CN107778377B - 四碘甲腺乙酸修饰的壳寡糖硬脂酸嫁接物及制备和应用 - Google Patents
四碘甲腺乙酸修饰的壳寡糖硬脂酸嫁接物及制备和应用 Download PDFInfo
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Abstract
本发明提供一种四碘甲腺乙酸修饰的壳寡糖硬脂酸嫁接物构建方法,以及在抗乳腺癌转移中的应用。通过氨基和羧基的酰胺反应,将四碘甲腺乙酸嫁接至壳聚糖上,得到靶向乳腺癌的壳寡糖硬脂酸嫁接物。该嫁接物具有在水性介质中通过自聚集形成胶束的特性,粒径为50~3OOnm、zeta电位为10~40mV。通过包载药物雷公藤红素可以达到显著的抗肿瘤及肿瘤转移的作用效果,可在制备抗肿瘤及抗肿瘤转移的治疗药物中应用。具代表性的结构通式为:
Description
技术领域
本发明属肿瘤靶向功能的嫁接物制备方法及应用,涉及四碘甲腺乙酸修饰的壳寡糖硬脂酸嫁接物及制备和在制备肿瘤转移治疗药物中的应用。
背景技术
乳腺癌转移是女性癌症患者死亡的主要原因。普通的治疗手段,例如肿瘤化疗,由于药物本身缺乏靶向性,到达作用位点的药物浓度有限,因而出现治愈率低、毒副作用大等问题。通过合适的载体技术,将药物直接靶向病变组织是解决癌症化疗治愈率低和毒副作用的重要手段之一。目前国内外的科学家通过载体技术在***转移上取得了一定的进展,例如激素治疗、抗血管治疗和基因治疗等,但是药物难以高浓度聚集在肿瘤部位发挥作用,无法取得突破性的疗效,因此肿瘤靶向性载体材料技术的研究开发是突破癌症化疗瓶颈的关键。
近年来主动靶向技术发展日益成熟,通过连接可识别肿瘤细胞高表达受体的特异性配体,达到靶向的目的。聚合物胶束是由两亲性的嵌段或接枝共聚物在水性介质中自聚集形成,具有核壳结构。其疏水性链段构成胶束的内核,亲水性链段形成胶束的外壳。疏水核可为水难溶性药物提供储库的作用;亲水性外膜保持胶束在水性环境中的稳定性,并可进行理化性质修饰,如化学连接主动靶向的配体等。
αvβ3整合素受体高表达在乳腺癌等多种肿瘤细胞系中,研究发现肺转移位点及新生血管也同样表达该受体。四碘甲腺乙酸是一种甲状腺激素类似物,相关研究已证明其会与肿瘤细胞表面αvβ3受体特异性结合,因此四碘甲腺乙酸可作为靶向载体的靶头,借助载体将包封的药物递送至肿瘤部位及转移位点。
雷公藤红素是天然的蛋白酶抑制剂,具有抗肿瘤细胞增殖、促进凋亡等功能。研究证明,雷公藤红素具有抑制NF-κB的药理作用。NF-κB参与调节多种肿瘤转移的相关通路,影响肿瘤细胞的增殖,血管生成和相关基质金属蛋白酶的表达。其中,基质金属蛋白酶MMP-9和MMP-2能够降解细胞外基质,促进肿瘤转移。雷公藤红素药物水溶性差,到达肿瘤部位和转移灶的药物浓度有限,无法发挥其应有的疗效,因此需要借助于主动靶向给药技术,实现药物分子在转移灶的高浓度聚集。
本发明在我们前期的研究工作基础上,对壳寡糖硬脂酸嫁接物进行四碘甲腺乙酸修饰,包封药物雷公藤红素应用于抗肿瘤及肿瘤转移的治疗。
发明内容
本发明的一个目的是提供四碘甲腺乙酸修饰的壳寡糖硬脂酸嫁接物,其具有代表性的结构通式为:
其中壳寡糖硬脂酸(CSOSA)为:
