CN114983991A - 一种兼具抗炎及抗氧化作用的药物 - Google Patents
一种兼具抗炎及抗氧化作用的药物 Download PDFInfo
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Abstract
本发明涉及一种兼具抗炎及抗氧化作用的药物，该药物含有超支化聚赖氨酸。在所述药物中，超支化聚赖氨酸可作为唯一抗氧化及抗炎活性物质，也可与其他生物相容性材料以接枝、吸附、共混等形式复配使用，用于各种急慢性炎症或氧化应激相关疾病的预防和治疗中。
Description
技术领域
本发明属于药物技术领域，涉及一种兼具抗炎及抗氧化作用的药物。
背景技术
炎症反应是机体抵御组织损伤或病原体不可或缺的防御机制，涉及组织微环境的动态演变。在组织损伤后，由受损或受感染组织释放的损伤相关分子模式(DAMPs)或病原体相关分子模式(PAMPs)介导机体在局部组织微环境中产生炎症反应。通常，正常组织修复进程中的炎症反应包括以下几个阶段：①固有免疫反应启动，募集重要的免疫细胞使其浸润到损伤部位处以启动早期促炎症急性阶段，与此同时免疫细胞迅速极化为促炎症表型；②通过促进巨噬细胞等免疫细胞从促炎症表型极化为促修复表型来促进组织修复；③炎症细胞从损伤部位消失或通过细胞凋亡消除的方式实现组织稳态的恢复。然而，一旦炎症反应过于强烈且得不到及时有效的调控，其对于机体组织的持续刺激可能导致慢性炎症发生，并且通常会导致大范围的细胞凋亡、坏死或丢失，损害修复再生的进程。甚至可导致空洞、纤维化或瘢痕的形成，进而造成组织或器官的失能。
活性氧(ROS)是功能正常的线粒体在细胞呼吸过程中由于电子泄露而产生的代谢副产物，主要包括超氧阴离子、羟基自由基、过氧化氢和单线态氧等。通常，损伤部位的炎症反应会导致ROS的过量产生和聚集。这些过量产生的ROS会对细胞中的DNA、蛋白质以及脂质等造成氧化损伤从而诱导细胞大量凋亡或坏死并引起组织损伤。不仅如此，过量产生的ROS也会造成对线粒体功能的破坏，引发更多ROS的产生。ROS还可以作为DAMPs募集免疫细胞，使促炎因子的表达增加，而炎症因子表达的上调则将募集更多免疫细胞并进一步产生更多ROS，从而引起恶性循环。因此，ROS与炎症密切相关。而除ROS外，其他常见的DAMPs如由氧化损伤过程中外泄的胞外DNA、高迁移率组蛋白(HGMB1)、热休克蛋白(HSP)等也作为炎症介质，向炎症组织外周募集和激活免疫细胞，分泌大量炎症因子。
及时有效地调控炎症反应、减少氧化应激损伤可促进患者损伤的组织器官的修复与再生，不仅可以降低医疗健康体系和社会的经济负担，同时也可以提高患者劳动能力的恢复，从而有利于国家经济的发展。然而现有治疗手段难以充分满足临床治疗和患者的需求。当前多数报道的高效抗氧化剂都基于由CeO2或MnO2等无机纳米颗粒或纳米片。然而，CeO2在较高浓度下已被证实可抑制细胞增殖且具有胚胎毒性。此外，文献也报道了MnO2对大鼠神经母细胞的细胞毒性。不仅如此，锰元素的过量暴露也被证实与临床神经元疾病有关。常规的抗炎手段往往依赖于白介素-4(IL-4)、白介素-10(IL-10)、托珠单抗等生长因子或其抗体以及地塞米松、甲基泼尼松龙等糖皮质激素的应用。而生长因子或其抗体明显存在易失活、生物利用度不高、价格昂贵等不足而限制其进一步应用；糖皮质激素类药物也容易引发伤口感染、消化道出血、肺炎、血管栓塞和败血症等副作用。此外，DAMPs多为负电性物质，已有文献报道阳离子聚合物如聚酰胺胺(PAMAM)树枝状大分子和聚乙烯亚胺(PEI)可通过静电相互作用吸附和中和组织微环境中过表达的DAMPs，减少其向外周募集和激活免疫细胞，从而在多种疾病模型中实现炎症的减轻，但这些正电荷聚合物往往具有较大的细胞毒性和较低的生物安全性。
