘代乙酰)氨基)-2,2,5,5-四甲基吡咯烷-1-氧(PROXYL1A);琥珀酰胺2,2,5,5-四甲基-3-吡咯啉-1-氧-3-羧酸;2,2,5,5-四甲基-3-吡咯啉-1-氧-3-羧基酸;2,2,6,6-四甲基哌啶-1-氧;4-氨基-2,2,6,6-四甲基哌啶-1-氧;4-羧基-2,2,6,6-四甲基哌啶-1-氧;4-乙酰氨基-2,2,6,6-四甲基哌啶-1-氧;4-溴-2,2,6,6-四甲基哌啶-1-氧;4-(N,N-二甲基-N-(2-羟乙基))铵-2,2,6,6-四甲基哌啶-1-氧;4-(N,N-二甲基的N-(3-磺丙基)铵-2,2,6,6-四甲基哌啶-1-氧;N-(4-(碘代乙酰)氨基-2,2,6,6-四甲基哌啶-1-氧;N-(2,2,2,6,6-四甲基哌啶-1-氧-4-基)马来酰亚胺;及其混合物。特别优选的化合物是4-氨基-2,2,6,6-四甲基哌啶-1-氧基。
一氧化氮类似物也可与PEA相结合。适宜的一氧化氮类似物已经公开在例如U.S.专利5,650,447中,以及可以是牛或人血清白蛋白的S-亚硝基硫醇衍生物(加合物)。参考,如Inhibitionofneointimalproliferationinrabbitsaftervascularinjurybyasingletreatmentwithaproteinadductofnitricoxide.DavidMarks等人J.Clin.Invest.(1995);96:2630-2638。
抗微生物剂是可杀死或抑制微生物例如细菌、真菌、原生动物或病毒生长的物质。抗微生物剂可以是抗病毒、抗细菌、抗真菌剂或金属(如Ag,Cu,或Hg)。在一个优选的方面,抗微生物剂不与PEA相连接,而是浸渍在PEA中或其周围。在另一个实施例中,银是优选的抗微生物剂。
术语生长因子是指,可刺激细胞生长、增殖及细胞分化的天然存在的蛋白。生长因子在多种细胞过程的调节进程中发挥着重要的作用。生长因子典型的作为细胞间的信号分子,例如与其靶细胞表面的特异性受体相结合的细胞因子及激素。生长因子通常促进细胞分化及成熟,不同生长因子的促进细胞分化及成熟的作用是不同的。例如,成骨蛋白刺激骨细胞分化,而成纤维细胞生长因子及血管内皮生长因子则刺激血管分化(血管发生)。根据请求保护的发明,可以使用的生长因子的实例包括但不限于,内皮生长因子(EGF),促红细胞生成素(EPO),成纤维细胞生长因子(FGF),粒细胞集落刺激因子(G-CSF),粒细胞-巨噬细胞集落刺激因子(GM-CSF),生长分化因子-9(GDF9),肝细胞生长因子(HGF),胰岛素样生长因子(IGF),筒箭毒碱(GDF-8),神经生长因子(NGF),血小板源性生长因子(PDGF),血小板生成素(TPO),转化生长因子-α(TGF-α),转化生长因子-β(TGF-β),血管内皮生长因子(VEGF)。
本发明的PEA也可与其他聚合物发生反应。例如,当PEA具有羟基侧基时,该官能团可作为醇基并用作化学连接到合成的吸附脂肪族聚合物大分子上的反应起始位点,例如连接到聚-ε-羧基乙酸内酯(PCL)或/和聚乳酸(PLA)(也就是具有PCL或/和PLA接枝侧链的PEA骨架)。
除了直接或通过连接物间接地与一或多个活性物质相连接或结合,本发明的PEA还可以物理混杂一种或多种生物活性物质。本发明所使用的术语“混杂”是指本发明的PEA物理接触或混合生物活性和/或活性物质。
在组合物制备过程中,PEA及生物活性物质可以是任意适宜用量的。PEA可以占组合物的约0.1wt%至约99.9wt.%。典型地,PEA可以占组合物的约25wt%以上;组合物的约50wt%以上;组合物的约75wt%以上;或组合物的约90wt%以上。
该实施例的一个特点是将PEA与多糖例如右旋糖酐,透明质酸,壳聚糖,海藻酸钠,菊粉,淀粉,纤维素,普兰,果聚糖,甘露聚糖,甲壳素,木聚糖,果胶,葡萄糖酸聚醣,海带多糖,半乳甘露聚糖,直链淀粉,支链淀粉,phytophtoorglucans或乙基纤维素反应。多糖如葡聚糖,菊粉,淀粉,纤维素,普兰,果聚糖,甘露聚糖,甲壳素,木聚糖,果胶,葡萄糖酸聚醣,海带多糖,半乳甘露聚糖,直链淀粉,支链淀粉以及phytophtoorglucans可以提供羟基侧基官能团。
第一实施例的PEA通过化合物如羰二咪唑可以与多糖发生反应,该化合物有助于NH2基和COOH基发生反应。例如,具有游离NH2侧基的PEA化合物(如PEA-Lys-25)可与多糖如玻璃酸酶发生反应。玻璃酸酶是一种带负电荷的多糖,如下所示:
在该实施例的另一方面,制得凝胶。该实施例中凝胶可通过若干不同方法制得。
在制备凝胶的第一个方法中,可以使用具有游离氨基的式IPEA化合物通过胺反应活性的双功能交联剂来制备凝胶。胺反应活性的双功能交联剂(比如戊二醛)与PEA反应生成凝胶。除了戊二醛,二甲基亚氨酸酯(DMA),二甲基辛二亚氨酸酯(DMS),二甲基庚二亚胺(DMP),N-羟基琥珀酰亚胺(NHS)酯,二硫代二(琥珀酰亚胺丙酸盐),以及二硫代二(磺基琥珀酰亚胺丙酸盐)DTSSP也可被使用。
