CN103483591B - 含有抗体trc105和显影剂的双亲梳形聚合物及制备 - Google Patents
含有抗体trc105和显影剂的双亲梳形聚合物及制备 Download PDFInfo
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Abstract
本发明公开了一种含有抗体TRC105和显影剂的双亲梳形聚合物及制备方法。该聚合物的结构如下式所示。其制备方法包括:以甲基丙烯酸羟乙酯为单体制备梳型大分子引发剂,再以开环聚合的方法将L-丙交酯引入到梳型聚合物侧链上,通过含有端羟基的疏水链段聚乳酸连接含有两种不同端基的聚乙二醇亲水链段,通过亲水段的端马来酰亚胺基连接抗体TRC105和显影剂NOTA,得到该双亲梳型聚合物。本发明优点,该聚合物用于疏水性抗癌药物的包覆,具有载药量高,生物相容性好,靶向识别性能高,成像效果好的特点。
Description
技术领域
本发明涉及一种含有抗体TRC105和显影剂的双亲梳形聚合物及制备方法,特别是涉及一种含有抗体TRC105和正电子发射成像技术(PET)显影剂的双亲梳形聚合物及制备方法,属于具有造影功能的靶向药物载体技术领域。
背景技术
恶性肿瘤严重威胁着全人类的健康和生命,尽管科学家一直在花费很大的精力寻求高效的抗肿瘤药物,但是传统的化疗试剂仍然存在特异性差这一问题,因此无法准确快速地识别病灶组织,通常对正常组织器官造成损伤,从而使其应用受到限制。目前有关癌症治疗的研究重点在于开发靶向药物传导体系,提高靶点的抗癌药物浓度,而对正常组织没有作用。由于固态肿瘤细胞显示出的一些特质,纳米粒是一种十分理想的靶向肿瘤传导体系。纳米药物传递系统集治病基团,分子靶向和成像诊断能力于一身,已逐渐成为新一代多功能纳米药物载体。
双亲性高分子聚合物胶束是由疏水性聚酯内核和亲水链段组成,在水溶液中具有内核疏水和外腔亲水的特质。由于这种结构的双重性质,疏水性药物可以被包裹在疏水内核中,而外部的亲水层形成的水化层屏障可以保持每一个胶束分子的完整性。因此,这种聚合物胶束在生理环境中可以被有效地用于包裹溶解性低或稳定性差的药物。近年来,这类双亲聚合物胶束在医学和生物学领域受到了极大地关注。然而,传统的聚合物胶束分子均为球形,有关梳形聚合物胶束的研究还相对较少。有关研究已经表明,梳形聚合物胶束分子有着载药能力高,在体内循环时间长,生物相容性好的特点。在梳型聚合物胶束表面引入生物活性抗体和显影剂基团,不仅可以有效提高生物靶向识别性能,而且可以增强对肿瘤细胞的早期监测,这种集治疗药物,生物靶向及检测能力于一身的梳形双亲聚合物胶束分子有望应用于肿瘤细胞治疗中。
TRC105是一种靶向针对CD105(180kDa的通道蛋白)的单克隆抗体,能有效增强纳米载体对肿瘤细胞的特异性识别。
1,4,7-三氮杂环壬烷-1,4,7-三乙酸(NOTA)作为一种螯合剂,可与一些核素螯合形成稳定的络合剂用于PET成像,近年来已逐渐成为肿瘤核医学分子影像领域的研究热点。
发明内容
本发明的目的是在提供一种含有抗体TRC105和显影剂的双亲梳形聚合物及制备方法。该聚合物用于包合疏水性抗癌药物阿霉素,具有载药量高,定点释放能力强,生物靶向性能好的特点;便于体外监测,且其制备过程简单。
本发明是通过以下技术方案加以实现的:一种含有抗体TRC105和显影剂的双亲梳形聚合物,其特征在于,该双亲梳形聚合物胶束在水溶液中的粒径分布范围在55-150 nm之间,在干态下的粒径在22-30 nm之间,该聚合物的结构如式1所示,主链为聚甲基丙烯酸羟乙酯,通过主链的侧基羟乙基连接L-丙交酯,再通过含有端羟基的疏水链段聚乳酸连接含有两种不同端基的聚乙二醇亲水链段,其中一种是含有羧基和马来酰亚胺基修饰的聚乙二醇,另一种是含有羧基和甲氧基修饰的聚乙二醇,通过马来酰亚胺基连接抗体TRC105和显影剂1,4,7-三氮杂环壬烷-1,4,7-三乙酸(NOTA),其中,该双亲梳型聚合物的数均分子量为350-600 