因此，针对急慢性创伤致病机理，构建能够同时调控损伤部位氧化微环境和减轻炎症反应并且生物相容性好的药物及生物材料是当务之急。
发明内容
本发明的目的在于针对现有技术的不足，提供一种兼具抗炎及抗氧化作用的药物，该药物具有抗氧化活性、抗炎功能且对如皮肤伤口等炎症能够有效治疗。
本发明所提供的技术方案为：
本发明提供一种兼具抗炎及抗氧化作用的药物，其主要成分为超支化聚赖氨酸，其化学结构如下所示：
所述超支化聚赖氨酸可以作为药物中的唯一抗炎及抗氧化活性成分；
所述药物可以以超支化聚赖氨酸溶液形式单独使用。
作为优选，所述药物中超支化聚赖氨酸的使用浓度为0.01-2mg/mL。其浓度在低于0.5mg/mL时依然能够有效发挥抗炎及抗氧化作用。
所述超支化聚赖氨酸可作为抗炎和抗氧化功能物质与其他生物相容性材料通过接枝、吸附、共混复配，其他生物相容性材料可以为多孔支架、水凝胶、膜材料、纳米粒子或其他形式。
本发明提供一种如上述的含有超支化聚赖氨酸的抗炎及抗氧化剂在预防和治疗各种急慢性炎症或氧化应激相关疾病中的应用。
所述炎症包括变态反应性炎症、非特异性炎症、感染性炎症以及炎症相关性疾病。所述的非特异性炎症为物理性炎症，包括外伤或手术引起的红肿、疼痛；感染性炎症包括细菌、细菌产物或病毒造成的炎症；炎症相关性疾病包括炎症性皮肤创面炎症、肠炎、肺炎、口腔炎、皮肤炎等。
本发明以细菌感染性创面炎症为模型，验证了本发明的如上述的含有超支化聚赖氨酸的抗炎及抗氧化药物在抑制氧化应激和抗炎方面的作用。
本发明的有益效果在于：
本发明提供了一种兼具抗炎及抗氧化作用的药物，该药物含有超支化聚赖氨酸，是天然赖氨酸的聚合物，体内可降解，降解产物为人体可代谢的氨基酸，生物安全性好，且制备简易，成本低。在所述药物中，超支化聚赖氨酸可作为唯一抗氧化及抗炎活性物质，用于各种急慢性炎症或氧化应激相关疾病的预防和治疗中。此外，所述药物也可由超支化聚赖氨酸与其他生物相容性材料复配使用。所述药物使用方式灵活，适用范围广。
附图说明
图1超支化聚赖氨酸随时间变化的1，1-二苯基-2-三硝基苯肼(DPPH)清除率
图2多孔支架(Sca)和负载超支化聚赖氨酸的多孔支架(Sca/HBPL)的形貌
图3负载超支化聚赖氨酸的多孔支架(Sca/HBPL)随时间变化的DPPH清除率
图4负载超支化聚赖氨酸的多孔支架(Sca/HBPL)随时间变化的双氧水清除率
图5超支化聚赖氨酸交联的水凝胶照片
图6(a)用活性氧特异性荧光染料二氢乙锭(DHE)标记伤口和周围新生皮肤组织中的ROS水平及(b)活性氧探针DHE荧光强度定量分析
图7(a)皮肤组织的髓过氧化物酶(MPO)免疫组化染色以及其中(b)MPO染色面积定量分析
图8皮肤组织的细胞因子水平
具体实施方式
下面结合具体实施例和说明书附图对本发明作进一步说明。
实施例1：超支化聚赖氨酸的自由基清除能力测定
将100μg超支化聚赖氨酸与1mL 200μM 1，1-二苯基-2-三硝基苯肼(DPPH)/乙醇溶液在37℃的避光条件下共同孵育，分别在预设时间点取上清液，测定其在517nm处的吸光度，以100μg水代替超支化聚赖氨酸作为对照组样品，通过计算每个时间点样品组和对照组的相对吸光度计算DPPH的清除率。
如图1所示，随着时间延长，超支化聚赖氨酸对DPPH的清除率逐渐增加，24小时可以清除过半的DPPH自由基。证明了超支化聚赖氨酸的抗氧化能力。
实施例2：负载超支化聚赖氨酸的多孔支架制备和抗氧化性能测定