壳寡糖的分子量约为20kDa,壳寡糖链上的部分伯氨基被四碘甲腺乙酸取代,取代度约为5~20%。n为壳寡糖硬脂酸中糖单元的数目,约为120,m为四碘甲腺乙酸修饰的壳寡糖硬脂酸中聚乙二醇单体的数目,约为40。
本发明所使用的壳寡糖硬脂酸嫁接物已为国家发明专利“荧光标记疏水改性壳聚糖聚合物及制备方法和应用”(专利号:ZL2005100507981)所涵盖。
本发明的第二个目的是提供壳寡糖硬脂酸嫁接物胶束的四碘甲腺乙酸修饰方法,通过以下方案实现:
称取四碘甲腺乙酸1~20mg/mL的二甲基甲酰胺溶液,按照摩尔比四碘甲腺乙酸:碳二亚胺=2:1~1:5,加入碳二亚胺,;按照摩尔比四碘甲腺乙酸:氮-羟基琥珀酰亚胺=2:1~1:5,加入氮-羟基琥珀酰亚胺,室温反应2小时后,按照加四碘甲腺乙酸:双氨基终端的聚乙二醇=5:1~1:5,加入双氨基终端的聚乙二醇,继续反应8小时后,以摩尔比四碘甲腺乙酸:氮氮-二琥珀酰亚胺基碳酸酯=2:1~1:3室温搅拌过夜,得到的反应中间物以摩尔比四碘甲腺乙酸:壳寡糖硬脂酸嫁接物游离氨基=1:5~1:20滴加入水溶液中,反应24小时后,透析(截留分子量为7000Da,杭州华东医药集团)48小时,冷冻干燥,得四碘甲腺乙酸修饰的壳寡糖硬脂酸嫁接物固体粉末。
本发明的第三个目的是提供壳寡糖硬脂酸嫁接物胶束作为整合素αvβ3配体靶向载体,包封药物雷公藤红素在制备抗肿瘤及抗肿瘤转移药物中的应用。结果表明,包封雷公藤红素的四碘甲腺乙酸修饰的壳寡糖硬脂酸具有显著的抗肿瘤活性和抑制肿瘤转移效果。
本发明的有益之处是:在前期的研究工作基础上,利用壳寡糖硬脂酸嫁接物上残留的氨基和四碘甲腺乙酸的羧基,通过聚乙二醇的化学交联,合成整合素αvβ3靶向的胶束,提高抗肿瘤转移药物在体内的靶向分布,降低化疗药物的毒性。本发明已在细胞水平证明四碘甲腺乙酸修饰的壳寡糖硬质酸嫁接物良好的抗肿瘤及肿瘤转移疗效。
附图说明
图1:四碘甲腺乙酸修饰的壳寡糖硬质酸嫁接物核磁共振图谱。
图2:流式细胞检测壳寡糖硬质酸嫁接物与四碘甲腺乙酸修饰的壳寡糖硬质酸嫁接物在4T1细胞系中摄取差异。
图3:壳寡糖硬质酸嫁接物与四碘甲腺乙酸修饰的壳寡糖硬质酸嫁接物对4T1细胞的早期凋亡作用流式检测。
图4:四碘甲腺乙酸修饰的壳寡糖硬质酸嫁接物抗肿瘤转移细胞药效。
具体实施方式
本发明结合附图和实施例作进一步的说明。
实施例一:
1.壳寡糖硬脂酸嫁接物的合成
采用碳二亚胺法合成酰胺键连接的糖脂纳米载体。取处方量壳寡糖800mg,溶于30mL去离子水。取253mg硬脂酸,溶于20mL热无水乙醇,80℃水浴条件下将两者混合,加入204.2mg碳二亚胺,搅拌6h后停止加热,待反应产物冷却后,将其置于透析袋中(分子量7000),用去离子水透析48h,透析纯化物冷冻干燥,得酰胺键连接的糖脂纳米载体固体粉末。
2.四碘甲腺乙酸修饰的壳寡糖硬质酸嫁接物的合成
称取四碘甲腺乙酸1mg/mL的二甲基甲酰胺溶液,按照摩尔比四碘甲腺乙酸:碳二亚胺=2:1加入碳二亚胺;按照摩尔比四碘甲腺乙酸:氮-羟基琥珀酰亚胺=2:1加入氮-羟基琥珀酰亚胺,室温反应2小时后,按照加四碘甲腺乙酸:双氨基终端的聚乙二醇=5:1加入双氨基终端的聚乙二醇,继续反应8小时后,以摩尔比四碘甲腺乙酸:氮氮-二琥珀酰亚胺基碳酸酯=2:1室温搅拌过夜,得到的反应中间物以摩尔比四碘甲腺乙酸:壳寡糖硬脂酸嫁接物游离氨基=1:5滴加入水溶液中,反应24小时后,透析(截留分子量为7000Da,杭州华东医药集团)48小时,冷冻干燥,得四碘甲腺乙酸修饰的壳寡糖硬脂酸嫁接物固体粉末。