kDa,疏水链段乳酸的重复单元为10-20,亲水段端基为羧基和马来酰亚胺基修饰的聚乙二醇与端基为羧基和甲氧基修饰的相同分子量的聚乙二醇的比为1:(1-4),抗体TRC105与显影剂NOTA的摩尔比为1:(1-3),该聚合物主链聚甲基丙烯酸羟乙酯的核磁氢谱特征峰为1H NMR (DMSO-d6, δ, ppm): 4.78 (OH), 3.88 (COOCH 2 ), 3.58 (CH 2 OH), 1.74 (CH 2 ), 0.76 (CH 3 );在主链上引入疏水链L-丙交酯后的核磁氢谱特征峰为1H NMR (DMSO-d6, δ, ppm): 5.17 (C(O)CH(CH3)O)), 4.18 (C(O)CH(CH3)OH), 1.46 (C(O)CH(CH 3 )O), 1.27 (C(O)CH(CH 3 )OH);接上亲水链聚乙二醇后的双亲性聚合物核磁特征峰为 1H NMR (CDCl3-d, δ, ppm): 6.68 (C(O)CH=CHC(O)), 5.17 (C(O)CH(CH3)O)), 3.67(CH 2 ), 3.4(OCH 3 ), 1.46 (CH 3 ),
式1
式中:n为甲基丙烯酸羟乙酯的重复单元数,m为疏水链段乳酸的重复单元数;
R'代表甲氧基、TRC105和NOTA。
上述结构的含有抗体和显影剂的双亲梳形聚合物的制备方法,其特征在于包括以下过程:
(1)梳型大分子引发剂聚甲基丙烯酸羟乙酯的合成:
以甲基丙烯酸羟乙酯(HEMA)为单体,2-溴代异丁酸乙酯为引发剂,溴化亚铜和2,2'-联吡啶为催化剂,采用原子转移自由基聚合方法在温度为30-50oC反应5-10h合成梳型大分子引发剂聚甲基丙烯酸羟乙酯(PHEMA);
(2)疏水性聚酯内核的制备:
在氩气氛保护下,将步骤(1)制得的梳型大分子引发剂和L-丙交酯(LA)加入到无水的N,N-二甲基甲酰胺溶剂中,配制成每毫升含梳型大分子引发剂60-80mg和L-丙交酯665-1772mg的溶液,按催化剂辛酸亚锡与 L-丙交酯的摩尔比为1:500-1000再向溶液中加入催化剂辛酸亚锡,在油浴中于温度110-130oC中聚合反应20-30 h,冷却到室温后,用四氢呋喃溶解得到粗产物,粗产物经冰甲醇沉析、真空干燥后得到白色的疏水性聚酯内核(PHEMA-PLA)产物;
(3)双亲梳形聚合物胶束的制备:
在氩气氛保护下,将步骤(2)制备的疏水性聚酯内核、端基为羧基和马来酰亚胺基修饰的聚乙二醇(HOOC-PEG-Mal)、端基为羧基和甲氧基修饰的聚乙二醇(HOOC-PEG-OCH3)、二环己基碳二亚胺(DCC)和4-二甲氨基吡啶(DMAP)按质量比为1:(0.67-4):(1.33-6):(0.13-0.33):(0.003-0.033)加入到无水的二氯甲烷中搅拌反应20-35h,经在冰乙醚中沉析得到粗产物,粗产物在去离子水中用分子量为15 kDa的透析管透析24-48h,冷冻干燥后得到双亲聚合物胶束(PHEMA-PLA-b-PEG-OCH3/Mal);
(4)显影剂NOTA的修饰:
在氮气氛保护下,将(S)-2-(4-异硫氰酸苄基酯)-1,4,7-三氮杂环壬烷-1,4,7-三乙酸(p-SCN-Bn-NOTA)与巯基乙胺盐酸盐以质量比1:(0.2-0.3)加入到磷酸缓冲液中,反应1-3h后得到巯基修饰的1,4,7-三氮杂环壬烷-1,4,7-三乙酸(NOTA-SH);
(5)TRC105的修饰:
将TRC105 和 2-亚氨基硫烷盐酸盐以摩尔比1:10-30加入到pH为8.0的磷酸缓冲溶液中,在室温下反应2-5h后得到巯基修饰的TRC105(TRC105-SH),以磷酸缓冲液为流动相,在体积排阻色谱(size exclusion chromatography)中对TRC105-SH进行纯化;
