CN110050001A - 被多巴胺官能化的硫酸化透明质酸 - Google Patents
被多巴胺官能化的硫酸化透明质酸 Download PDFInfo
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- CN110050001A CN110050001A CN201780070534.3A CN201780070534A CN110050001A CN 110050001 A CN110050001 A CN 110050001A CN 201780070534 A CN201780070534 A CN 201780070534A CN 110050001 A CN110050001 A CN 110050001A
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- China
- Prior art keywords
- dopa
- hyaluronic acid
- dopamine
- has2
- sulphated hyaluronic
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- 229960003638 dopamine Drugs 0.000 title claims abstract description 36
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical class CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 title claims abstract description 35
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Abstract
公开了2级硫酸化透明质酸,其具有2‑60%摩尔、优选15‑35%并且甚至更优选20‑25%的被多巴胺官能化的羧基,所述多巴胺通过酰胺键或通过间隔体直接缀合,所述间隔体具有用于与透明质酸的羧基形成酰胺键的氨基和用于与多巴胺的氨基形成酰胺键的羧基。
Description
本发明涉及通过酰胺键被多巴胺官能化的硫酸化透明质酸,所述酰胺键可以是直接的或通过适合的间隔体基团。本发明化合物与具有带正电荷的可电离基团的药物、特别是抗生素形成盐。本发明的另一个目的是所述盐及其用于涂覆一般可植入活生物体或生物医学装置中的钛内假体的用途。
现有技术
透明质酸(HA)是由D-葡糖醛酸和N-乙酰基-D-葡糖胺的交替残基组成的杂多糖,其具有直链,分子量范围在50000至13×106Da之间,这取决于获得它的来源和使用的制备方法。
透明质酸在人体中实际上普遍存在,它在其中起重要作用,特别是作为许多组织的细胞的机械支持物,例如皮肤、肌腱、肌肉和软骨。HA与其CD44膜受体和阿片样受体的相互作用也是已知的。
已知O-硫酸化HA衍生物,其中-OH基团被硫酸酯化。O-硫酸化可以通过已知技术进行(参见,例如EP702699和EP940410);“硫酸化度”是指每摩尔HA二聚体(DSmol)中的硫酸酯基团的摩尔数;特别地:
1级硫酸化定义DSmol介于0.5与1.5之间;
2级硫酸化定义DSmol介于1.5与2.5之间;
3级硫酸化定义DSmol介于2.5与3.5之间。
通常,HAS容易穿过皮肤屏障,从而简化了与其相关的物质的通过,因此是药理学和生物学活性分子的皮肤吸收的优异载体。
还发现(WO2010130468;WO2010130466)HAS具有药理学性质:它是有效的抗炎剂,其通过有效调节许多促炎细胞因子和抗炎细胞因子的活性来发挥其作用。因此,HAS适用于治疗由细胞因子水平改变介导的障碍(类风湿性关节炎、哮喘、全身和皮肤自身免疫疾病、病毒感染、特应性皮炎、湿疹、白癜风、淋巴瘤等)。
多巴胺合成中的氨基酸中间体DOPA(1-3,4-二羟基苯丙氨酸)是已知的神经递质,并且最近也作为粘附物质进行了研究。已经在称为“紫贻贝(Mytilus edulis)足蛋白”(Mefp,特别是Mefp-3和Mefp-5)的蛋白质的氨基酸组成中发现了显著浓度的DOPA残留物,其构成了紫贻贝(Mytilus edulis)的花序梗,通常称为贻贝,粘附在表面上。DOPA的关键特征是儿茶酚基团;这启示高浓度的儿茶酚单元在促进与多个表面的粘附方面起着关键作用,包括玻璃、塑料、陶瓷和基于金属和金属氧化物的表面。尽管尚未完全理解发生所述粘附的机理,但是当儿茶酚基团采取醌的形式时,已知在酸性介质(pH=5)和碱性介质(pH=8)中都发生粘附。由于多巴胺衍生物也具有相同的特性,所以DOPA和多巴胺在粘附活性方面被无差别地定义并且用于科学文献中。