在制备凝胶的第二个方法中,使用羰二咪唑以助于游离NH2侧基和游离COOH侧基反应生成凝胶。具有游离NH2或COOH侧基的式IPEA化合物与羰二咪唑及具有相对应的NH2或COOH官能团的化合物发生反应。例如,具有游离氨基的PEA化合(如PEA-Lys-25)可通过羰二咪唑与具有羧基的PEA反应以生成透明凝胶。
在该实施例的另一方面,可以制成水凝胶。例如,在一个制备水凝胶的方法中,将光引发剂加入到含有式IPEA以及分子量为700的PEG-DA组成的二甲基亚砜溶液中。PEA前体和PEG-DA的重量比是0.1-0.3∶1,优选0.2∶1。
可以使用任何光引发剂,但优选的光引发剂是2,2-二甲氧基2-苯基苯乙酮,4-(2-羟乙氧基)苯基-(2-羟基-2丙基)酮(佳固2959)及DMPAP。光引发剂的优选加入量是0.01-10%,0.1-3.0%(w/w)。根据所用光引发剂的类型(如DMPAP)再可选地加入溶剂。溶剂例如N-甲基吡咯烷酮、四氢呋喃、二甲基甲酰胺或二甲基亚砜被加入到溶液中。
光交联在紫外线照射下进行,如在室温下,优选20℃至30℃,照射5至30分钟,优选10至20分钟。未反应的化学试剂随后优选从所制凝胶中滤去。
由PEA制得的凝胶或水凝胶可用于多种用途,包括生物活性和/或活性物质的控释。在该方面中,生物活性和/或活性物质可与PEA中的游离官能团反应以形成生物活性和/或活性物质与前体间的共价键,和/或物理包封或包入前体中。该生物活性和/或活性物质通过水凝胶的代谢作用得以释放,且与水凝胶的结合或包入或包封作用可以推迟其释放,例如,推迟2至48小时或更多。
由本发明的PEA制得的水凝胶或凝胶还可用作暂时的皮肤涂覆层,如作为伤口辅料或人工皮。在此种情况中,该水凝胶或凝胶可以有利地掺入前述的抗微生物剂和/或伤口愈合生长因子。
由本发明的PEA制得的水凝胶或凝胶还可以用来包封用于基因治疗的病毒,以保护该病毒在到达发生基因变异的位点前免受人体免疫系统的影响。在常规基因治疗中,需将病毒注入预期导入的位点且为应对病毒失活而需要多次注射。本发明的水凝胶可保护病毒,从而减少注射次数。
由本发明的PEA制得的水凝胶还可以用于包覆种子的农业用途。该水凝胶包覆可促进种子萌发过程中的水贮留及通过其孔结构促进氧的输送,而且其还可以包括化学试剂如杀虫剂以用于递送至种子。
由本发明的PEA制得的水凝胶可用于碱性成纤维细胞生长因子(bFGF)的给药以刺激成骨细胞(即促进骨生成)及血管发生(即血管发育)。本发明前体中的游离羧酸侧基用作bFGF离子结合的位点。掺入bFGF的该水凝胶用于局部的骨或血管。通过水凝胶的生物降解,可获得bFGF促进骨生长和血管形成的控释效果。由于bFGF对酸性化合物具有内在亲和力,bFGF与本发明前体发生结合可保护bFGF免受酶降解或变性的影响,从而发挥其生物学功效。
由本发明的PEA制得的水凝胶可用于微装置中的整合元件,例如,生物传感器。水凝胶中的官能团对各种环境中的刺激例如pH和金属离子浓度十分敏感,水凝胶的溶胀率和其他性质可根据所控制的外界刺激的改变而相应地发生改变。
由本发明的PEA制得的水凝胶还可用于水凝胶的各种常规应用领域,比如,用于食品加厚,用于植物释水,用于卫浴空间中的液体吸收和贮留,作为织物应用中的亲水涂层,用于隐形眼镜及用作层析和电泳中的分离及扩散凝胶。
在该实施例的一方面,药物、生物活性和/或活性物质不与本发明的水凝胶形式组分发生反应,而是通过在光交联生成水凝胶的过程中在反应混合物中加入上述物质而使其物理地包入或包封于生成的水凝胶中。
本发明的前述说明描述了特定可实施的及优选的实施例。但是其无意限制本发明,在不脱离本发明的主旨和保护范围的情况下,本领域技术人员还可以对上述内容进行各种修饰和改变。
本发明的操作实施例如下所示。
实施例1
合成具有氨基侧基的PEA
采用下述五个主要步骤合成具有氨基侧基的PEA:(1)合成被保护的ε-(苄氧羰基)-L-赖氨酸N-羧酸酐(Z-LysNCA),(2)合成二-L-苯丙氨酸酯的二-对甲苯磺酸盐(Phe-6)及其Z-LysNCA衍生物单体(Z-Lys-Phe-6);(3)合成二羧酸的二-对硝基苯酯(NS);(4)单体Z-Lys-Phe-6和NS发生溶液缩聚反应;以及(5)脱保护所得聚合物(PEA-Z-Lys)。
合成二-L-苯丙氨酸己烷-1,6-二酯单体的二-对甲苯磺酸盐(Phe-6)
在对甲苯磺酸单水化物(57.00g,0.30mol)存在的情况下,在回流甲苯(500mL)中直接缩合苯丙氨酸(42.95g,0.26mol),1,6-己二醇(14.20g,0.12mol)来制得Phe-6。将该非均相固-液反应混合物加热至120℃并回流24小时,直至采用Dean-Stark装置收集到14.90mL(0.83mol)的水。将所得反应混合物冷却至室温。用布氏漏斗过滤沉淀并在水中重结晶三次以进行纯化,再次过滤并真空干燥。产率:68%。
合成ε-(苄氧羰基)-L-赖氨酸N-羧酸酐(Z-LysNCA)