(6)含有抗体TRC105和显影剂的双亲梳形聚合物(PHEMA-PLA-b-PEG-OCH3/TRC105/NOTA)的制备:
按每毫克步骤(3)制得的双亲聚合物胶束,与4-10μL步骤(4)制得的NOTA-SH和280-420μL步骤(5)制得的TRC105-SH体积比计量,将它们加入pH为7.5的磷酸缓冲液中,在室温下反应1-2h得到粗产物,粗产物经分子量为30kDa的透析管以5000-8000r/min的转速离心分离20-30min后,得到含有抗体TRC105和显影剂的双亲梳形聚合物(PHEMA-PLA-b-PEG-OCH3/TRC105/NOTA)。
本发明所提供的含有抗体TRC105和显影剂的双亲梳形聚合物用于载药,特别用于疏水性抗癌药物的负载。
本发明的优点在于,所提供的双亲梳形聚合物胶束用于药物负载,生物靶向活性高,PET成像效果好。载有抗体TRC105的梳形大分子聚合物载体可以使抗癌药物在病灶部位定点富集,释放,发挥药物最大疗效,减轻对正常组织的伤害。同时通过PET成像技术可以监测药物在体内肿瘤细胞处的分布情况,该药物载体集生物靶向与监测、治疗功能与一身,有望应用于肿瘤靶向治疗中。
附图说明
图1梳形大分子引发剂的1H NMR图。
图2疏水性聚酯内核的1H NMR图。
图3 双亲梳形聚合物胶束的1H NMR图。
图中所示结构式中R为马来酰亚胺基或甲氧基。
图4双亲梳形聚合物胶束的动态光散射粒径分布图。
图5双亲梳形聚合物胶束的的透射电镜图。
具体实施方式
实施例1:
在氩气氛保护下,在两颈烧瓶中加入4.29g甲基丙烯酸羟乙酯,引发剂2-溴代异丁酸乙酯12.85mg,溴化亚铜7.56mg,2,2'-联吡啶20.6mg,溴化铜2.95mg,12mL丁酮和甲醇混合溶剂(丁酮:甲醇体积比为2:1)采用原子转移自由基聚合方法在50℃下反应5 小时,粗产品过硅胶柱除去铜,然后用四氢呋喃沉淀后真空干燥得白色产物聚甲基丙烯酸羟乙酯,凝胶渗透色谱测得数均分子量为12510,分子量分布为1.379。1H NMR (DMSO-d6, δ, ppm): 4.78 (OH), 3.88 (COOCH 2 ), 3.58 (CH 2 OH), 1.74 (CH 2 ), 0.76 (CH 3 )。
在氩气氛保护下,将梳型大分子引发剂和L-丙交酯(LA)加入到无水的N,N-二甲基甲酰胺溶剂中,配制成每毫升含梳型大分子引发剂70mg和L-丙交酯1164mg的溶液,再向溶液中加入0.008mmol催化剂辛酸亚锡,在油浴中于温度110℃时聚合反应22 h,冷却到室温后,用四氢呋喃溶解得到粗产物,粗产物经冰甲醇沉析3次、真空干燥后得到白色的PHEMA-PLA。1H NMR (DMSO-d6, δ, ppm): 5.17 (C(O)CH(CH3)O)), 4.18 (C(O)CH(CH3)OH),1.46 (C(O)CH(CH 3 )O), 1.27 (C(O)CH(CH 3 )OH),由聚乳酸主链上的甲基(C(O)CH(CH 3 )O)特征吸收峰面积和连接端羟基的甲基(C(O)CH(CH 3 )OH)特征吸收峰面积比得到疏水链聚乳酸的重复单元为15,PHEMA-PLA的数均分子量为73662, 分子量分布为1.328。
在氩气氛保护下,加入30 mg PHEMA-PLA,35.5 mg HOOC-PEG-Mal,46.2 mg HOOC-PEG-OCH3,3.37mg二环己基碳二亚胺和0.20 mg 4-二甲氨基吡啶到10 mL 无水二氯甲烷中,在室温下搅拌反应20h。经过滤除掉副产物二环己基脲,在冰乙醚中沉析得到粗产物,粗产物在去离子水中用透析管(截留分子量 15 kDa)透析48h后冷冻干燥,得到PAMAM-PLA-b-PEG-OCH3/Mal。1H NMR (CDCl3-d, δ, ppm): 6.68 (C(O)CH=CHC(O)), 5.17 (C(O)CH(CH3)O)), 3.67(CH 2 ), 3.4(OCH 3 ), 1.46 (CH 3 ),由马来酰亚胺基特征吸收峰面积和聚乙二醇主链上的亚甲基特征吸收峰面积比得到此双亲性共聚物PAMAM-PLA-b-PEG-OCH3/Mal端基中马来酰亚胺基含量为32%,甲氧基含量为68%。数均分子量为 355580, 分子量分布为1.472。