HA,“原样”和其硫酸化形式,已经与其它聚合物组合用于金属(通常是钛)和聚合物(例如PU)假体的涂层中,以促进生物和血液相容性(EP1060204)。
DOPA也已经用作粘合剂以促进与具有金属核的其它分子(通常是聚合物)的键合(Lee等人,Adv Mat,2008,20,4154-4157)。
最后,存在这样的实例,其中金属假体涂覆有与聚合物缀合的DOPA,所述聚合物又可以与抗生素键合,从而降低细菌增殖的可能性。例如,Lee等人(Bone,2012,50,974-982)描述了与肝素缀合并且进一步被抗生素和BMP2官能化的DOPA,以促进钛牙科假体的骨整合。选择肝素是因为它含有硫酸酯基团,使得缀合物完全带负电荷,因此能够与带正电荷的抗生素键合。然而,肝素的存在是至关重要的,因为其众所周知的抗凝活性可能存在问题并且在植入期间和之后产生异常出血。
本发明的描述
现已发现,硫酸化透明质酸(HAS)和多巴胺的缀合物可以有利地用于通过静电相互作用吸附带正电荷的生物学和/或药理学活性抗生素或分子。用药物或其它活性化合物功能化的HAS与多巴胺的缀合物可用于一般地涂覆生物医学制品,并且特别是钛假体,以使它们具有生物相容性,并且特别是在钛假体的情况下,从而改善它们与植入它们的骨基质的整合。本文所述的硫酸化透明质酸(HAS)与多巴胺的缀合物在与具有紧凑结构的经典钛假体或具有多孔(小梁)交联结构的最新一代假体一起使用时证明是特别有效的,优选可与骨整合。植入后,用本文所述的缀合物处理的小梁假体不仅是生物相容性的,而且由于其特定的结构,也被细胞定植并且与骨完全整合。
形成本发明目的的硫酸化透明质酸(HAS)与多巴胺的缀合物在减少来源于植入物可能产生的感染方面也起主导作用。后一方面特别重要,因为细菌生长和随后的生物膜形成代表一个主要的并发症,而不是在人工膝关节、髋关节等的初次植入阶段,如在第一次检查假体后的并发症如此之多,导致需要在5-40%的病例中移除。据估计,导致假体移除的约80%的感染由于细菌生物膜形成导致。
生物膜是具有高细菌密度的微生物(金黄色葡萄球菌(Staphylococcus aureus)、表皮葡萄球菌(S.epidermidis)、溶血葡萄球菌(S.haemolyticus)等)的蓄积,其包封在多糖基质中并且粘附于固体生物或非生物表面,通常对用抗生素全身治疗具有抗性。
本发明使用的硫酸化透明质酸是2级(HAS2),即其中每摩尔HA二聚体中的硫酸酯基团的摩尔数(DSmol)范围在1.5与2.5之间的HAS。
HAS2的羧基与直接键合或通过间隔体键合的多巴胺的官能化百分比范围对于直接和间接键二者为2至60%摩尔;对于直接键,优选为15至40%,甚至更优选为20至32%,而对于间接键,优选范围为2至20%。
多巴胺与HAS2之间的键是酰胺类型,并且可以是方案A中所示的直接键(多巴胺的HA-NH2的COOH),或者为间接的,在多巴胺与HAS之间插入间隔体时,始终通过酰胺键键合,以便最大化多巴胺与待官能化的钛表面的相互作用,从而降低HAS2的空间效应。所用的间隔体可以是具有长度范围为5至10个亚甲基单元、优选5或10个的烷基链(方案B),或式HOOC-(CH2)n-O-[(CH2)2-O]m-(CH2)2-NH2的聚乙二醇链(方案C)。
方案A
方案B
方案C
因此,间隔体具有用于与透明质酸的羧基形成酰胺键的氨基,和用于与多巴胺的氨基形成酰胺键的羧基。
适用于制备本发明的2级硫酸化透明质酸的间隔体化合物具有下式:
-HOOC-(CH2)n-NH2,其中n为5至10的整数,并且优选5或10;
-HOOC-CH2-(O-CH2-CH2)m-O-CH2-CH2-NH2,其中m为1或2。
所述化合物是已知的或者可以通过公知方法制备。
HAS2与多巴胺之间的反应使用已知的形成酰胺键的条件进行,例如在缩合剂例如羰基二咪唑(CDI)或二酰亚胺的存在下进行。
为了制备衍生物,其中多巴胺通过间隔体与硫酸化透明质酸键合,优选首先合成多巴胺-间隔体中间体,然后使中间体与HAS2缀合。在氨基上适当地保护的间隔体可以在常规缩合剂和碱的存在下与多巴胺盐酸盐反应。在除去保护基之后,所得中间体然后在上述用于形成酰胺键的条件下与HAS2反应。