3.采用三硝基苯磺酸法,测定所得壳寡糖硬脂酸嫁接物的氨基取代度
取不同重量的壳寡糖(1~10mg)分别溶于2ml的蒸馏水,加入4%碳酸氢钠2ml和0.1%三硝基苯磺酸2mL,37℃下孵育2h,加入2mol/L盐酸2mL,摇匀,344nm处测定吸光度,制备标准曲线。取上述壳寡糖硬脂酸4mg溶于2mL蒸馏水中,同法操作,按标准曲线计算壳寡糖硬脂酸嫁接物的氨基取代度为5.0%。
4.吡荧光法测定临界胶束浓度
采用芘荧光法测定四碘甲腺乙酸修饰的壳寡糖硬脂酸嫁接物的临界胶束浓度。取芘12mg,精密称定,置100mL容量瓶,加丙酮溶解并定容。移取上述芘溶液1mL,置100mL容量瓶中稀释并定容。移取稀释后的芘溶液0.5mL分别置10mL玻璃试管中,50℃挥去丙酮。分别加入不同浓度的四碘甲腺乙酸修饰的壳寡糖硬脂酸嫁接物溶液5mL,控制芘终浓度为7×10~7mol/l,室温水浴超声30min。扫描芘的激发光谱和发射光谱(Ex=337nm,Em:I1=374,I3=384,狭缝宽度=2.5nm和10nm),测定荧光强度,并计算临界胶束浓度,为197.1μg/mL。另取四碘甲腺乙酸修饰的壳寡糖硬脂酸嫁接物10mg,精密称定,溶解于10mL蒸馏水,探头超声30次(400w,工作2s,间歇3s),得到1mg/mL的聚合物溶液。微粒粒度与表面电位分析仪测定四碘甲腺乙酸修饰的壳寡糖硬脂酸嫁接物的粒径为300.6nm,Zeta电位为10.3mV。
实施例二:
1.壳寡糖硬脂酸嫁接物的合成
采用碳二亚胺法合成酰胺键连接的糖脂纳米载体。取处方量壳寡糖800mg,溶于30mL去离子水。取253mg硬脂酸,溶于20mL热无水乙醇,80℃水浴条件下将两者混合,加入204.2mg碳二亚胺,搅拌6h后停止加热,待反应产物冷却后,将其置于透析袋中(分子量7000),用去离子水透析48h,透析纯化物冷冻干燥,得酰胺键连接的糖脂纳米载体固体粉末。
2.四碘甲腺乙酸修饰的壳寡糖~硬质酸嫁接物的合成
称取四碘甲腺乙酸10mg/mL的二甲基甲酰胺溶液,按照摩尔比四碘甲腺乙酸:碳二亚胺=1:1加入碳二亚胺,按照摩尔比四碘甲腺乙酸:氮-羟基琥珀酰亚胺=1:1加入氮-羟基琥珀酰亚胺,室温反应2小时后,按照加四碘甲腺乙酸:双氨基终端的聚乙二醇=2:1加入双氨基终端的聚乙二醇,继续反应8小时后,以摩尔比四碘甲腺乙酸:氮氮-二琥珀酰亚胺基碳酸酯=1:1室温搅拌过夜,得到的反应中间物以摩尔比四碘甲腺乙酸:壳寡糖硬脂酸嫁接物游离氨基=1:10滴加入水溶液中,反应24小时后,透析(截留分子量为7000Da,杭州华东医药集团)48小时,冷冻干燥,得四碘甲腺乙酸修饰的壳寡糖硬脂酸嫁接物固体粉末。
3.采用三硝基苯磺酸法,测定所得壳寡糖硬脂酸嫁接物的氨基取代度
取不同重量的壳寡糖(1~10mg)分别溶于2ml的蒸馏水,加入4%碳酸氢钠2ml和0.1%三硝基苯磺酸2mL,37℃下孵育2h,加入2mol/L盐酸2mL,摇匀,344nm处测定吸光度,制备标准曲线。取上述壳寡糖硬脂酸4mg溶于2mL蒸馏水中,同法操作,按标准曲线计算壳寡糖硬脂酸嫁接物的氨基取代度为10.3%。