PHEMA-PLA-PEG-OCH3/NOTA/TRC105的合成: (1)将摩尔比为1:20的TRC105与2-亚氨基硫烷盐酸盐(26μg)在pH=8.0的磷酸盐缓冲液中混匀。在室温下孵育2h后,得到巯基修饰的TRC105粗产品。以磷酸缓冲液作为流动相,运用体积排阻色谱法对TRC105进行纯化。运用Ellman试剂在96孔板上进行紫外滴定分析,据此可以计算得到每个TRC105-SH含有5个硫醇基团。(2)称取2.8mg p-SCN-Bn-NOTA和0.57mg巯基乙胺,在三乙胺和磷酸缓冲液(预先用Chelex 100树脂吸附,已防止硫醇的氧化)的混合液中混匀,氮气保护下,在室温下反应2h即得NOTA-SH。(3)按每毫克制备得到的PHEMA-PLA-b-PEG-OCH3/Mal量计,加入7μL NOTA-SH和280μL TRC105-SH到pH=7.5的磷酸缓冲液中,在室温下反应1h得到粗产物,粗产物经分子量为30kDa的透析管以5000r/min的转速离心分离20min后,得到PHEMA-PLA-b-PEG-OCH3/TRC105/NOTA。
实施例2:
本实施例与实施例1步骤相同,不同的是将步骤1中采用原子转移自由基聚合方法制备聚甲基丙烯酸羟乙酯的反应温度由50℃变为30℃,反应时间由5小时调整为10小时,得到数均分子量为16221,分子量分布范围为1.609的聚甲基丙烯酸羟乙酯,1H NMR (DMSO-d6, δ, ppm): 4.78 (OH), 3.88 (COOCH 2 ), 3.58 (CH 2 OH), 1.74 (CH 2 ), 0.76 (CH 3 ),以其为大分子引发剂,最终制得PHEMA-PLA-b-PEG-OCH3/TRC105/NOTA。
实施例3:
本实施例与实施例1步骤相同,不同的是将步骤1中采用开环聚合方法制备疏水性聚酯内核的L-丙交酯的浓度由1164mg/mL调整为1552mg/mL,相应的辛酸亚锡的加入量由0.008mmol调整为0.02mmol,得到白色的PHEMA-PLA。1H NMR (DMSO-d6, δ, ppm): 5.17 (C(O)CH(CH3)O)), 4.18 (C(O)CH(CH3)OH), 1.46 (C(O)CH(CH 3 )O), 1.27 (C(O)CH(CH 3 )OH),由聚乳酸主链上的甲基(C(O)CH(CH 3 )O)特征吸收峰面积和连接端羟基的甲基(C(O)CH(CH 3 )OH)特征吸收峰面积比得到疏水链聚乳酸的重复单元为20,PHEMA-PLA的数均分子量为87390, 分子量分布为1.439。以其为疏水链段连接聚乙二醇亲水链段,再经亲水段的端马来酰亚胺基连接抗体TRC105和NOTA, 最终得到PHEMA-PLA-b-PEG-OCH3/TRC105/NOTA。
实施例4:
本实施例与实施例1步骤相同,不同的是将步骤1中采用开环聚合方法制备疏水性聚酯内核的L-丙交酯的浓度由1164 mg/mL 调整为938mg/mL,相应的辛酸亚锡的加入量由0.008mmol调整为0.007mmol,得到白色的PHEMA-PLA。1H NMR (DMSO-d6, δ, ppm): 5.17 (C(O)CH(CH3)O)), 4.18 (C(O)CH(CH3)OH), 1.46 (C(O)CH(CH 3 )O), 1.27 (C(O)CH(CH 3 )OH),由聚乳酸主链上的甲基(C(O)CH(CH 3 )O)特征吸收峰面积和连接端羟基的甲基(C(O)CH(CH 3 )OH)特征吸收峰面积比得到疏水链聚乳酸的重复单元为12,PHEMA-PLA的数均分子量为64350, 分子量分布为1.301。以其为疏水链段连接聚乙二醇亲水链段,再经亲水段的端马来酰亚胺基连接抗体TRC105和NOTA, 最终得到PHEMA-PLA-b-PEG-OCH3/TRC105/NOTA。