(1)负载超支化聚赖氨酸的多孔支架制备
将含有23mg 1，6-己二胺，0.4g聚(甲基丙烯酸环氧丙酯-co-甲氧基聚乙二醇单甲基丙烯酸酯)和15mg聚乙烯醇的2mL混合溶液在37℃条件下反应过夜后获得水凝胶，将水凝胶冻干后得到多孔支架Sca。将Sca浸泡在2mg/mL超支化聚赖氨酸溶液中过夜，获得负载超支化聚赖氨酸的多孔支架Sca/HBPL。
(2)负载超支化聚赖氨酸的多孔支架的DPPH清除能力测定
将10mg含有超支化聚赖氨酸的多孔支架Sca/HBPL和不含超支化聚赖氨酸的多孔支架Sca在避光条件下分别浸入到1mL 200μM DPPH/乙醇溶液中。在预设时间点下取样，用酶标仪测定每种溶液在517nm波长处的吸光度。使用10mg水代替支架制备对照样品。以样品组对对照组的相对吸光度来计算DPPH的清除率。
(3)负载超支化聚赖氨酸的多孔支架的双氧水清除能力测定
将100mg上述两种支架浸于37℃的500μL 10mM双氧水中，在预设测定时间，取20μL上清液与100μL硫酸钛溶液(5mM)混合。用酶标仪测定混合溶液在405nm波长处的吸光度，使用100mg水代替支架制备对照样品。以样品组对对照组的相对吸光度来计算双氧水的清除率。
所制备的负载超支化聚赖氨酸前后的多孔支架Sca和Sca/HBPL如图2所示，在负载超支化聚赖氨酸后，支架体积稍有膨胀，并且由于超支化聚赖氨酸的有效负载，Sca/HBPL呈现出超支化聚赖氨酸的淡黄色。DPPH自由基清除(图3)和双氧水清除(图4)测定结果显示，随着时间延长，负载或不负载超支化聚赖氨酸的多孔支架对DPPH和双氧水的清除率都逐渐增加，但负载超支化聚赖氨酸的多孔支架清除能力明显更强，说明超支化聚赖氨酸负载到多孔支架中可以增强支架的活性氧清除能力。
实施例3：超支化聚赖氨酸交联的水凝胶制备及自由基清除能力测定
(1)超支化聚赖氨酸交联的水凝胶制备
将含有70mg/mL聚(甲基丙烯酸缩水甘油酯-co-丙烯酰胺-co-聚乙二醇甲醚甲基丙烯酸酯)和22.68mg/mL的超支化聚赖氨酸的混合溶液在37℃条件下反应过夜，制备超支化聚赖氨酸交联的水凝胶。
(2)水凝胶的DPPH清除能力测定
50μL的上述超支化聚赖氨酸交联的水凝胶置于1ml 200μM DPPH的乙醇溶液中，在37℃的避光条件下孵育，在预设时间点取样，用酶标仪测定每种溶液在517nm波长处的吸光度。使用50μL水代替支架制备对照样品。以样品组对对照组的相对吸光度来计算DPPH的清除率。
(3)水凝胶的羟基自由基清除能力测定
将100μL超支化聚赖氨酸交联的水凝胶与500μL 10mM H2O2和500μL 1mM Fe(SO4)2溶液混合，并于37℃孵育。1小时后，将样品冷却至室温。从每个样品中取出100μL上清液并与100μL显色液TMB(3,3',5,5'-四甲基联苯胺，1mM，DMSO溶液)混合。用酶标仪其测量在650nm处的吸光度。在对照样品中，使用100μL H2O代替水凝胶样品。以样品组对对照组的相对吸光度来计算羟基自由基的清除率。
通过超支化聚赖氨酸的氨基与聚(甲基丙烯酸缩水甘油酯-co-丙烯酰胺-co-聚乙二醇甲醚甲基丙烯酸酯)的环氧基团反应制备的水凝胶如图5所示，验证了其可以作为交联剂制备水凝胶的特性。自由基清除测定结果显示，这种超支化聚赖氨酸交联的水凝胶的水凝胶4小时可以消除42％的DPPH，12小时可以消除70％的DPPH。1小时内可以消除全部的羟基自由基。说明，超支化聚赖氨酸作为交联剂，制备成水凝胶后仍可以保持高活性的自由基清除能力。
实施例4：负载超支化聚赖氨酸的多孔支架用于细菌感染创面抗氧化和抗炎研究
