CN113563608A - 一种基于组胺衍生物的纳米水凝胶及其制备和应用方法 - Google Patents
一种基于组胺衍生物的纳米水凝胶及其制备和应用方法 Download PDFInfo
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- CN113563608A CN113563608A CN202110854887.0A CN202110854887A CN113563608A CN 113563608 A CN113563608 A CN 113563608A CN 202110854887 A CN202110854887 A CN 202110854887A CN 113563608 A CN113563608 A CN 113563608A
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- histamine derivative
- histamine
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Abstract
一种基于组胺衍生物的纳米水凝胶及其制备和应用方法,属于医用高分子材料及化学药物技术领域,本发明通过沉淀聚合法制备一种新型的基于组胺衍生物的生物可降解的新型还原响应性纳米水凝胶,并评估其在纳米药物递送系统方面的应用潜力。本发明制备的纳米水凝胶具有良好的稳定性以及还原敏感性,由于该纳米水凝胶是通过共价键交联形成的,所以其稳定性明显高于其他通过分子间作用力自组装制备的纳米水凝胶。且含有大量的酰胺基团及咪唑基团,对结构不同的多种化疗药物及核酸显示出较高的载药量或包载效率,在癌症治疗和诊断方面展现出良好的应用前景。
Description
技术领域
本发明属于医用高分子材料及化学药物技术领域,具体涉及一种基于组胺衍生物的纳米水凝胶及其制备和应用方法。
背景技术
纳米水凝胶材料是由内部共价交联的高分子骨架,在水中吸水溶胀后均匀的分散在水中而不会溶解在水中形成的一种高分子互穿网络体系。在生物医药、化学化工以及电子信息等方面具有巨大的应用价值,因而得到广泛研究。其中,纳米水凝胶材料与生物医药之间的关系最为密切,常被用于新型给药系统的开发。
研究发现,肿瘤细胞中的谷胱甘肽浓度为正常细胞的5~10倍,是血液中谷胱甘肽浓度的上千倍。利用肿瘤细胞内这一特殊环境,用于细胞内靶向药物释放的还原敏感型药物载体的研究一直备受大家关注。目前,已报道的药物载体有生物可降解高分子微球、基于脂质体的纳米胶束等。其中,智能纳米水凝胶由于体积小、生物相容性好、易于修饰、灵活通用、可响应不同的刺激因素等优点,在纳米药物递送系统开发领域受到了广泛的关注。在纳米水凝胶的制备方法中,沉淀聚合法具有操作简单、质量可控、无需添加表面活性剂及稳定剂和易于放大等优点。然而,在目前已报道的纳米水凝胶药物递送系统中,用于沉淀聚合的功能单体数量非常有限。本发明以组胺及其衍生物为原料,经丙烯酰胺化,得到一系列N,N’-双(丙烯酰)组胺衍生物单体,并通过沉淀聚合法开发了基于组胺衍生物的生物可降解的新型还原响应性纳米水凝胶,用来包载药物分子、核酸、染料等功能分子。此外,纳米水凝胶被癌细胞摄取后,纳米水凝胶中的咪唑基团在内涵体弱酸性环境下容易质子化,有助于其内涵体逃逸及药物控释。因此,本发明中的纳米水凝胶在纳米药物递送和癌症诊疗方面展现出广泛的应用前景。
发明内容
本发明的目的是通过沉淀聚合法制备一种新型的基于组胺衍生物的生物可降解的新型还原响应性纳米水凝胶,并评估其在纳米药物递送系统方面的应用潜力。