实施例5:
本实施例与实施例1步骤相同,不同的是将步骤1中HOOC-PEG-Mal的量由35.5 mg调整为20.5mg,HOOC-PEG-OCH3的量由46.2 mg调整为61.2mg,得到PAMAM-PLA-b-PEG-OCH3/Mal。1H NMR (CDCl3-d, δ, ppm): 6.68 (C(O)CH=CHC(O)), 5.17 (C(O)CH(CH3)O)), 3.67(CH 2 ), 3.4(OCH 3 ), 1.46 (CH 3 ),由马来酰亚胺基特征吸收峰面积和聚乙二醇主链上的亚甲基特征吸收峰面积比得到此双亲性共聚物PAMAM-PLA-b-PEG-OCH3/Mal端基中马来酰亚胺基含量为20%,甲氧基含量为80%,数均分子量为 367210, 分子量分布为1.491。最后连接TRC105和NOTA后得到PHEMA-PLA-b-PEG-OCH3/TRC105/NOTA。
实施例6:
本实施例与实施例1步骤相同,不同的是将步骤1中HOOC-PEG-Mal的量由35.5 mg调整为40.8mg,HOOC-PEG-OCH3的量由46.2 mg调整为40.9mg,得到PAMAM-PLA-b-PEG-OCH3/Mal。1H NMR (CDCl3-d, δ, ppm): 6.68 (C(O)CH=CHC(O)), 5.17 (C(O)CH(CH3)O)), 3.67(CH 2 ), 3.4(OCH 3 ), 1.46 (CH 3 ),由马来酰亚胺基特征吸收峰面积和聚乙二醇主链上的亚甲基特征吸收峰面积比得到此双亲性共聚物PAMAM-PLA-b-PEG-OCH3/Mal端基中马来酰亚胺基含量为40%,甲氧基含量为60%,数均分子量为 359369, 分子量分布为1.469。最后连接TRC105和NOTA后得到PHEMA-PLA-b-PEG-OCH3/TRC105/NOTA。
Claims (2)
1.一种含有抗体TRC105和显影剂的双亲梳形聚合物,其特征在于,该双亲梳形聚合物胶束在水溶液中的粒径分布范围在55-150 nm之间,在干态下的粒径在22-30 nm之间,该聚合物的结构如式1所示,主链为聚甲基丙烯酸羟乙酯,通过主链的侧基羟乙基连接L-丙交酯,再通过含有端羟基的疏水链段聚乳酸连接含有两种不同端基的聚乙二醇亲水链段,其中一种是含有羧基和马来酰亚胺基修饰的聚乙二醇,另一种是含有羧基和甲氧基修饰的聚乙二醇,通过马来酰亚胺基连接抗体TRC105和显影剂1,4,7-三氮杂环壬烷-1,4,7-三乙酸,其中,该双亲梳型聚合物的数均分子量为350-600 kDa,疏水链段乳酸的重复单元为10-20,亲水段端基为羧基和马来酰亚胺基修饰的聚乙二醇与端基为羧基和甲氧基修饰的相同分子量的聚乙二醇的比为1:(1-4),抗体TRC105与显影剂1,4,7-三氮杂环壬烷-1,4,7-三乙酸的摩尔比为1:(1-3),该聚合物主链聚甲基丙烯酸羟乙酯的核磁氢谱特征峰为1H NMR (DMSO-d6, δ, ppm): 4.78 (OH), 3.88 (COOCH 2 ), 3.58 (CH 2 OH), 1.74 (CH 2 ), 0.76 (CH 3 );在主链上引入疏水链L-丙交酯后的核磁氢谱特征峰为1H NMR (DMSO-d6, δ, ppm): 5.17 (C(O)CH(CH3)O)), 4.18 (C(O)CH(CH3)OH), 1.46 (C(O)CH(CH 3 )O), 1.27 (C(O)CH(CH 3 )OH);接上亲水链聚乙二醇后的双亲性聚合物核磁特征峰为 1H NMR (CDCl3-d, δ, ppm): 6.68 (C(O)CH=CHC(O)), 5.17 (C(O)CH(CH3)O)), 3.67(CH 2 ), 3.4(OCH 3 ), 1.46 (CH 3 ),