通过使用利用三光气的Fuchs-Farthing法合成ε-(苄氧羰基)-L-赖氨酸N-羧酸酐。将H-Lys(Z)-OH(6.00g,21.40mmol)混悬于150mL乙酸乙酯中并在氮气氛下进行回流。将三光气(2.37g,8.00mmol)溶于30mL乙酸乙酯,所得溶液加入进行搅拌的反应混合物中。当反应混合物开始变透明时,将一股氮气流通入溶液中以冒泡的方式除去HCl。待反应进行完全后,真空条件下蒸发除去溶剂以获得无色油状残渣,将残渣在冰箱中冷却以获得结晶。为进一步纯化所制Z-LysNCA,将其在乙酸乙酯/石油醚混合物中重结晶三次并进行真空干燥。产率为87%。
合成氨基被保护的N-苄氧羰基-L-赖氨酸-二-L-苯丙氨酸己烷-1,6-二酯的二-对甲苯磺酸盐单体(Z-Lys-Phe-6)
与PEA相结合的Z-LysNCA单体量取决于最终PEA聚合物中的预期氨基含量,该含量由Phe-6和Z-LysNCA的摩尔比控制。Phe-6和Z-LysNCA的不同摩尔组合汇总于表1并如下述图示1所示。将Phe-6(6.00g,7.93mmol)溶于30mLN,N-二甲基乙酰胺(DMA)中并加入Z-LysNCA(2.43g,7.93mmol)。反应混合物在40℃下搅拌3小时并在氮气氛中将溶液温度升高至80℃持续24小时。随后将反应冷却至室温并在未经纯化的情况下用于下步缩聚反应。
合成二-对硝基苯基癸二酸酯单体(NS)
通过癸二酰氯与对硝基苯酚反应制备二-对硝基苯基癸二酸酯。在装有磁力搅拌及滴液漏斗的单颈圆底烧瓶中将对硝基苯酚(43.00g,0.31mol)及三乙胺(43.13mL,0.31mol)溶于500mL丙酮。采用冰/水混合物冷却使烧瓶中内容物温度保持在0℃。将癸二酰氯(28.54mL,0.13mol)加入100mL丙酮中后滴入已冷却的溶液中搅拌三小时,并在室温下搅拌过夜。所得NS在蒸馏水中进行沉淀,在室温下真空干燥并随后采用乙酸乙酯重结晶三次以进行纯化。产率:75%。
Phe-6,NS及Z-Lys-Phe-6的合成如下所示:
合成氨基被保护的聚(酯酰胺),PEA-Z-Lys
PEA-Z-Lys-50(参见下表1中样品6)的合成例如可以采用如下合成步骤。在氮气氛中将Z-Lys-Phe-6-50(8.08g,7.93mmol)溶于30mLDMA中,往里加入NS(3.52g,7.93mmol)和干燥的NEt3(2.41mL,17.45mmol)。反应溶液在室温下搅拌5分钟后再在80℃下搅拌24小时。所得溶液冷却至室温,用30mlDMA进行稀释并加入过量冷乙酸乙酯中进行沉淀。将聚合物溶于二氯甲烷并慢慢加入过量冷乙酸乙酯中以进行纯化。将柏油状聚合物进行过滤并在50℃下真空干燥。用DMSO-d6做溶剂,该PEA-Z-Lys组合物采用1H和13CNMR进行结构测定。该聚合物用于制备脱保护的PEA-Lys-NH2。
合成氨基侧基聚(酯酰胺),PEA-Lys-NH2
利用三氟乙酸/甲磺酸/苯甲醚混合物脱除赖氨酸单元侧链氨基中的保护基(Z基团)。将PEA-Z-Lys-50(5.00g)溶于20mL三氟乙酸中并在室温下搅拌1小时。随后,将1.30mL甲磺酸溶于2.60mL苯甲醚并加入PEA-Z-Lys-50溶液中。在额外搅拌1小时后,采用过量冷乙酸乙酯对溶液进行沉淀。为除去过量的酸,将聚合物溶于DMA中并采用三乙胺进行中和,随后采用过量冷乙酸乙酯进行沉淀。将产物聚合物进行过滤,并在50℃下真空干燥。
反应如下所示:
PEA-Z-Lys和PEA-Z-Lys-NH2合成过程中的单体组合如下所示:
表1
荧光染料结合,PEA-Lys-dy
为证实PEA聚合物链上氨基侧基的存在及作用,将荧光染料结合于PEA-Lys-NH2-05的游离氨基位点。制备得到荧光染料-标记的PEA(PEA-Lys-NH2-05-Dye)。将PEA-Lys-NH2-0.5(1.00g)和NHS-荧光素染料(10mg)溶于15mlDMSO中并在室温下进行搅拌。6小时后,通过蒸馏水对该溶液进行沉淀。随即采用蒸馏水清洗聚合物以除去所有物理吸附的荧光素染料并在真空中进行过夜干燥。将干燥过的聚合物(0.10g)溶于10mL氯仿,并将溶液滴至玻璃盖玻片上。将已包被的盖载玻片在真空中干燥12小时并用于荧光测定。
反应如下所示:
表征
使用Varian(PaloAlto,CA)UnityInova400-MHz光谱仪记录1HNMR及13CNMR谱,其中采用残余质子共振或氘代溶剂的碳原子信号作为内标物。使用配置有两个WatersStyragel柱(HT6E,HT3)以及一个差示折光检测器的Waters410分子筛析色谱测定产物聚合物的数均分子量及量均分子量。使用氯仿作为洗脱剂(1.0mL/min)且聚合物的平均分子量基于使用聚苯乙烯标准品校正后进行计算。使用PerkinElmer(Madison,WI)NicoletMagana560FTIR光谱仪记录红外光谱数据,其中采用KBr进行压片。使用OlympusBX41荧光显微镜检测结合NHS-萤光素的PEA样品。使用TAInstrumentsDSC2920差示扫描热量计(TAInstruments,NewCastle,DE)分析单体及聚合物的热性质,其中DSC样品的分析温度范围为-42-270℃,扫描速度为10℃/min。使用Cannon-Ubbelohde粘度计测定产物聚合物的比浓粘度,其中将聚合物溶于DMSO且配制成25℃下0.25g/dL的浓度。