起始透明质酸可以衍生自任何已知来源,例如通过从公鸡冠中提取(EP138572),发酵或生物合成(来自芽孢杆菌属(Bacillus),WO2012032154);在该特定情况下,使用2级HAS,由HA制备,其重均MW范围为100,000至250,000Da,特别是180,000至230,000Da,下文称为“MW 200kDa”。制备通过已知方法(EP0702699;IT102015000073016)进行,并且在实施例中报道。
“平均分子量”(MW)在此是指通过“特性粘度”方法计算的重均MW(Terbojevich等人,Carbohydr.Res.,1986,363-377)。
本发明化合物可以用作药物载体和用于涂覆内假体。
主要由基于钛的金属制成具有紧凑或小梁结构的可植入的假体单纯地通过将本发明化合物的溶液喷洒到假体上、任选随后喷洒抗生素或者生物学或药理学活性物质的溶液来涂覆,适当处理以具有正电荷,例如生长因子(BMP-2;TGF1β;IGF)或合成分子,已知它们对生物膜形成具有抑制作用(例如酸形式的双氯芬酸)。
可用的抗生素是可带正电荷的抗生素,特别是庆大霉素、达托霉素、万古霉素、环丙沙星、美罗培南、阿米卡星、妥布霉素、多粘菌素、粘菌素和杆菌肽,优选庆大霉素、粘菌素和达托霉素。
所述抗生素与被多巴胺官能化的2级硫酸化透明质酸形成盐。所述盐和吸附它们的假体是本发明的另一个目的。
本发明的HAS2-多巴胺化合物相对于现有技术具有如下优点:
·它是可喷涂的。现有技术需要将假体浸入在含有“粘合剂”聚合物的溶液中,有时长时间(数小时),但本发明通过简单的喷涂,甚至直接在手术室中进行,确保平坦、均匀的覆盖,无菌的总体维持性,并且特别是在植入假体之前粘附和干燥时间显著减少甚至消除;
·它完美地粘附在金属假体上;
·它是生物可相容的;
·它保留了假体的表面粗糙度,这是促进与骨基质整合所必需的;
·它可通过最著名的技术(用β或γ射线照射)灭菌,并且在灭菌后维持其结构特征完整(多巴胺无氧化降解),因此,在与抗生素缀合后,也能维持其生物功效(未改变的抗菌活性)。这意味着,必要时,植入的假体可以被涂覆HAS2-DOPA,灭菌,在手术室使用前长久存放,并且在使用时喷洒抗生素,在这种情况下无需等待直到手术室假体粘附和干燥时间结束,这在长时间手术操作的情况下特别重要;
·它刺激成骨细胞再生;
·它产生一组负电荷,适用于与带正电荷的抗生素(或一般的活性分子)的静电相互作用。以这种方式,感染的发作显著减少,因为细菌生物膜的形成被防止或强烈限制;
·它几乎没有肝素样作用,它含有硫酸酯基团,并且因此不会引起异常出血;
·它以极其有效、快速、持久的方式发挥作用。
附图描述
图1:未处理的钛圆柱体表面的ESEM图像和突出显示区域的相应XPS谱。
图2:涂覆有实施例3的衍生物的钛圆柱体表面的ESEM图像和突出显示区域的相应XPS谱。
图3:用实施例3的衍生物处理,然后洗涤的圆柱体表面的ESEM图像。
图4:显示金黄色葡萄球菌(S.aureus)在被实施例3的HAS2-DOPA官能化或涂覆有庆大霉素的实施例12的HA-DOPA官能化的钛圆柱上的生长抑制的曲线。
图5:与键合至庆大霉素的实施例11的肝素-DOPA(HEPA-DOPA)缀合物相比的实施例3的HAS2-DOPA缀合物以CFU/mL表示的抗微生物活性。
图6:通过与实施例11的HEPA-DOPA比较的实施例6的HAS2-DOPA的抗凝作用。
图7:通过与纤连蛋白比较的实施例3和12的HAS2-DOPA对成骨细胞增殖的影响。
制备实施例
2级硫酸化透明质酸与多巴胺的缀合物(下文称为HAS2-DOPA)分两步合成:HAS2的合成和HAS2与多巴胺之间的反应。由此,HAS2可以由与四丁基铵(TBA;EP702699)成盐的HA或与钠成盐的HA(IT102015000073016)制备。
实施例1:由HA-TBA制备HAS2
将2.0g d.m.(3.22×10-3mol;1当量)HA-TBA+(MW 200kDa)溶于200mL DMSO。当溶解完成时,加入3.59g Pyr·SO3(8当量)。在室温保持过夜后,用EtOH沉淀产物,并且过滤得到的沉淀,用EtOH洗涤2次,并且再溶于150mL去离子水;加入8mL NaCl饱和溶液和115mLDMSO,用3M NaOH将pH校正至3.4±0.1。用440mL EtOH沉淀产物,并且过滤得到的沉淀,用EtOH/H2O混合物(80:20)和EtOH洗涤,并且最终在37℃真空干燥。