4.吡荧光法测定临界胶束浓度
采用芘荧光法测定四碘甲腺乙酸修饰的壳寡糖硬脂酸嫁接物的临界胶束浓度。取芘12mg,精密称定,置100mL容量瓶,加丙酮溶解并定容。移取上述芘溶液1mL,置100mL容量瓶中稀释并定容。移取稀释后的芘溶液0.5mL分别置10mL玻璃试管中,50℃挥去丙酮。分别加入不同浓度的四碘甲腺乙酸修饰的壳寡糖硬脂酸嫁接物溶液5mL,控制芘终浓度为7×10~7mol/l,室温水浴超声30min。扫描芘的激发光谱和发射光谱(Ex=337nm,Em:I1=374,I3=384,狭缝=2.5nm和10nm),测定荧光强度,并计算临界胶束浓度,为176.4μg/mL。另取四碘甲腺乙酸修饰的壳寡糖硬脂酸嫁接物10mg,精密称定,溶解于10mL蒸馏水,探头超声30次(400w,工作2s,间歇3s),得到1mg/mL的聚合物溶液。微粒粒度与表面电位分析仪测定四碘甲腺乙酸修饰的壳寡糖硬脂酸嫁接物的粒径为230.2nm,Zeta电位为13.7mV。
实施例三:
1.壳寡糖硬脂酸嫁接物的合成
采用碳二亚胺法合成酰胺键连接的糖脂纳米载体。取处方量壳寡糖800mg,溶于30mL去离子水。取253mg硬脂酸,溶于20mL热无水乙醇,80℃水浴条件下将两者混合,加入204.2mg碳二亚胺,搅拌6h后停止加热,待反应产物冷却后,将其置于透析袋中(分子量7000),用去离子水透析48h,透析纯化物冷冻干燥,得酰胺键连接的糖脂纳米载体固体粉末。
2.四碘甲腺乙酸修饰的壳寡糖硬质酸嫁接物的合成
称取四碘甲腺乙酸15mg/mL的二甲基甲酰胺溶液,按照摩尔比四碘甲腺乙酸:碳二亚胺=1:3加入碳二亚胺,按照摩尔比四碘甲腺乙酸:氮-羟基琥珀酰亚胺=1:3加入氮-羟基琥珀酰亚胺,室温反应2小时后,按照加四碘甲腺乙酸:双氨基终端的聚乙二醇=1:1加入双氨基终端的聚乙二醇,继续反应8小时后,以摩尔比四碘甲腺乙酸:氮氮-二琥珀酰亚胺基碳酸酯=1:2室温搅拌过夜,得到的反应中间物以摩尔比四碘甲腺乙酸:壳寡糖硬脂酸嫁接物游离氨基=1:15滴加入水溶液中,反应24小时后,透析(截留分子量为7000Da,杭州华东医药集团)48小时,冷冻干燥,得四碘甲腺乙酸修饰的壳寡糖硬脂酸嫁接物固体粉末。核磁共振氢谱表征嫁接物的结构,见附图1。
3.采用三硝基苯磺酸法,测定所得壳寡糖硬脂酸嫁接物的氨基取代度
取不同重量的壳寡糖(1~10mg)分别溶于2ml的蒸馏水,加入4%碳酸氢钠2ml和0.1%三硝基苯磺酸2mL,37℃下孵育2h,加入2mol/L盐酸2mL,摇匀,344nm处测定吸光度,制备标准曲线。取上述壳寡糖硬脂酸4mg溶于2mL蒸馏水中,同法操作,按标准曲线计算壳寡糖硬脂酸嫁接物的氨基取代度为13.5%。
4.吡荧光法测定临界胶束浓度