式1
式中:n为连有聚乙二醇侧链的甲基丙烯酸羟乙酯的重复单元数:52-103;m为疏水链段乳酸的重复单元数;
R'代表甲氧基、马来酰亚胺基修饰的TRC105和马来酰亚胺基修饰的1,4,7-三氮杂环壬烷-1,4,7-三乙酸。
2. 按权利要求1所述的含有抗体和显影剂的双亲梳形聚合物的制备方法,其特征在于包括以下过程:
(1)梳型大分子引发剂聚甲基丙烯酸羟乙酯的合成:
以甲基丙烯酸羟乙酯为单体,2-溴代异丁酸乙酯为引发剂,溴化亚铜和2,2'-联吡啶为催化剂,采用原子转移自由基聚合方法在温度为30-50oC反应5-10h合成梳型大分子引发剂聚甲基丙烯酸羟乙酯;
(2)疏水性聚酯内核的制备:
在氩气氛保护下,将步骤(1)制得的梳型大分子引发剂和L-丙交酯加入到无水的N,N-二甲基甲酰胺溶剂中,配制成每毫升含梳型大分子引发剂60-80mg和L-丙交酯665-1772mg的溶液,按催化剂辛酸亚锡与 L-丙交酯的摩尔比为1:500-1000再向溶液中加入催化剂辛酸亚锡,在油浴中于温度110-130oC中聚合反应20-30 h,冷却到室温后,用四氢呋喃溶解得到粗产物,粗产物经冰甲醇沉析、真空干燥后得到白色的疏水性聚酯内核产物;
(3)双亲梳形聚合物胶束的制备:
在氩气氛保护下,将步骤(2)制备的疏水性聚酯内核、端基为羧基和马来酰亚胺基修饰的聚乙二醇、端基为羧基和甲氧基修饰的聚乙二醇、二环己基碳二亚胺和4-二甲氨基吡啶按质量比为1:(0.67-4):(1.33-6):(0.13-0.33):(0.003-0.033)加入到无水的二氯甲烷中搅拌反应20-35h,经在冰乙醚中沉析得到粗产物,粗产物在去离子水中用分子量为15 kDa的透析管透析24-48h,冷冻干燥后得到双亲聚合物胶束,该双亲聚合物胶束的端基包括甲氧基和马来酰亚胺基;
(4)显影剂1,4,7-三氮杂环壬烷-1,4,7-三乙酸的修饰:
在氮气氛保护下,将(S)-2-(4-异硫氰酸苄基酯)-1,4,7-三氮杂环壬烷-1,4,7-三乙酸与巯基乙胺盐酸盐以质量比1:(0.2-0.3)加入到磷酸缓冲液中,反应1-3h后得到巯基修饰的1,4,7-三氮杂环壬烷-1,4,7-三乙酸;
(5)TRC105的修饰:
将TRC105 和 2-亚氨基硫烷盐酸盐以摩尔比1:10-30加入到pH为8.0的磷酸缓冲溶液中,在室温下反应2-5h后得到巯基修饰的TRC105,以磷酸缓冲液为流动相,在体积排阻色谱中对TRC105-SH进行纯化;
(6)含有抗体TRC105和显影剂的双亲梳形聚合物的制备:
按每毫克步骤(3)制得的端基为甲氧基和马来酰亚胺基修饰的双亲聚合物胶束,加入4-10μL的步骤(4)制得的巯基修饰的1,4,7-三氮杂环壬烷-1,4,7-三乙酸,以及加入280-420μL的步骤(5)制得的巯基修饰的TRC105计量,将端基为甲氧基和马来酰亚胺基修饰的双亲聚合物胶束、巯基修饰的1,4,7-三氮杂环壬烷-1,4,7-三乙酸和巯基修饰的TRC105加入pH为7.5的磷酸缓冲液中,在室温下反应1-2h得到粗产物,粗产物经分子量为30kDa的透析管以5000-8000r/min的转速离心分离20-30min后,得到端基为甲氧基、马来酰亚胺基修饰的TRC105和马来酰亚胺基修饰的1,4,7-三氮杂环壬烷-1,4,7-三乙酸的双亲梳形聚合物,即为含有抗体TRC105和显影剂的双亲梳形聚合物。
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