实施例2:由HA-Na制备HAS2
将4.0g d.m.(9.96×10-3mol;1当量)HA-Na+(MW 200kDa)分散于220mL DMSO中;加入3.6mL甲磺酸(5当量),并且将该混合物在室温保持搅拌24小时。当溶解完成时,加入12.8g Pyr·SO3(8当量)。在室温保持过夜后,用EtOH沉淀产物,并且用Gooch过滤得到的沉淀,用EtOH洗涤2次,并且再溶于150mL去离子水;加入8mL NaCl饱和溶液和115mL DMSO,并且用3M NaOH将pH校正至3.4±0.1。用440mL EtOH沉淀产物,并且过滤得到的沉淀,用EtOH/H2O混合物(80:20)和EtOH洗涤,并且最终在37℃真空干燥。
实施例3:具有23%衍生化度的HAS2-DOPA缀合物的合成(直接键)
将如实施例2制备的2.0g d.m.(3.3×10-3mol,1当量)HAS2钠盐溶于100mL去离子水,并且将3.0g苯扎氯铵(BA+Cl-)单独地溶于100mL去离子水。当溶解完成时,将BA+Cl-溶液加入到HAS2溶液中,由此得到沉淀,过滤,用H2O、EtOH洗涤,然后用丙酮洗涤,并且在旋转蒸发器中高真空干燥。将分离的沉淀溶于160mL DMSO;然后加入0.267g(0.5当量)CDI和0.1mL甲磺酸(0.5当量)。在40℃搅拌30分钟后,加入0.5g(0.8当量)多巴胺盐酸盐,并且将该反应在40℃持续缓慢搅拌过夜。第二天加入16mL饱和NaCl溶液,并且用EtOH沉淀产物。过滤得到的沉淀,并且用2个体积的EtOH/H2O(85:15)组成的混合物、然后用EtOH、并且最终用丙酮洗涤。将得到的产物溶于50mL去离子H2O,并且在0.05M乙酸盐缓冲液pH 5中透析(具有截止值=12,000-14,000Da的Spectra/透析膜)3天,并且在通过添加1M HCl调整至pH 5的H2O中透析1天。
调节透析时间,通过GPC验证透析膜中游离多巴胺的消失。最后,将透析的产物冷冻并且冷冻干燥。
实施例4:具有55%衍生化度的HAS2-DOPA缀合物的合成(直接键)
如实施例3所述合成和表征衍生物,从2g HAS2钠盐开始,用BA成盐并且与1.34g(2.5当量)CDI和2.5g(4.0当量)多巴胺盐酸盐反应。
实施例5:具有31%衍生化度的HAS2-DOPA缀合物的合成(直接键)
如实施例3所述合成和表征衍生物,从2g HAS2钠盐开始,用BA成盐并且与0.801g(1.5当量)CDI和1.25g(2.0当量)多巴胺盐酸盐反应。
实施例6:具有21%衍生化度的HAS2-DOPA缀合物的合成(直接键)
如实施例3所述合成和表征衍生物,从2g HAS2钠盐开始,用BA成盐并且与0.134g(0.25当量)CDI和0.25g(0.4当量)多巴胺盐酸盐反应。
实施例7:具有6%衍生化度的HAS2-DOPA缀合物的合成(直接键)
如实施例3所述合成和表征衍生物,从2g HAS2钠盐开始,用BA成盐并且与0.067g(0.125当量)CDI和0.25g(0.4当量)多巴胺盐酸盐反应。
实施例8:具有5%衍生化度的HAS2-CONH-(CH2)10-CONH-多巴胺缀合物的合成(通过具有10个碳原子的烷基间隔体的间接键合)
间接键合包括两个步骤:多巴胺-间隔体种类的合成,随后是具有HAS2的多巴胺-间隔体的合成:
-8.1:多巴胺-间隔体合成:NH2-(CH2)10-CONH-多巴胺
0.55g 11-(Boc-氨基)十一酸溶于10mL DMF,并且用0.56g EDC(N-乙基-N’-(3-二甲基氨基丙基)碳二亚胺盐酸盐活化羧基,在0℃,在搅拌下在叔碱(TEA,0.31mL)存在下加入DMAP(0.07g)。10分钟后加入0.4g多巴胺盐酸盐,并且在RT将该混合物搅拌过夜。然后加入40mL二氯甲烷和40mL H2O,并且萃取有机相,用水洗涤,并且用旋转蒸发器干燥。通过加入5mL如下酸混合物:TFA 15%/H2O 5%/DCM 80%,并且在搅拌下将得到的混合物保持在RT下20分钟释放BOC保护基。然后蒸发溶剂,并且干燥产物。
-8.2:HAS2-CONH-(CH2)10-CONH-DOPA的合成
如实施例3所述合成和表征衍生物,从1g HAS2钠盐开始,用BA成盐并且与0.45gCDI和如实施例8.1中得到的0.5g NH2-(CH2)10-CONH-DOPA反应。