本发明是通过以下方法实现的:
本发明的基于组胺衍生物的纳米水凝胶,是以丙烯酰基组胺衍生物作为聚合单体,加入交联剂和引发剂,采用沉淀聚合法制备得到的,反应结束后,丙烯酰基组胺衍生物单体和交联剂中的双键消失,单体间以自由基聚合的方式连接。
所述的丙烯酰基组胺衍生物的结构为:
其中,
R为H或甲基;1≤n≤6,优选n=2。
所述的引发剂为:偶氮二异丁腈(AIBN)、偶氮二异庚腈(ABVN)或4,4’-偶氮双(4-氰基戊酸);所述的交联剂为:N,N’-双(甲基丙烯酰)胱氨酸二甲酯、N,N’-双(丙烯酰)胱氨酸二甲酯、N,N’-双(丙烯酰)胱胺、N,N’-双(甲基丙烯酰)胱氨酸、N,N’-双(丙烯酰)胱氨酰胺或聚乙二醇二甲基丙烯酸酯。
本发明还提供所述的基于组胺衍生物的纳米水凝胶的制备方法,包括以下步骤:
(1)制备丙烯酰基组胺衍生物;
(2)将丙烯酰基组胺衍生物溶解在有机溶剂中,搅拌溶解完全;
(3)将交联剂、自由基聚合的引发剂加入到步骤(2)的溶液中,进行反应;
(4)反应结束后,高速离心,弃上清;
(5)对离心后的下层固体进行洗涤、冻干,得到基于组胺衍生物的纳米水凝胶粉末。
上述基于组胺衍生物的纳米水凝胶的制备方法,其中:
所述步骤(1)中,所述的丙烯酰基组胺衍生物的结构如上述结构所示,通过如下方法制备得到:
以含咪唑基的伯胺化合物为原料,在低温条件下,与丙烯酰氯或甲基丙烯酰氯进行酰胺化反应,得到丙烯酰基组胺衍生物。
具体地,包括如下步骤:
将含咪唑基的伯胺化合物溶于水中,0~5℃冰浴10~30min。在氩气氛围中,将NaOH水溶液(NaOH为含咪唑基的伯胺化合物的3倍当量)与丙烯酰氯或甲基丙烯酰氯的无水二氯甲烷溶液(丙烯酰氯或甲基丙烯酰氯为含咪唑基的伯胺化合物的1倍当量),同时缓慢滴入含咪唑基的伯胺化合物的水溶液中,搅拌,滴加完毕后,在0~25℃下反应2~4h,制得的粗品经二氯甲烷:甲醇=10:1~30:1洗脱纯化,得目标产物丙烯酰基组胺衍生物。
所述步骤(2)中,所述丙烯酰基组胺衍生物的重量体积浓度为0.1~200mg/mL,优选为0.1~50mg/mL;所选有机溶剂为:乙腈、无水乙醇或任意比例的乙腈与无水乙醇的混合溶剂。
所述步骤(3)中,所选自由基聚合的引发剂为:偶氮二异丁腈(AIBN)、偶氮二异庚腈(ABVN)或4,4'-偶氮双(4-氰基戊酸);其用量为:使其在溶液中的重量体积浓度为0.1~0.75mg/mL。
所述步骤(3)中,所选交联剂为:N,N’-双(甲基丙烯酰)胱氨酸二甲酯、N,N’-双(丙烯酰)胱氨酸二甲酯、N,N’-双(丙烯酰)胱胺、N,N’-双(甲基丙烯酰)胱氨酸、N,N’-双(丙烯酰)胱氨酰胺或聚乙二醇二甲基丙烯酸酯;其用量为:使其在溶液中的重量体积浓度为0.1~40mg/mL,优选浓度为0.5~20mg/mL。
所述步骤(3)中,反应温度为25~90℃,反应时间为30~90min。
所述步骤(4)中,离心的转速为7000~15000r/min;离心时间为10~30min。
所述步骤(5)中,所选洗涤下层固体的溶剂为:水、乙腈、乙醇、四氢呋喃、二氯甲烷、甲醇、丙酮、乙酸乙酯、四氯化碳、1,4-二氧六环、乙二醇、环己烷或正己烷;优选为:乙腈。
本发明还提供所述的基于组胺衍生物的纳米水凝胶在载物方面的应用方法,具体包括:
将制得的基于组胺衍生物的纳米水凝胶(简称纳米水凝胶)粉末分散到水中,然后与需要包载的药物分子、核酸或功能染料混合,室温下搅拌8~48h,进行高速离心,转移上清,洗涤下层,冻干,得到基于组胺衍生物的载物纳米水凝胶(简称载物纳米水凝胶)。
所述的载物,包括:载药物分子、载核酸及载功能染料。