细胞培养
将购自VECTechnologies的牛血管内皮细胞(BAEC,原代细胞)培育在37℃,5%CO2的199培养液基(Invitrogen,Carlsbad,CA)中,该培养基中还含有10%的FetalCloneIII胎牛血清(HyClone,Logan,UT),以及各为1%的青霉素-链霉素,MEM氨基酸(Invitrogen,Carlsbad,CA),和MEM维生素(Mediatech,Manassas,VA)。使用传代8-12次的BAEC。培养基每两天更换一次。待细胞生长至70%汇合度时,传代或收集。
细胞粘附及增殖测定
随后采用MTT测定法测定细胞增殖,继而评价聚合物表面的细胞粘附能力及培养基中聚合物的细胞毒性。通过将玻片浸入聚合物/DMF溶液(5wt%)并进行真空干燥以在圆形微盖玻片(直径12mm,2号,VWR,WestChester,PA)上包被聚合物。该包被及干燥步骤重复进行三次。在最后一次真空干燥后,将包被PEA-Lys-NH2-25的玻璃盖玻片置于细胞培养板中。采用2wt%明胶水溶液处理细胞培养板,将未处理的孔作为对照。
将培养过的细胞接种于24-孔培养板中的每个测试孔中,每个孔中接种几乎相同且适当的细胞密度浓度(20,000个细胞/孔),随后在培养箱中进行培养。细胞培养基每天进行更换。在经过预定的培养时间(24小时,48小时,72小时)后,从培养箱中取出细胞培养板。随后吸走孔中的培养基,并在每个孔中加入0.5ml新鲜培养基。然后,在每个孔中再加入40μlMTT溶液(5mg/ml),并在37℃,5%CO2的条件下培养4小时。小心移除细胞培养基并加入400μL酸性异丙醇(含0.1MHCl)以溶解生成的甲臜结晶。轻轻振摇培养板30分钟并从每个孔中转移100uL溶液至96孔培养皿中。使用全自动定量绘图酶标仪在570nm(扣除690nm处的本底读数)处测量每个孔的吸光度(OD)。
结果
Z-Lys-Phe-6的结构通过1HNMR及13CNMR得到确证。如图1所示,标记为数字1至18的1HNMR峰分别归属于Z-Lys-Phe-6及Phe-6中相应的质子。与Phe-6的1HNMR相比较,Z-Lys-Phe-6光谱在5.00ppm处出现的不同峰归属于源自赖氨酸片段保护基的ArCH2质子。在13CNMR谱中也存在相同的观测结果(图2),在64.67ppm处出现的峰对应于ArCH2的碳原子。在羰基区,156.15,169.00,169.09及171.06ppm出现的峰归属于苯丙氨酸和赖氨酸片段中的不同C=O碳。赖氨酸片段的存在破坏了二醇部分中亚甲基碳原子的对称结构,所以Z-Lys-Phe-613CNMR谱图中每个亚甲基碳原子均显示两个分裂的峰。
每个Phe-6分子中Z-赖氨酸片段的掺入度可通过计算1HNMR中归属于Z基团亚甲基质子信号的5.00ppm处的积分值和归属于Phe-6亚甲基质子信号的4.00ppm处的积分值的比例而得到。由此,Z-Lys-Phe-6中Z-赖氨酸单元结合入Phe-6单元的程度可以通过改变Phe-6及Z-LysNCA反应物的投料摩尔比而进行量化控制(参考表1)。
PEA-Z-Lys的合成
如路线3所示,氨基被保护的PEA-Z-Lys通过Z-Lys-Phe-6及Phe-6与NS单体的溶液缩聚反应制得。所进行的缩聚反应提供了PEA-Z-Lys的高产率。在该缩聚反应中,三乙胺被用作产自Z-Lys-Phe-6和Phe-6单体中氨基再生过程的甲苯磺酸的酸吸收剂。NS是一种稳定的固体单体,因此,缩聚反应中氨基和羧基的化学当量平衡可以利用准确称量的单体而得到控制。
表2显示聚合产率以及PEA-Z-Lys的ηred,如下所示:
表2
a通过1HNMR测得的赖氨酸摩尔比。
b通过GPC测得的Mn。
c通过GPC测得的Mw。
在25℃的DMSO中测得(浓度=0.25g/dL)。
所有获得的PEA-Z-Lys都是固体且不溶于甲醇,但溶于常见有机溶剂例如氯仿,DMF以及THF。
FTIR及NMR都证实了氨基被保护的PEA-Z-Lys聚合物的结构。PEA-Z-Lys-25的FTIR光谱,如图3所示,具有酯羰基吸收峰(1737cm-1),酰胺I键(1644cm-1)以及酰胺II键(1534cm-1)。在1H谱中(图4),可观测到5.00ppm处的归属于赖氨酸片段保护基的亚甲基的特征峰。