麻醉条件下，在每只小鼠背部剪出直径为8mm的圆形全层皮肤伤口，然后在每个伤口上注射等量浓度为1ⅹ107CFU的金黄葡萄球菌，感染1小时后，分别在伤口上使用PBS(Ctrl组)、商用抗菌药膏百多邦(MP组)和含有超支化聚赖氨酸的多孔支架(Sca/HBPL组)治疗，在治疗的前九天每三天换一次药。取第三天，第六天的皮肤组织样本通过活性氧荧光探针二氢乙锭(DHE)和细胞核染料4',6-二脒基-2-苯基吲哚(DIPI)对组织染色进行活性氧水平评估。取第三天，第八天和第十二天的皮肤组织样本，通过髓过氧化物酶(MPO)免疫组化染色对中性粒细胞进行分析，用酶联免疫吸附测定试剂盒(ELISA)测定细胞因子白介素-1β(IL-1β)，IL-6，IL-10和肿瘤坏死因子-α(TNF-α)的表达水平。
如图6所示，用DHE染料标记伤口和周围新生皮肤组织中的ROS水平。与不治疗的Ctrl组相比，在第三天和第六天，MP组和Sca/HBPL组处理的伤口中ROS荧光探针强度都有所降低(图6a)。但从定量统计结果(图6b)中发现，MP组个体差异较大，与不处理的对照组(Ctrl)无显著性差异，而Sca/HBPL组可以明显降低伤口组织的ROS水平。这是由于两种治疗材料均有抗菌作用，因而对细菌引起的炎症有一定抑制作用，从而均在一定程度上能够缓解受感染的炎症组织内的氧化应激反应。但由于超支化聚赖氨酸本身具有自由基清除能力，因而相比之下，负载了超支化聚赖氨酸的多孔支架能够非常显著地降低伤口组织的ROS水平。
由于伤口愈合的炎症阶段以伤口部位的中性粒细胞浸润为特征，因此使用髓过氧化物酶(MPO，一种活化的中性粒细胞的标志物)来表征中性粒细胞浸润。MPO储存在中性粒细胞的中性颗粒中，直到中性粒细胞被激活或脱粒以实现其相应的生理功能时才被释放。MPO产生的过程和ROS导致氧化组织损伤并引起过度严重的炎症反应的过程息息相关。图7a，b显示MPO的表达随着时间的推移普遍下降，并且负载超支化聚赖氨酸的多孔支架Sca/HBPL组中明显低于Ctrl组和MP组，这与ROS水平的抑制情况一致。说明超支化聚赖氨酸可以抑制炎症反应，减少中性粒细胞浸润，减少MPO表达，从而减少炎症组织部位的ROS产物，从而强烈加速组织再生和伤口愈合。
此外，如图8所示，在感染后第三天，经过负载超支化聚赖氨酸的多孔支架Sca/HBPL治疗的伤口中各种促炎细胞因子如IL-6、TNF-α和IL-1β的水平下调，而抗炎细胞因子IL-10表达升高，并且Sca/HBPL组的TNF-α和IL-10水平分别显著低于和高于Ctrl组。虽然第八天和第十二天IL-6和IL-10水平在各组间无显着差异，但Sca/HBPL组TNF-α和IL-1β的表达明显低于Ctrl组。相比之下，只具有抗菌功能的百多邦药膏(MP组)几乎不具有下调促炎细胞因子和上调抗炎细胞因子的能力。这些数据表明，超支化聚赖氨酸能够在分子水平上抑制过度炎症并促进感染伤口愈合过程中的抗炎反应启动。这种强效的抗炎能力来自于其分子结构上高密度的正电荷，可以强有力地吸附带负电的DAMPs，阻断其刺激免疫细胞大量分泌炎症因子的过程，从而高效地抑制炎症反应。
Claims (10)
1.一种兼具抗炎及抗氧化作用的药物，其特征在于，所述药物中含有超支化聚赖氨酸。
2.根据权利要求1所述的药物，其特征在于，所述药物中以超支化聚赖氨酸为唯一抗炎及抗氧化活性组分。
3.根据权利要求1所述的药物，其特征在于，所述药物为超支化聚赖氨酸溶液。
4.根据权利要求1所述的药物，其特征在于，所述药物为超支化聚赖氨酸与其他生物相容性材料通过接枝、吸附、共混所形成的复合物。
5.根据权利要求4所述的药物，其特征在于，所述其他生物相容材料为水凝胶、多孔支架、膜材料、或纳米粒子。