所述的药物包括:抗肿瘤药、抗菌药、抗炎药,其中,抗肿瘤药物包括:紫杉醇、阿霉素、埃罗替尼,抗菌药包括:苯酰甲硝唑、头孢呋辛钠、利福平,抗炎药包括:地塞米松、氯霉素;所述的核酸包括DNA、RNA。
优选包载对象为埃罗替尼和由20个A碱基组成的单链DNA,即polyA。
所述药物与纳米水凝胶粉末的重量比为(1~10):5,优选为(2~4):5;所选的药物终浓度为0.05~10mg/mL,优选为0.1~2mg/mL。
洗涤下层,所用溶剂为甲醇或乙醇。
通过本发明方法得到的载药纳米水凝胶粒度在30~500nm,优选在30~100nm范围内,载药量达到20%以上,大小可控,稳定性好;得到的载DNA纳米水凝胶粒度在30~500nm,DNA包载率达到90%以上。
本发明通过对含咪唑基的伯胺化合物的氨基进行酰胺化得到一系列组胺衍生物,并以此作为原料制备载物(药物分子、核酸或功能染料)纳米水凝胶。
与现有技术相比,本发明具有如下优点:
1.采用组胺衍生物作为聚合单体制备的纳米水凝胶,聚合单体简单,可以采用沉淀聚合技术、耗时短、无需添加乳化剂或稳定剂、反应温和容易控制,制备工艺十分简单。
2.本发明制备的纳米水凝胶具有良好的稳定性以及还原敏感性,由于该纳米水凝胶是通过共价键交联形成的,所以其稳定性明显高于其他通过分子间作用力自组装制备的纳米水凝胶。此外,由图5可以看出该纳米水凝胶在10mM谷胱甘肽的条件下20min后的降解可达90%,表现出良好的还原敏感性。
3.本发明制备的纳米水凝胶的内部含有大量的酰胺基团及表面含有大量的咪唑基团,因此包载药物(埃罗替尼等)时可以通过氢键等分子间作用增加药物的载药量;载药量可达27%以上,包载率达63%以上。DNA的包载率达99.94%。
附图说明
图1为本发明实施例1制备的N-[2-(4-咪唑基)乙基]丙烯酰胺的1H NMR谱图;
图2为本发明实施例1制备的纳米水凝胶PNIEAA、单体N-[2-(4-咪唑基)乙基]丙烯酰胺和交联剂N,N’-双(丙烯酰基)胱胺的红外谱图结果;
图3为本发明实施例2制备的基于N-[2-(4-咪唑基)乙基]丙烯酰胺的载埃罗替尼纳米水凝胶ELB-PNIEAA的粒径分布图;
图4为本发明实施例2制备的基于N-[2-(4-咪唑基)乙基]丙烯酰胺的载埃罗替尼纳米水凝胶ELB-PNIEAA的扫描电镜图;
图5为本发明实施例5中纳米水凝胶PNIEAA在10mM谷胱甘肽的条件下降解动力学曲线图;
图6为本发明实施例6中埃罗替尼在PBS pH7.4的条件下释放行为曲线图。
具体实施方式
为了进一步说明本发明,以下结合实施例对本发明提供的基于组胺衍生物的纳米水凝胶进行详细描述。
实施例1
基于N-[2-(4-咪唑基)乙基]丙烯酰胺的纳米水凝胶的制备:
(1)丙烯酰基组胺衍生物N-[2-(4-咪唑基)乙基]丙烯酰胺的制备;
将4.0g组胺二盐酸盐溶于20mL纯水中,0~5℃冰浴10min。在氩气氛围中,将NaOH水溶液(2.62g NaOH,20mL纯水)与丙烯酰氯的无水二氯甲烷溶液(1.967g丙烯酰氯,20mL无水二氯甲烷),同时缓慢滴入组胺二盐酸盐的水溶液中,剧烈搅拌,在1h内滴加完,滴加完毕后,在25℃下反应4h。反应完后,转移至分液漏斗中,静置分液,取水层,旋干后用200mL乙醇溶解,通过抽滤除去不溶物,滤液旋蒸,粗品经硅胶柱层析纯化,以二氯甲烷:甲醇=10:1洗脱,将洗脱液旋干后在真空干燥箱中烘干,得到1.682g目标产物N-[2-(4-咪唑基)乙基],为白色固体粉末,收率46.85%。
其核磁结果如图1所示。
(2)称取制得的N-[2-(4-咪唑基)乙基]丙烯酰胺单体(175mg,1.061mmol)溶于40mL乙腈中,搅拌溶解完全。