图5显示了PEA-Z-Lys-0(无赖氨酸片段)和PEA-Z-Lys-2513CNMR谱羰基区的比较。171.67ppm及172.27ppm处峰分别与(Phe)CONH及(Phe)COO相关。在羰基区171.33ppm,171.98ppm及156ppm处观测到的另外三个峰则分别归属于(Z-Lys)CONH,(Z-Lys)COO以及Z基团。这些FTIR及NMR谱图证实PEA-Z-Lys骨架中存在Z-Lys单元。聚合物的GPC数据汇总于表2。所有PEA-Z-Lys聚合物具有相似的分子量及分子量分布。GPC迹线是单峰,不存在共存的可能生成于未受控制的缩聚作用的低或高分子量物种信号。通过1HNMR检测,在一些情况下PEA-Z-Lys组合物轻微偏离了预期(表2)。当LysNCA单元含量更少时偏离更明显。我们相信这是纯化过程中移除了具有高赖氨酸含量的低分子量聚合物的结果。
PEA-Z-Lys的脱保护
赖氨酸α-氨基上的苄氧羰基(Z)保护基可通过催化氢解或催化氢化转移进行脱除。然而,ω-氨位点上的Z基团通常通过强酸水解或催化氢解进行脱除。PEA-Z-LysN-端赖氨酸单元Z基团的脱除可通过用甲磺酸,苯甲醚以及三氟乙酸的混合溶剂处理一小时,随后使用三乙胺中和而得以实现。在PEA-Lys-NH2的1HNMR分析中,5.00ppm处不存在Z基团的质子峰,证实保护基几乎完全被脱除了(图4)。在13CNMR谱中,165ppm处Z基团羰基碳信号的消失也证实了脱保护进行完全(图5)。
Z基团脱除过程中的脱保护PEAs的分子量损失也被检测。如表2所示,在用混合酸脱保护介质处理后,PEAs(PEA-Z-Lys-05,PEA-Lys-NH2-05)的分子量从67,000减少至45,300(分子量减少32%)。随着赖氨酸含量的增加,PEA-Lys-NH2分子量的减少更加显著。在脱保护步骤中分子量的减少可能归因于(1)失去Z保护基以及(2)在强酸脱保护条件下,PEA骨架的酯键发生了部分水解。
为直接证实游离氨基的存在,合成了结合NHS-荧光素染料的PEA,如路线4所示。
该荧光素染料具有与氨基以及PEA反应的活性。图6的左图显示结合NHS-荧光素的PEA样品显示特征性绿色。相反,右图的对照样品(PEA-Z-Lys-05)显示不同的黑色。
该PEA-Lys-NH2家族在相同的重复单元内具有两个氨基酸。此外,该PEA-Lys-NH2家族还具有游离的氨基官能团。因此,该PEA在生理pH条件下是带有负电荷的。
热性质
表2所示的聚合物玻璃转化温度(Tg)通过差示扫描测热法(DSC)测得。所有含赖氨酸的PEA聚合物都是无定形的并显示18至32℃范围的Tg,同时未检测到熔化温度。这些PEA的典型DSC迹线如图7所示。PEA-Z-Lys-0(不具有赖氨酸单元的PEA)的Tg是32.35℃。PEA-Z-Lys-25的Tg是19.85℃,相比PEA-Z-Lys-0的Tg减少了约12℃。Tg减少的原因归因于赖氨酸单元中柔性侧保护基的存在,其作为内在的增塑剂可减少聚合物链间的摩擦作用。在脱保护后,赖氨酸单元中复原的侧氨基通过氢键增强了聚合链酯键的相互作用。因此,脱保护的PEA-Lys-NH2-25相比被保护的PEA-Z-Lys-25类似物显示出更高的Tg(Tg=32.39℃)。
PEA的化学结构对于Tg有影响。在PEA二醇和二羧酸部分引入C=C双键会增加PEA聚合物链的刚性,以及提高Tg至109℃。然而,不饱和PEA中的强分子间相互作用确信会导致其不易溶于常规有机溶剂。PEA骨架的聚亚甲基链长度也可影响聚合物链的柔性以及Tg。通过改变二醇和二羧酸片段聚亚甲基链的长度,可以调节所制得的PEA的Tg。已发现当二醇和二羧酸聚亚甲基链的长度为6和8时,可提供PEA柔性及溶解性。图10显示PEA中存在的游离氨基减少聚合物链的柔性并增加其玻璃转化温度。
溶解性
表3显示了具有不同赖氨酸含量的PEA-Z-Lys及PEA-Lys-NH2在室温下的溶解性。所有PEA-Z-Lys均可完全溶于极性溶剂,如CHCl3、DMF以及DMSO,但不溶于乙酸乙酯、丙酮和水。PEA-Lys-NH2可溶于DMF和DMSO但不溶于水。具有更高赖氨酸含量的PEA-Lys-NH2如PEA-Lys-NH2-50可以形成强的氢键并且一旦被干燥就难以复溶。
表3
H2O | DMF | DMSO | THF | 甲醇 | 乙酸乙酯 | 氯仿 | 丙酮 | |
PEA-Z-Lys-0 | - | + | + | + | - | - | + | - |
PEA-Z-Lys-05 | - | + | + | + | - | - | + | - |
PEA-Lys-NH2-05 | - | + | + | ± | - | - | + | - |
PEA-Z-Lys-15 | - | + | + | + | - | - | + | - |
PEA-Lys-NH2-15 | - | + | + | - | - | - | + | - |
PEA-Z-Lys-25 | - | + | + | + | - | - | + | - |
PEA-Lys-NH2-25 | - | + | + | - | - | - | + | - |