6.根据权利要求1所述的药物，其特征在于，所述药物用于皮肤创面炎症、肠炎、肺炎、口腔炎、皮肤炎的炎症治疗或氧化应激相关疾病治疗中。
7.根据权利要求6所述的药物，其特征在于，所述炎症为细菌感染引起的皮肤创面炎症。
8.根据权利要求1所述的药物，其特征在于，所述药物为含超支化聚赖氨酸的多孔支架。
9.根据权利要求8所述的药物，其特征在于，所述的多孔支架采用如下方法制得：将1,6-己二胺、聚(甲基丙烯酸环氧丙酯-co-甲氧基聚乙二醇单甲基丙烯酸酯)和聚乙烯醇的混合溶液在37℃条件下反应过夜后获得水凝胶，将水凝胶冻干后得到多孔支架，将其浸泡在超支化聚赖氨酸溶液中过夜，即获得负载超支化聚赖氨酸的多孔支架。
10.根据权利要求1所述的药物，其特征在于，所述药物为聚(甲基丙烯酸缩水甘油酯-co-丙烯酰胺-co-聚乙二醇甲醚甲基丙烯酸酯)和超支化聚赖氨酸的混合溶液在37℃条件下反应过夜得到的含超支化聚赖氨酸的水凝胶。
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| CN103316330A (zh) * | 2012-06-28 | 2013-09-25 | 西藏贝珠雅药业有限公司 | 一种软组织创伤护理材料的组方与用途 |
| CN110507845A (zh) * | 2019-09-25 | 2019-11-29 | 广州沁瀚生物科技有限公司 | 生物复合透气敷料及其制备方法 |
| US20210330623A1 (en) * | 2017-05-16 | 2021-10-28 | Polyneuros | Active ingredient consisting of a mixture of polylysine compounds and use in the prevention of strokes and the treatment of the post-stroke inflammatory phase |
| CN113577377A (zh) * | 2021-08-17 | 2021-11-02 | 浙江大学 | 一种活性氧消除抗菌消炎水凝胶皮肤敷料及其制备方法 |
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| CN103316330A (zh) * | 2012-06-28 | 2013-09-25 | 西藏贝珠雅药业有限公司 | 一种软组织创伤护理材料的组方与用途 |
| US20210330623A1 (en) * | 2017-05-16 | 2021-10-28 | Polyneuros | Active ingredient consisting of a mixture of polylysine compounds and use in the prevention of strokes and the treatment of the post-stroke inflammatory phase |
| CN110507845A (zh) * | 2019-09-25 | 2019-11-29 | 广州沁瀚生物科技有限公司 | 生物复合透气敷料及其制备方法 |
| CN113577377A (zh) * | 2021-08-17 | 2021-11-02 | 浙江大学 | 一种活性氧消除抗菌消炎水凝胶皮肤敷料及其制备方法 |
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