(3)向步骤(2)的溶液中加入N,N’-双(丙烯酰基)胱胺(75mg,0.288mmol),加入引发剂AIBN(5mg,0.030mmol),超声10min。水浴锅加热,30min左右水温从室温加热到83℃,继续反应60min后,停止反应,降至室温。
(4)将上述溶液转移至15mL离心管中,然后以8000r/min,高速离心10min。转移上清,加入乙腈,超声分散30min,然后再以8000r/min,高速离心10min,弃上清。
(5)对离心后的下层固体加入乙腈,超声分散30min,得到混浊溶液,冻干后,得到白色纳米水凝胶PNIEAA粉末。
制得的纳米水凝胶PNIEAA、单体N-[2-(4-咪唑基)乙基]丙烯酰胺和交联剂N,N’-双(丙烯酰基)胱胺的红外谱图对比结果如图2所示。
实施例2
基于N-[2-(4-咪唑基)乙基]丙烯酰胺的纳米水凝胶PNIEAA在载药物埃罗替尼中的应用方法:
称取埃罗替尼(ELB)6mg,溶于1mL甲醇中;称取实施例1中制得的纳米水凝胶PNIEAA10mg,分散在5mL超纯水中。在超声条件下,将ELB的甲醇溶液缓慢滴入纳米水凝胶PNIEAA水分散液中,随后在室温下避光搅拌24h。24h后,离心(10000rpm,10min),下层沉淀用甲醇洗涤两遍后,少量水分散、冻干得基于N-[2-(4-咪唑基)乙基]丙烯酰胺的载药(埃罗替尼)纳米水凝胶ELB-PNIEAA。
收集的上清液旋干后用一定量的乙醇溶解,用紫外可见分光光度计检测游离的埃罗替尼的浓度。下层固体冻干后即为载埃罗替尼纳米水凝胶,其载药量为27.56%,包载率为63.40%。
用马尔文激光粒度仪和扫描电镜对所得到的载埃罗替尼纳米水凝胶进行测试表征,其动态光散射平均为200.8nm,扫描电镜的平均粒径在40nm左右,结果见图3和图4。
实施例3
基于N-[2-(4-咪唑基)乙基]丙烯酰胺的纳米水凝胶PNIEAA在载药物盐酸阿霉素中的应用方法:
称取盐酸阿霉素(DOX)5mg,溶于5mL PBS中,加入实施例1中制得的纳米水凝胶PNIEAA10mg,超声分散使二者充分混匀,随后在室温下避光搅拌24h。24h后,离心(10000rpm,10min),下层沉淀用纯水洗涤一遍后,少量水分散、冻干得基于N-[2-(4-咪唑基)乙基]丙烯酰胺的载药(盐酸阿霉素)纳米水凝胶DOX-PNIEAA。
收集上清液,用紫外可见分光光度计检测游离的盐酸阿霉素的浓度。下层固体冻干后即为载盐酸阿霉素纳米水凝胶。本实施例制备的载盐酸阿霉素纳米水凝胶,其载药量为12.85%,包载率为43.51%。
实施例4
基于N-[2-(4-咪唑基)乙基]丙烯酰胺的纳米水凝胶PNIEAA在载药物紫杉醇中的应用方法:
称取紫杉醇(PTX)6mg,溶于1mL甲醇中;称取实施例1中制得的纳米水凝胶PNIEAA10mg,分散在5mL超纯水中。在超声条件下,将PTX的甲醇溶液缓慢滴入纳米水凝胶PNIEAA水分散液中,随后在室温下避光搅拌24h。24h后,离心(10000rpm,10min),下层沉淀用甲醇洗涤两遍后,少量水分散、冻干得基于N-[2-(4-咪唑基)乙基]丙烯酰胺的载药(紫杉醇)纳米水凝胶PTX-PNIEAA。
收集上清液,用UV检测游离的紫杉醇的浓度。下层固体冻干后即为载紫杉醇纳米水凝胶。本实施例制备的载紫杉醇纳米水凝胶,其载药量为16.18%,包载率为32.17%。
上述实验结果表明,制备载药纳米水凝胶时,载体与不同结构的药物作用,其载药量与包载率均不同。结果如下:
实施例 | 药物 | 载药量(%) | 包载率(%) |