PEA-Z-Lys-35 | - | + | + | + | - | - | + | - |
PEA-Lys-NH2-35 | - | + | + | - | ± | - | ± | - |
PEA-Z-Lys-50 | - | + | + | + | - | - | + | - |
PEA-Lys-NH2-50 | - | ± | ± | - | ± | - | - | - |
PEA-Z-Lys及PEA-Lys-NH2在室温(25℃)下的溶解性a
a+可溶的;-不可溶的;±部分可溶的或可溶胀的
细胞粘附及增殖
图8所示显微镜图像表明明胶包被的对照组和PEA-Lys-NH2-25包被的组在3天后都显示出BAEC(牛主动脉内皮细胞)细胞融合,而未处理组的融合小于50%。采用MTT法检测活细胞。图9显示在所有3个时期内,空白组的BAEC增殖率与包被组相比都要低。对于两个包被组而言,均显示出高的增殖率,且PEA-Lys-NH2-25包被组显示出相同或略好的细胞增殖。
实施例2
合成具有侧基COOH的PEA
合成8-Phe-4-Glu-COOH25
合成8-Phe-4-Glu-COOH25的反应如下所示:
合成γ-苄基-L-谷氨酸酯N-羧酸酐(GluNCA)
将L-谷氨酸γ-苄酯(5.07g,21.40mmol)混悬于150mL乙酸乙酯中并在氮气氛下进行回流。将三光气(2.37g,8.00mmol)溶于30mL乙酸乙酯,所得溶液加入进行搅拌的反应混合物中。当反应混合物开始变透明时,将一股氮气流通入溶液中以冒泡的方式除去HCl。待反应进行完全后,在真空条件下蒸发除去溶剂以获得无色油状残渣,将残渣在冰箱中冷却以获得结晶。为进一步纯化所制γ-苄基-L-谷氨酸酯N-羧酸酐,将其在乙酸乙酯/石油醚混合物中重结晶三次并进行真空干燥。产率为79%。
在此给出合成衍生物单体1的典型实验步骤。Phe-4和GluNCA的摩尔比为75∶25。将Phe-4(8.30g,11.40mmol)溶于30mLN,N-二甲基乙酰胺(DMA)中并加入GluNCA(1.00g,3.80mmol)。反应混合物在40℃下搅拌3小时并在氮气氛中将溶液温度升高至80℃持续24小时。随后将反应冷却至室温并在未经纯化的情况下用于下步缩聚反应。
合成8-Phe-4-Glu-25-Bn(被保护的)
在氮气氛中将衍生物单体1(8.04g,11.40mmol)溶于30mLDMA中,往里加入NS(5.06g,11.40mmol)和干燥的NEt3(3.48mL,25.08mmol)。反应溶液在室温下搅拌5分钟后再在80℃下搅拌24小时。所得溶液冷却至室温,用30mlDMA进行稀释并加入过量冷乙酸乙酯中进行沉淀。将聚合物溶于二氯甲烷并慢慢加入过量冷乙酸乙酯中以进行纯化。将柏油状聚合物进行过滤并在50℃下真空干燥。产率75%。
合成8-Phe-4-Glu-COOH25(脱保护步骤)
在500mL反应烧瓶中将8-Phe-4-Glu-25-Bn(3g)加入50mL乙醇中,在氮气保护下往烧瓶中加入10wt%Pd/C(0.5g,购自Aldrich)。缓慢加热反应混合物至70℃,然后将通入的气泡从氮气变为氢气。在24小时的催化氢化反应后将混合物冷却至室温并将通入的气泡从氢气变为氮气。弃去上面的乙醇层,将剩余的聚合物溶于CH2Cl2。通过高速离心除去Pd/C。纯化步骤与8-Phe-4-Glu-25-Bn制备方法中的相同。
实施例3
合成具有侧OH基的PEA
合成8-Val-4-Ser-OH25
8-Val-4-Ser-OH25的合成如下所示:
合成二-L-缬氨酸丁烷-1,4-二酯(Val-4)的二-对甲苯磺酸盐
在带有Dean-Stark装置和搅拌棒的反应烧瓶中,将L-缬氨酸(20.60g,0.176mol),对甲苯磺酸单水化物(33.44g,0.176mol)以及1,4-丁二醇(7.2g,0.08mol)加入300mL甲苯中。将该非均相固-液反应混合物加热回流24小时,然后冷却至室温。在蒸发除去溶剂后,采用水重结晶三次以纯化粗产物,并进行真空干燥。
合成O-苄基-L-丝氨酸N-羧酸酐(SerNCA)
将O-苄基-L-丝氨酸(4.18g,21.40mmol)混悬于150mL乙酸乙酯中并在氮气氛下进行回流。将三光气(2.37g,8.00mmol)溶于30mL乙酸乙酯,所得溶液加入进行搅拌的反应混合物中。当反应混合物开始变透明时,将一股氮气流通入溶液中以冒泡的方式除去HCl。待反应进行完全后,在真空条件下蒸发除去溶剂以获得无色油状残余物,将残余物在冰箱中冷却以获得结晶。为进一步纯化所制O-苄基-L-丝氨酸N-羧酸酐,将其在乙酸乙酯/石油醚混合物中重结晶三次并进行真空干燥。
合成路线5合成8-Val-4-Ser-OH25中的衍生物单体1
将Val-4(6.03g,9.54mmol)溶于30mLN,N-二甲基乙酰胺(DMA)中并加入SerNCA(0.70g,3.18mmol)。反应混合物在40℃下搅拌3小时并在氮气氛中将溶液温度升高至80℃持续24小时。随后将反应冷却至室温并在未经纯化的情况下用于下步缩聚反应。