采用芘荧光法测定四碘甲腺乙酸修饰的壳寡糖硬脂酸嫁接物的临界胶束浓度。取芘12mg,精密称定,置100mL容量瓶,加丙酮溶解并定容。移取上述芘溶液1mL,置100mL容量瓶中稀释并定容。移取稀释后的芘溶液0.5mL分别置10mL玻璃试管中,50℃挥去丙酮。分别加入不同浓度的四碘甲腺乙酸修饰的壳寡糖硬脂酸嫁接物溶液5mL,控制芘终浓度为7×10~7mol/l,室温水浴超声30min。扫描芘的激发光谱和发射光谱(Ex=337nm,Em:I1=374,I3=384,狭缝=2.5nm和10nm),测定荧光强度,并计算临界胶束浓度,为92.3μg/mL。另取四碘甲腺乙酸修饰的壳寡糖硬脂酸嫁接物10mg,精密称定,溶解于10mL蒸馏水,探头超声30次(400w,工作2s,间歇3s),得到1mg/mL的聚合物溶液。微粒粒度与表面电位分析仪测定四碘甲腺乙酸修饰的壳寡糖硬脂酸嫁接物的粒径为126.2nm,Zeta电位为33.1mV。
5.载药纳米粒的细胞定量摄取
流式细胞仪定量检测细胞摄取情况,以3×104个/孔的细胞密度接种4T1细胞于24孔板中,置37℃的5%CO2孵箱中孵育培养,待细胞贴壁生长后,分别加入FITC标记的壳寡糖硬脂酸和四碘甲腺乙酸修饰的壳寡糖硬脂酸纳米粒,分辨孵育2h,8h和12h后弃去细胞培养液,用磷酸盐平衡生理盐水洗三次,除去吸附在细胞表面的药物。用胰酶消化,磷酸盐平衡生理盐水清洗后离心,重悬细胞,立即使用流式细胞仪检测细胞摄取阳性百分率。经TET修饰后的胶束对于空白壳寡糖硬脂酸表现出了更强的细胞摄取能力,且细胞摄取程度具有时间依赖性,结果如图2所示。
6.Annexin V染色结合流式细胞术检测细胞凋亡
取对数生长期4T1细胞,以lxl05细胞/孔接种于六孔板中,培养过夜,待细胞贴壁后给药。分别加入1μg/mL的雷公藤红素,包载雷公藤红素的壳寡糖硬脂酸和四碘甲腺乙酸修饰的壳寡糖硬脂酸胶束作用6小时后,收集细胞。每管细胞加入100μL“结合缓冲液重悬后,加入5μLAnnexin V在室温避光染色15分钟,再加入400μL的结合缓冲液,混匀后用流式细胞仪进行检测分析,结果如图3所示,经四碘甲腺乙酸修饰后的载药胶束促进细胞凋亡的作用最明显。
7.划痕修复实验
取对数生长期细胞,以lxl05细胞/孔接种于24孔板,至细胞汇合度达到80%左右,用无菌的移液器吸头对已贴壁的细胞制造划痕,以新鲜培养液洗去漂浮细胞,显微镜下观察并拍照。分别加入1μg/mL的雷公藤红素,包载雷公藤红素的壳寡糖硬脂酸和四碘甲腺乙酸修饰的壳寡糖硬脂酸胶束作用12小时后,在显微镜下观察划痕变化情况并拍照。如图4所示,四碘甲腺乙酸修饰后的载药胶束显著抑制了肿瘤细胞的侵袭性,药效强于壳寡糖硬脂酸/雷公藤红素和雷公藤红素单独作用组。
实施例四:
1.壳寡糖硬脂酸嫁接物的合成
采用碳二亚胺法合成酰胺键连接的糖脂纳米载体。取处方量壳寡糖800mg,溶于30mL去离子水。取253mg硬脂酸,溶于20mL热无水乙醇,80℃水浴条件下将两者混合,加入204.2mg碳二亚胺,搅拌6h后停止加热,待反应产物冷却后,将其置于透析袋中(分子量7000),用去离子水透析48h,透析纯化物冷冻干燥,得酰胺键连接的糖脂纳米载体固体粉末。
2.四碘甲腺乙酸修饰的壳寡糖~硬质酸嫁接物的合成