实施例9:具有5%衍生化度的HAS2-CONH-(CH2)5-CONH-多巴胺缀合物的合成(通过具有5个碳原子的烷基间隔体的间接键合)
通过使用6-(Boc-氨基)己酸作为试剂并且按照实施例8.1中所述方法得到多巴胺-间隔体。
根据实施例8.2中所述的方法得到产物HAS2-CONH-(CH2)5-CONH-多巴胺。
实施例10:具有5%衍生化度的HAS2-CONH-(CH2)2-O-(CH2)2-O-CH2-CONH-DOPA缀合物的合成(通过聚乙二醇间隔体的间接键合)
间接键合包括2个步骤:DOPA-间隔体种类的合成,然后是具有HAS2的DOPA-间隔体的合成。
-DOPA-间隔体合成:NH2-(CH2)2-O-(CH2)2-O-CH2-CONH-DOPA
将0.64g Boc-NH-(PEG)-COOH.DCHA(9个原子)溶于10mL DMF,并且用0.56g EDC(N-乙基-N’-(3-二甲基氨基丙基)碳二亚胺盐酸盐活化羧基,在0℃,在搅拌下在叔碱(TEA,0.31mL)存在下加入DMAP(0.07g)。10分钟后加入DOPA(多巴胺盐酸盐),并且在RT将该混合物搅拌过夜。然后加入40mL二氯甲烷和40mL H2O,并且萃取有机相,用水洗涤,并且用旋转蒸发器干燥。通过加入5mL如下酸混合物:TFA 15%/H2O 5%/DCM80%,并且在搅拌下保持在RT下20分钟释放BOC保护基。然后蒸发溶剂,并且干燥产物。得到0.5g产物(83%收率)。
-HAS2-CONH-(CH2)2-O-(CH2)2-O-CH2-CONH-DOPA的合成
如先前对HAS2-DOPA衍生物所述合成该衍生物,从1g HAS2钠盐开始,与BA成盐并且与0.45g CDI和0.5g NH2-(CH2)2-O-(CH2)2-O-CH2-CONH-DOPA反应。
实施例11(比较):具有21%衍生化度的肝素(HEPA)-DOPA缀合物的合成(根据Lee等人,2012制备)
将1.0g d.m.(3.3×10-3mol,1当量)肝素钠(HEPA)溶于50mL去离子水,并且将1.5g苯扎氯铵(BA+Cl-)单独地溶于100mL去离子水。当溶解完成时,将BA+Cl-溶液加入到HEPA溶液中,由此得到沉淀,过滤,用H2O、EtOH洗涤,然后用丙酮洗涤,并且在旋转蒸发器中高真空干燥。将分离的沉淀溶于80mL DMSO;然后加入0.134g(0.5当量)CDI和0.05mL甲磺酸(0.5当量)。在40℃搅拌30分钟后,加入0.25g(0.8当量)多巴胺盐酸盐,并且将该反应在40℃持续缓慢搅拌过夜。第二天加入8mL饱和NaCl溶液,并且用EtOH沉淀产物。过滤得到的ppt,并且用2个体积的EtOH/H2O(85:15)组成的混合物、然后用EtOH、并且最终用丙酮洗涤。将得到的产物溶于50mL去离子H2O,并且在0.05M乙酸盐缓冲液pH 5中透析(具有截止值=3,000Da的Spectra/透析膜)3天,在通过添加1M HCl调整至pH 5的H2O中透析1天。
调节透析时间,通过GPC验证透析膜中游离多巴胺的消失。
实施例12(比较):具有23%衍生化度的HA-DOPA缀合物的合成
通过实施例3中描述的方法合成HA-DOPA衍生物,从1.32g(0.0033摩尔)HA钠盐200kDa开始,与BA成盐并且与0.267g(0.5当量)CDI和0.5g(0.8当量)多巴胺盐酸盐反应。
实施例13:HAS2-DOPA衍生物的粘附测试
由于多巴胺在多种pH值下充当粘合剂,因此测试了其在两个最具代表性的pH值即5和8下溶解在PBS中的HAS2-DOPA缀合物(如实施例5中所述制备)的涂覆能力:
-溶液A:在4mL 0.1M MES pH 5中的20mg HAS2-DOPA(31%)
-溶液B:在4mL 0.1M PBS pH 8中的20mg HAS2-DOPA(31%)
在任何pH下带正电荷的荧光探针(盐酸血根碱)用于本测试,以模拟所述衍生物与生理pH下的带正电荷的抗生素的相互作用。
将两个钛圆柱体(d=15×h=17mm)分别用溶液A和溶液B均匀喷涂,用去离子水洗涤,在气流中干燥并且浸入含在0.1M MES,pH 5中有浓度为0.5mg/mL的血根碱溶液的不同小瓶中。将圆柱体在RT温和搅拌过夜。第二天,用去离子水再次洗涤圆柱体,在N2流下干燥并且用UV灯在360nm下照射,进行目视检查。