合成8-Val-4-Ser-25
在氮气氛中将衍生物单体1(9.54mmol)溶于30mLDMA,往里加入NS(4.24g,9.54mmol)和干燥的NEt3(2.65mL,19.08mmol)。反应溶液在室温下搅拌5分钟后再在80℃下搅拌24小时。所得溶液冷却至室温,用30mlDMA进行稀释并加入过量冷乙酸乙酯中进行沉淀。将聚合物溶于二氯甲烷并慢慢加入过量冷乙酸乙酯中以进行纯化。将柏油状聚合物进行过滤并在50℃下真空干燥。
合成8-Val-4-Ser-OH25(脱保护步骤)
在500mL反应烧瓶中将8-Val-4-Ser25(2g)加入50mL甲醇和2.5mL蒸馏水的混合物中。在氮气保护下往烧瓶中加入10wt%Pd/C(0.5g,购自Aldrich)。使用甲醇相比乙醇的优势是脱保护可以几乎达到100%,例如,主要-OH基团都从保护阶段脱除。缓慢加热反应混合物至70℃,然后将通入的气泡从氮气变为氢气。在60小时的催化氢化反应后将混合物冷却至室温并将通入的气泡从氢气变为氮气。弃去上面乙醇层,将剩余的聚合物溶于CH2Cl2。通过高速离心除去Pd/C。纯化步骤与8-Val-4-Ser25制备方法中的相同。
合成8-Val-4-Ser-OH25的丙烯酸酯衍生物
如路线5所示,将8-Val-4-Ser-OH25(1g)溶于无水四氢呋喃(20mL),并将溶液加入装有磁力搅拌及滴液漏斗的三颈圆底烧瓶中。将烧瓶中内容物冷却至0℃,并加入三乙胺(0.15g,1.48mmol)。搅拌溶液,随后将新鲜蒸馏得到的分散在10mLTHF中的丙烯酰氯(0.13g,1.48mmol)精确滴加至溶液中。继续在0℃下搅拌2小时,然后在室温下搅拌12小时。纯化步骤与8-Val-4-Ser25制备方法中的相同。
实施例4
8-Val-4-Ser-OH25丙烯酸酯衍生物的紫外光胶凝化
将0.12g8-Val-4-Ser-OH25丙烯酸酯衍生物以及佳固2959光引发剂(用量为8-Val-4-Ser-OH25丙烯酸酯衍生物的5%w/w)溶于DMSO以制得20%w/v的溶液。将溶液加至特富龙模具中并用100W介压水银紫外灯照射20分钟以制得凝胶。反应如下所示:
实施例5
使用脱保护PEA-LysNCA-25化合物的游离氨基,通过戊二醛制备凝胶。在室温下将0.15g脱保护的PEA-LysNCA-25溶于5mLDMF。在搅拌下往瓶中加入4滴戊二醛(50%水溶液)。数分钟后溶液变成凝胶。
实施例6
在室温下将0.15gPEA-COOH-25以及0.15gDe-PEA-LysNCA-25溶于5mLDMF,在搅拌条件下加入摩尔当量的羰二咪唑。12小时后,溶液变成透明凝胶。
实施例7
可采用与实施例3相同的方法制备PEA-AspNCA-25。通过在室温下将0.25g壳聚糖以及0.15g脱保护的PEA-AspNCA-25溶于5mLDMF,在搅拌条件下加入摩尔当量的羰二咪唑以形成该化合物的透明凝胶。
实施例8
可采用与实施例2相同的方法制备PEA-GluNCA-25。通过在室温下将0.25g壳聚糖以及0.15g脱保护的PEA-GluNCA-25溶于5mLDMF,在搅拌条件下加入摩尔当量的羰二咪唑以形成该化合物的透明凝胶。
Claims (19)
1.式(I)所示的聚(酯酰胺)(PEA):
其中m为0.1-0.9;
n为0.9至0.1;n大于或等于m;
R3是具有在肽合成过程中不需要保护的取代基的第一氨基酸的残基;
R4及R6是(C2-C20)亚烃基;以及
R5是具有选自由NH2、COOH以及OH组成的组中的侧基的第二氨基酸的残基,以及
其中所述侧基可选地被保护,以及
其中所述PEA的Mn为1至500kg/mol。
2.根据权利要求1所述的PEA,其中R3选自由以下组成的组:CH(CH3)2,CH2CH(CH3)2,CH(CH3)CH2CH3,(CH2)CH3,H,CH3,以及(CH2)2SCH3;
R5选自由以下组成的组:(CH2)4NH2,CH2OH,CH2COOH,及(CH2)2COOH。
3.根据权利要求2所述的PEA,其中R5是(CH2)4NH2。
4.根据权利要求2所述的PEA,其中R5是CH2OH。
5.根据权利要求2所述的PEA,其中R5是CH2COOH。
6.根据权利要求2所述的PEA,其中R5是(CH2)2COOH。
7.根据权利要求2所述的PEA,R3是且R5是(CH2)4NH2。
8.根据权利要求2所述的PEA,其中R3是且R5是(CH2)4NH2。
9.根据权利要求1所述的PEA,其中所述第二氨基酸的残基的侧基用保护基修饰。
10.制备权利要求1式(I)所示的PEA的方法,包括:
将氨基酸二酯盐单体与氨基酸N-羧酸酐单体进行反应以获得反应产物,
将该反应产物与硝基酚二酸单体反应以获得式I所示的化合物。
11.根据权利要求10所述的方法,其中氨基酸二酯盐单体是二-(L-α-氨基酸)-α,ω-亚烃基二酯的二-对甲苯磺酸盐。
12.根据权利要求10所述的方法,其中所述氨基酸N-羧酸酐单体用保护基进行修饰。