称取四碘甲腺乙酸20mg/mL的二甲基甲酰胺溶液,按照摩尔比四碘甲腺乙酸:碳二亚胺=1:5加入碳二亚胺,按照摩尔比四碘甲腺乙酸:氮-羟基琥珀酰亚胺=1:5加入氮-羟基琥珀酰亚胺,室温反应2小时后,按照加四碘甲腺乙酸:双氨基终端的聚乙二醇=1:5加入双氨基终端的聚乙二醇,继续反应8小时后,以摩尔比四碘甲腺乙酸:氮氮-二琥珀酰亚胺基碳酸酯=1:3室温搅拌过夜,得到的反应中间物以摩尔比四碘甲腺乙酸:壳寡糖硬脂酸嫁接物游离氨基=1:20滴加入水溶液中,反应24小时后,透析(截留分子量为7000Da,杭州华东医药集团)48小时,冷冻干燥,得四碘甲腺乙酸修饰的壳寡糖硬脂酸嫁接物固体粉末。
3.采用三硝基苯磺酸法,测定所得壳寡糖硬脂酸嫁接物的氨基取代度
取不同重量的壳寡糖(1~10mg)分别溶于2ml的蒸馏水,加入4%碳酸氢钠2ml和0.1%三硝基苯磺酸2mL,37℃下孵育2h,加入2mol/L盐酸2mL,摇匀,344nm处测定吸光度,制备标准曲线。取上述壳寡糖硬脂酸4mg溶于2mL蒸馏水中,同法操作,按标准曲线计算壳寡糖硬脂酸嫁接物的氨基取代度为19.7%。
4.吡荧光法测定临界胶束浓度
采用芘荧光法测定四碘甲腺乙酸修饰的壳寡糖硬脂酸嫁接物的临界胶束浓度。取芘12mg,精密称定,置100mL容量瓶,加丙酮溶解并定容。移取上述芘溶液1mL,置100mL容量瓶中稀释并定容。移取稀释后的芘溶液0.5mL分别置10mL玻璃试管中,50℃挥去丙酮。分别加入不同浓度的四碘甲腺乙酸修饰的壳寡糖硬脂酸嫁接物溶液5mL,控制芘终浓度为7×10~7mol/l,室温水浴超声30min。扫描芘的激发光谱和发射光谱(Ex=337nm,Em:I1=374,I3=384,狭缝=2.5nm和10nm),测定荧光强度,并计算临界胶束浓度,为50.9μg/mL。另取四碘甲腺乙酸修饰的壳寡糖硬脂酸嫁接物10mg,精密称定,溶解于10mL蒸馏水,探头超声30次(400w,工作2s,间歇3s),得到1mg/mL的聚合物溶液。微粒粒度与表面电位分析仪测定四碘甲腺乙酸修饰的壳寡糖硬脂酸嫁接物的粒径为52.7nm,Zeta电位为39.9mV。
Claims (3)
2.根据权利要求1所述的四碘甲腺乙酸修饰的壳寡糖硬脂酸嫁接物的制备方法,其特征在于,通过以下步骤实现:
四碘甲腺乙酸1~20mg/mL的二甲基甲酰胺溶液,按照摩尔比四碘甲腺乙酸:碳二亚胺=2:1~1:5 加入碳二亚胺;按照摩尔比四碘甲腺乙酸:氮-羟基琥珀酰亚胺=2:1~1:5 加入氮-羟基琥珀酰亚胺,室温反应2小时后,按照四碘甲腺乙酸:双氨基终端的聚乙二醇=5:1~1:5 加入双氨基终端的聚乙二醇,继续反应8小时后,以摩尔比四碘甲腺乙酸:氮氮-二琥珀酰亚胺基碳酸酯=2:1~1:3室温搅拌过夜,得到的反应中间物以摩尔比四碘甲腺乙酸:壳寡糖硬脂酸嫁接物伯氨基=1:5~1:20 滴加入水溶液中,反应24小时后,透析,截留分子量为7000Da,48小时,冷冻干燥,得四碘甲腺乙酸修饰的壳寡糖硬脂酸嫁接物固体粉末;具有在水性介质中通过自聚集形成胶束的特性,氨基取代度为5~20%,1 mg/mL的壳寡糖硬脂酸嫁接物水溶液形成粒径为50~300nm 、zeta 电位为10~40mV的胶束。
3.根据权利要求1所述四碘甲腺乙酸修饰的壳寡糖硬脂酸嫁接物作为整合素αvβ3靶向载体,包封药物雷公藤红素在制备抗肿瘤及抗肿瘤转移药物中的应用。
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