通过处理的圆柱体发出的荧光的评估,推断出pH 8的多巴胺衍生物(溶液B)最佳地粘附在表面上。该发现表明,溶液B代表了用于实施本发明的理想方法。
13.1:钛表面涂覆的电子显微镜(ESEM)分析
本试验确立,通过喷涂在圆柱体表面上沉积的HAS2-DOPA衍生物不仅可以均匀地粘附在Ti上,而且维持了促进假体与骨基质骨整合所需的表面粗糙度。制备HAS2-DOPA(23%;实施例3)25mg/mL在0.1M PBS(pH 8)中的溶液,并且将1mL所述溶液喷涂到Ti圆柱体上;使其风干并且在ESEM下观察表面,将其与未处理的圆柱体进行比较(图1和2)。除了照相扫描之外,还进行定性XPS分析(光电子X射线光谱法,其检测在所分析的表面上有机物质的存在)。然后洗涤处理的圆柱体以确定衍生物是否继续粘附在表面上,甚至是在体内植入后它与生理流体流接触的情况(图3)。
通过XPS分析证实,处理的表面的图像清楚地显示了材料的存在。此外,干燥的衍生物产生表面不规则性,使表面具有粗糙的质地,这是促进植入物与骨基质整合的重要参数。
洗涤后,在表面上仍然可以看到衍生物残留物,证实衍生物与Ti活跃地相互作用,并且即使在洗涤后也继续粘附。
这表明HAS2-DOPA缀合物:
·完全粘附在钛表面,特别是在pH=8的溶液中制备时;
·洗涤后它仍然键合在表面上;
·并且为金属表面提供促进假体骨整合所需的粗糙质地。
实施例14:抑制金黄色葡萄球菌(S.aureus)细菌生长的体外试验(用HAS2-DOPA或HA-DOPA和庆大霉素官能团化的钛圆柱体)
制备如下:
HAS2-DOPA(23%,实施例3)在0.1M PBS pH=8中的溶液;
HA-DOPA(23%,实施例12)在0.1M PBS pH=8中的溶液;
庆大霉素溶液(25mg/5mL 0.25M MES,pH=5.2);
0.1M PBS pH=8溶液(对照)。
用HAS2-DOPA溶液喷涂2个钛圆柱体(d=15×h=17mm),保持风干15分钟,喷洒庆大霉素溶液,并且再保持风干15分钟。
对相同尺寸的另外两个钛圆柱体进行相同的处理,首先用HA-DOPA衍生物溶液,然后用庆大霉素溶液通过上述方法喷涂。
最后,将另外两个相同尺寸的钛圆柱体用PBS溶液,然后用庆大霉素溶液通过上述步骤喷涂。
然后将每个圆柱体(总共6个)浸入MQ水中一次5秒钟,风干15分钟并且插入培养肉汤中(缓冲蛋白胨水:蛋白胨10.0g/L、氯化钠5.0g/L、无水磷酸二钠3.6g/L、磷酸钾1.5g/L,Biokar Diagnostics)接种600,000,000CFU/mL金黄色葡萄球菌(Staphylococcus.aureus)。将肉汤在37℃温育,并且在预定时间(6小时、12小时、24小时、48小时、144小时)吸取1mL上清液并且用无菌盐水溶液以1:10标量稀释(根据细菌生长),进行板接种(PCA-平板计数琼脂:胰蛋白胨5.0g/L、酵母提取物2.5g/L、葡萄糖1.0g/L、细菌学琼脂12.0g/L。由Biokar Diagnostics制备)。然后进行CFU/mL计数。
与6亿CFU/mL金黄色葡萄球菌(S.aureus)的初始接种物相比,细菌生长抑制百分比数据随时间的变化如图4所示。
示意图表清楚地表明:
·HAS2-DOPA的作用的有效性远超过对照(PBS);这意味着HAS2-DOPA会随着时间的推移以可控的、恒定的方式释放庆大霉素;
·HAS2-DOPA的作用方式远比HA-DOPA更为显著;
·令人惊讶的是,除了在最初的24小时内完全抗微生物作用外,HAS2-DOPA可以长达144小时,即接种后7天保持长期抗菌覆盖,而HA-DOPA仅48小时后就恢复了金黄色葡萄球菌(S.aureus)的增殖。
用相同浓度的达托霉素进行类似的试验,并且得到相同的活性曲线。
实施例15:比较试验:与键合庆大霉素的肝素-DOPA(HEPA-DOPA)缀合物相比的HAS2-DOPA缀合物的抗微生物活性。
如实施例6制备HAS2-DOPA缀合物,并且如实施例11制备HEPA-DOPA衍生物(衍生度:21%)。