实施例2 | 埃罗替尼 | 27.56% | 63.40% |
实施例3 | 盐酸阿霉素 | 12.85% | 43.51% |
实施例4 | 紫杉醇 | 16.18% | 32.17% |
实施例5
纳米水凝胶PNIEAA的还原性响应性能测试:
(1)非还原条件
称取实施例1中制得的纳米水凝胶PNIEAA的粉末10mg于西林瓶中,加入5mL超纯水,超声分散10min。将西林瓶置于恒温水浴震荡器中震荡,温度设置为37℃,震荡频率设置为120rpm。在预设时间点(0、2、5、10、15、20、25、30、40、60、90、120min)各取样70μL,用紫外-可见分光光度计检测其在波长λ630nm处的透光率,绘制空白对照曲线。
(2)还原条件
称取实施例1中的制得的纳米水凝胶PNIEAA的粉末10mg于西林瓶中,加入5mL超纯水,超声分散10min。再向纳米水凝胶PNIEAA的分散液中加入15.4mg还原型谷胱甘肽(GSH),使其终浓度为10mM。将西林瓶置于恒温水浴震荡器中震荡,温度设置为37℃,震荡频率设置为120rpm。随着反应的进行,在预设时间点(0、2、5、10、15、20、25、30、40、60、90、120min)各取样70μL,用紫外-可见分光光度计检测其在波长λ630nm处的透光率,绘制纳米水凝胶PNIEAA的还原降解曲线。本实施例1制得的纳米水凝胶PNIEAA的还原降解动力学见图5。由图5可以看出该纳米水凝胶PNIEAA在10mM GSH的条件下25min后的降解可达70%,表现出良好的还原敏感性。
实施例6
配制100mL PBS(含1wt%吐温80)和100mL浓度为10mM的GSH的PBS溶液(含1wt%吐温80),分别作为非还原条件空白对照组和还原条件组的释放介质。然后精确称取实施例1中制得的ELB-PNIEAA纳米水凝胶3mg,用2mL PBS分散,将ELB-PNIEAA纳米水凝胶分散液转移至截留分子量为14000的透析袋中。使透析袋浸没于50mL释放介质中,开始计时。在37℃恒温水浴震荡器中温育,震荡频率设置为120rpm。随后分别在预设时间点(0min、5min、10min、20min、30min、45min、60min、1.5h、3h、5h、8h、12h、24h、26h、28h)各取样80μL并补加80μL预温的释放介质。用紫外可见分光光度计检测溶液在λ333nm波长处的吸光度值A。最后根据ELB PBS溶液的浓度校准曲线计算出累积释放量,绘制ELB-PNIEAA纳米水凝胶的药物释放曲线。
本实施例制得的还原纳米载药水凝胶的释药效果见图6。载药水凝胶在PBS pH=7.4溶液和10mM谷胱甘肽的PBS pH=7.4溶液中24h累计释药量分别为20%和72%。
实施例7
基于N-[2-(4-咪唑基)乙基]丙烯酰胺的纳米水凝胶PNIEAA在载DNA中的应用方法:
称取实施例1中制得的纳米水凝胶PNIEAA 5mg,分散在5mL PBS(pH=7.4)中,超声分散10min。加入8nmol含有20个A碱基的单链DNApolyA(序列:5’-AAAAAAAAAAAAAAAAAAAA-3’;摩尔吸光系数E=243400),超声分散2min。避光搅拌24h。离心,保留上清液,沉淀冻干后得载DNA的纳米水凝胶polyA-PNIEAA。通过乙醇沉淀法回收上清液中未负载的polyA,加100μL PBS溶解后用紫外可见分光光度计检测溶液在λ260nm波长处的吸光度值A。根据朗伯-比尔定律计算上清液中polyA的量,差量法计算得出PNIEAA纳米水凝胶的polyA包载率为99.94%。
Claims (10)