13.根据权利要求10所述的方法,其中所述二酸单体是二-对硝基苯基癸二酸。
14.根据权利要求10所述的方法,
其中所述氨基酸二酯盐单体是二-(L-α-氨基酸)-α,ω-亚烃基二酯的二-对甲苯磺酸盐;
其中所述氨基酸N-羧酸酐单体用保护基进行修饰;以及
其中所述二酸单体是二-对硝基苯基癸二酸。
15.根据权利要求10所述的方法,其中所述PEA第二氨基酸的侧基被保护。
16.根据权利要求15所述的方法,进一步包含对第二氨基酸的侧基进行脱保护。
17.含有权利要求1所述PEA的组合物。
18.含有权利要求1所述PEA的水凝胶。
19.含有权利要求1所述PEA的凝胶。
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US5219564A (en) | 1990-07-06 | 1993-06-15 | Enzon, Inc. | Poly(alkylene oxide) amino acid copolymers and drug carriers and charged copolymers based thereon |
US6503538B1 (en) | 2000-08-30 | 2003-01-07 | Cornell Research Foundation, Inc. | Elastomeric functional biodegradable copolyester amides and copolyester urethanes |
US7863406B2 (en) * | 2004-06-03 | 2011-01-04 | Cornell Research Foundation, Inc. | Unsaturated poly(ester-amide) biomaterials |
US8445007B2 (en) * | 2005-09-22 | 2013-05-21 | Medivas, Llc | Bis-(α-amino)-diol-diester-containing poly (ester amide) and poly (ester urethane) compositions and methods of use |
US7622533B2 (en) | 2006-08-04 | 2009-11-24 | Nerites Corporation | Biomimetic compounds and synthetic methods therefor |
US9737638B2 (en) * | 2007-06-20 | 2017-08-22 | Abbott Cardiovascular Systems, Inc. | Polyester amide copolymers having free carboxylic acid pendant groups |
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Title |
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Syntheses, Characterization, and Functionalization of Poly(ester amide)s with Pendant Amine Functional Groups;MATTHEW A.DE WIT et al.;《Journal of Polymer Science: Part A: Polymer Chemistry》;20080826;第46卷(第19期);第6376-6392页 * |
Synthesis and Characterization of Biodegradable Poly(ester amide)s with Pendant Amine Functional Groups and In Vitro Cellular Response;Mingxiao Deng et al.;《Biomacromolecules》;20091007;第10卷(第11期);第3037-3047页 * |
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EP2413909A4 (en) | 2014-03-05 |
CN102458367A (zh) | 2012-05-16 |
EP2413909A1 (en) | 2012-02-08 |
US8993686B2 (en) | 2015-03-31 |
US20120123064A1 (en) | 2012-05-17 |
EP2413909B1 (en) | 2016-11-30 |
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