两个钛圆柱体(d=15×h=17mm)分别用HAS2-DOPA或HEPA-DOPA在pH 8的PBS中以20mg/mL的浓度喷涂,随后用在MES pH 5.2中的5mg/mL的庆大霉素喷涂。然后在MQ水中进行3次连续浸渍洗涤(5秒);重复洗涤的目的在于消除所有实际上没有静电键合至测试种类上的庆大霉素。然后将圆柱体插入具有金黄色葡萄球菌(S.aureus)接种物(600,000,000CFU/mL)的试管中;在预定时间取出1mL上清液,然后用无菌盐水溶液1:10标量稀释(根据细菌生长)用于平板接种(PCA-平板计数琼脂:胰蛋白胨5.0g/L,酵母提取物2.5g/L、葡萄糖1.0g/L、细菌学琼脂12.0g/L(Biokar Diagnostics))。然后进行CFU/mL计数,如图5所示。
结果表明,HAS2-DOPA产物在抑制金黄色葡萄球菌(S.aureus)增殖、衍生化度和浓度相等方面更具活性,并且所述活性持续至少36小时。考虑到HEPA-DOPA衍生物在36小时后逐渐并且迅速地丧失其抗菌活性,等于“对照”(其没有抗菌活性)的事实,该结果特别显著。
实施例16:HAS2-DOPA与HEPA-DOPA之间抗凝作用的比较
制备实施例6的HAS2-DOPA缀合物和实施例11的HEPA-DOPA衍生物。
使用纯肝素作为标准品评估抗凝作用。使用采用比色法的试剂盒(HyphenBioMed,Biophen Heparin AT+Ref 221007);测定未被肝素或测试聚合物络合和抑制的凝血因子Xa。405nm处的吸光度与游离Xa因子成正比,因此与所测试种类的肝素样活性成反比(图6)。
显而易见,HAS2-DOPA的抗凝作用远小于浓度相等的HEPA-DOPA的抗凝作用;为了获得与HAS2-DOPA系统相同的效果(Abs减少50%),需要高约50倍的浓度。这意味着尽管含有像肝素一样的硫酸化聚合物,HAS2-DOPA缀合物比已知产品具有更低的抗凝作用。
与庆大霉素或类似抗菌剂键合的HAS2-DOPA缀合物是有利的,因为它既可以通过喷涂应用,也可以在很短的时间内使用,几乎没有肝素样作用,因此不会产生异常出血,并且以远比已知的等价物更有效、快速、持久的方式起作用。
实施例17:HAS2-DOPA和HA-DOPA对体外成骨细胞增殖的影响的评估
制备如下:
-HAS2-DOPA的水溶液(23%,实施例3)10mg/mL
-HA-DOPA的水溶液(23%,实施例12)10mg/mL
-纤连蛋白水溶液20μg/mL(阳性对照)。
用HAS2-DOPA溶液喷涂两个2个钛圆柱体(d=15×h=17mm)的圆形上表面并且风干15分钟;将相同的处理应用于相同尺寸的另外两个钛圆柱体,根据上述方法用HA-DOPA溶液喷涂。最后,根据上述方法,用纤连蛋白在水中的溶液喷涂另外两个相同尺寸的钛圆柱体。纤连蛋白在体外细胞增殖试验中被广泛用作参比标准,因为它刺激细胞粘附、增殖和迁移。
然后,将每个圆柱体(总计6个)浸入MilliQ水中一次5秒,保持风干15分钟并且插入板孔中;然后将在培养基(McCOY’S 5A+10%FBS)中的0.10mL成骨细胞(来自骨肉瘤的Saos-2细胞系),相当于约50000个细胞/cm2的钛沉积在每个圆柱体的表面上。将细胞在钛上于37℃(5%CO2)温育4小时以使其粘附;然后加入培养基直至浸没圆柱体,并且在相同条件下继续温育过夜。
第二天除去培养基,并且用PBS洗涤圆柱体以消除未粘附的细胞;然后向每个圆柱体中加入等体积的相同培养基与10%阿拉玛蓝,并且将圆柱体在37℃(5%CO2)保持温育24小时。温育后,进行荧光读数(λ激发:530nm,发射:590nm);荧光的强度与细胞代谢成正比,因此与活的成骨细胞的数量成正比。
结果(图7)表明,衍生化度和浓度相等,HAS2-DOPA具有极高的几乎等于纤连蛋白的骨整合活性,并且令人惊讶地,几乎是HA-DOPA的两倍。这些值具有统计学显著性。
C-表示阴性对照,即“原样”的钛圆柱体,没有接种成骨细胞。
实施例18:如实施例3中制备的23%HAS2-DOPA粉末对β-射线和γ射线灭菌的稳定性评估
如实施例3中所述,制备三个1g 23%HAS2-DOPA粉末样品。样品分别进行:
·用β射线灭菌;
·用γ射线灭菌;
·无灭菌(对照)。
然后通过不同的已知方法分析样品,即在粉末在重水(D2O)中溶解后的1H-NMR(质子核磁共振谱)中的结构分析与IR分析(在KBr颗粒中)和最后在水中溶解后的可见UV分析(UV-Vis)。
分析结果证实,灭菌样品的信号是相同的,最重要的是它们与未灭菌对照的信号之间没有差异。特别地,没有观察到由于副产物的形成而产生的信号(NMR和IR分析)或UV-Vis吸收信号由于例如多巴胺氧化而发生移位。
因此,HAS2-DOPA聚合物稳定并且与β-射线或γ-射线灭菌相容。