2.一种权利要求1所述的基于组胺衍生物的纳米水凝胶的制备方法,其特征在于,包括以下步骤:
(1)制备丙烯酰基组胺衍生物;
(2)将丙烯酰基组胺衍生物溶解在有机溶剂中,搅拌溶解完全;
(3)将交联剂、自由基聚合的引发剂加入到步骤(2)的溶液中,进行反应;
(4)反应结束后,高速离心,弃上清;
(5)对离心后的下层固体进行洗涤、冻干,得到基于组胺衍生物的纳米水凝胶粉末。
3.根据权利要求2所述的一种基于组胺衍生物的纳米水凝胶的制备方法,其特征在于,所述步骤(1)中,所述的丙烯酰基组胺衍生物的制备方法,包括如下步骤:
将含咪唑基的伯胺化合物溶于水中,0~5℃冰浴,在氩气氛围中,将NaOH水溶液与丙烯酰氯或甲基丙烯酰氯的无水二氯甲烷溶液,同时缓慢滴入含咪唑基的伯胺化合物的水溶液中,搅拌,滴加完毕后,在0~25℃下反应,制得的粗品经二氯甲烷/甲醇的混合溶剂洗脱纯化,得目标产物丙烯酰基组胺衍生物。
4.根据权利要求2所述的一种基于组胺衍生物的纳米水凝胶的制备方法,其特征在于,所述步骤(2)中,所述丙烯酰基组胺衍生物的重量体积浓度为0.1~200mg/mL;所选有机溶剂为:乙腈、无水乙醇或任意比例的乙腈与无水乙醇的混合溶剂。
5.根据权利要求2所述的一种基于组胺衍生物的纳米水凝胶的制备方法,其特征在于,所述步骤(3)中,所选自由基聚合的引发剂为:偶氮二异丁腈、偶氮二异庚腈或4,4'-偶氮双(4-氰基戊酸);其用量为:使其在溶液中的重量体积浓度为0.1~0.75mg/mL;所选交联剂为:N,N’-双(甲基丙烯酰)胱氨酸二甲酯、N,N’-双(丙烯酰)胱氨酸二甲酯、N,N’-双(丙烯酰)胱胺、N,N’-双(甲基丙烯酰)胱氨酸、N,N’-双(丙烯酰)胱氨酰胺或聚乙二醇二甲基丙烯酸酯;其用量为:使其在溶液中的重量体积浓度为0.1~40mg/mL;反应温度为25~90℃,反应时间为30~90min。
6.根据权利要求2所述的一种基于组胺衍生物的纳米水凝胶的制备方法,其特征在于,所述步骤(5)中,所选洗涤下层固体的溶剂为:水、乙腈、乙醇、四氢呋喃、二氯甲烷、甲醇、丙酮、乙酸乙酯、四氯化碳、1,4-二氧六环、乙二醇、环己烷或正己烷。
7.一种权利要求1所述的基于组胺衍生物的纳米水凝胶在载物方面的应用方法,其特征在于,具体包括:
将基于组胺衍生物的纳米水凝胶粉末分散到水中,然后与需要包载的药物分子、核酸或功能染料混合,室温下搅拌,进行高速离心,转移上清,洗涤下层,冻干,得到基于组胺衍生物的载物纳米水凝胶;得到的载药纳米水凝胶粒度在30~500nm,载药量达到20%以上,得到的载DNA纳米水凝胶粒度在30~500nm,DNA包载率达到90%以上。
8.根据权利要求7所述的基于组胺衍生物的纳米水凝胶在载物方面的应用方法,其特征在于,所述的载物,包括:载药物分子、载核酸及载功能染料;所述的药物包括:抗肿瘤药、抗菌药、抗炎药,其中,抗肿瘤药物包括:紫杉醇、阿霉素、埃罗替尼,抗菌药包括:苯酰甲硝唑、头孢呋辛钠、利福平,抗炎药包括:地塞米松、氯霉素;所述的核酸包括DNA、RNA。
9.根据权利要求7所述的基于组胺衍生物的纳米水凝胶在载物方面的应用方法,其特征在于,所述药物与基于组胺衍生物的纳米水凝胶粉末的重量比为(1~10):5;所选的药物终浓度为0.05~10mg/mL。
10.根据权利要求7所述的基于组胺衍生物的纳米水凝胶在载物方面的应用方法,其特征在于,所述药物与基于组胺衍生物的纳米水凝胶粉末的重量比为(2~4):5;所选的药物终浓度为0.1~2mg/mL。
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