实施例19:在被HAS2-DOPA官能化并且用β射线灭菌并且随后用万古霉素处理的钛圆柱体上金黄色葡萄球菌(S.aureus)细菌生长抑制的体外试验
制备如下:
HAS2-DOPA的溶液(23%,实施例3),10mg/mL,在水中;
万古霉素溶液,5mg/mL,在水中。
一个钛圆柱体(d=15×h=17mm)(样品A,对照)未经过任何处理,而相同尺寸的第二个钛圆柱体(样品B)用HAS2-DOPA溶液喷涂并且保持风干15分钟。
两个圆柱体通过用β射线照射进行灭菌,随后用制备的万古霉素溶液喷涂,并且最后保持风干15分钟。
然后将两个圆柱体在不同的MQ水溶液中浸渍10次,持续5秒,以消除存在的过量抗生素,并且保持风干15分钟。将金黄色葡萄球菌(Staphylococcus.aureus)混悬液(200μLO.D.,在650nm>0.5)均匀地分布在板中的Mueller-Hinton琼脂(BD Biosciences)的表面上,并且将两个钛圆柱体中的每一个置于接种琼脂表面的中心。将板在35℃温育18小时,然后测量抗生素抑制细菌生长的表面的直径。
用HAS2-DOPA处理并且灭菌的样品B证明比仅对其进行灭菌的对照样品远远更有效地抑制细菌生长。
这意味着灭菌不会改变HAS2-DOPA的结构或性质,HAS2-DOPA继续保持锚定在Ti上,从而保留了与万古霉素键合并且随后释放它的能力。
用相同浓度的庆大霉素和交联钛样品上的万古霉素在相同条件和相同浓度下进行类似的试验,获得与上述相同的细菌生长抑制曲线。
因此,β射线灭菌:
不会改变HAS2-DOPA与钛的粘附性
不会改变HAS2-DOPA的结构特性
并且因此不会改变HAS2-DOPA与抗生素键合并且发挥期望的抗菌作用的能力。
Claims (14)
1.2级硫酸化透明质酸,其具有2-60%摩尔的羧基,该基团被多巴胺官能化,所述多巴胺通过酰胺键直接缀合或者通过间隔体缀合,所述间隔体具有用于与透明质酸的羧基形成酰胺键的氨基和用于与多巴胺的氨基形成酰胺键的羧基。
2.权利要求1的硫酸化透明质酸,其中多巴胺通过酰胺键直接缀合至15-40%、优选20-32%的硫酸化透明质酸的羧基。
3.权利要求1的硫酸化透明质酸,其中多巴胺与硫酸化透明质酸通过间隔体缀合,所述间隔体具有用于与2-20%的硫酸化透明质酸的羧基形成酰胺键的氨基和用于与多巴胺的氨基形成酰胺键的羧基。
4.权利要求3的硫酸化透明质酸,其中间隔体为式HOOC-(CH2)n-NH2化合物,其中n为5至10的整数,优选5或10。
5.权利要求3的硫酸化透明质酸,其中间隔体为式HOOC-(CH2)n-O-[(CH2)2-O]m-(CH2)2-NH2化合物,其中n为1或2,并且m为1或2。
6.权利要求1-5任一项的硫酸化透明质酸,其通过2级硫酸化透明质酸的官能化得到,所述2级硫酸化透明质酸由具有100,000至250,000Da、特别是180,000-230,000Da的重均分子量的透明质酸制备。
7.权利要求1-6的硫酸化透明质酸与具有带正电荷的药物的盐。
8.权利要求7的盐,其中带正电荷的药物选自抗生素、生长因子和酸形式的双氯芬酸。
9.权利要求8的盐,其中带正电荷的药物选自氨基糖苷抗生素、达托霉素、环丙沙星、美罗培南、万古霉素、多粘菌素、粘菌素和杆菌肽。
10.权利要求9的盐,其中氨基糖苷抗生素选自阿米卡星、庆大霉素和妥布霉素。
11.权利要求7的盐,其中带正电荷的药物为庆大霉素、达托霉素、多粘菌素或粘菌素。
12.权利要求1-6的硫酸化透明质酸,其用作药物载体。
13.权利要求1-6的硫酸化透明质酸,其用于涂覆生物医学制品。
14.用权利要求7-11的盐涂覆的钛内假体。
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CN114163662A (zh) * | 2021-12-16 | 2022-03-11 | 江南大学 | 一种纳米酶功能化水凝胶及其制备方法 |
CN114452450A (zh) * | 2022-01-07 | 2022-05-10 | 华南理工大学 | 一种载多聚赖氨酸/角质细胞生长因子透明质酸水凝胶及其制备与应用 |
CN115068368B (zh) * | 2022-06-30 | 2023-05-23 | 杭州求是医学科技有限公司 | 一种导光凝胶及其制备方法 |
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