CN109568597A - 靶向胎盘样硫酸软骨素a的多肽药物偶联物及其制备方法和应用 - Google Patents
靶向胎盘样硫酸软骨素a的多肽药物偶联物及其制备方法和应用 Download PDFInfo
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Abstract
本发明提供了一种靶向胎盘样硫酸软骨素A的多肽药物偶联物,包括小分子药物部分、多肽部分,以及分别与所述小分子药物部分与多肽部分相连接的连接子部分,其中,所述多肽部分所对应的多肽能特异性靶向胎盘样硫酸软骨素A,所述多肽的氨基酸序列选自SEQ ID NO:1‑SEQ ID NO:3所示的氨基酸序列中的一种或多种。该多肽药物偶联物能特异地靶向到胎盘样硫酸软骨素A不恰当表达的靶组织,控制药物在靶组织附近释放,降低了药物对正常组织的毒副作用。本发明还提供了该多肽药物偶联物的制备方法和应用。
Description
技术领域
本发明属于药物技术领域,特别涉及一种靶向胎盘样硫酸软骨素A的多肽药物偶联物及其制备方法和应用。
背景技术
恶性肿瘤严重危害人类健康,近年来开发出的抗肿瘤药物中,许多新型药物虽有优异的药物活性,但由于稳定性较差和缺乏对肿瘤组织的靶向性等原因,未能经过临床期试验。针对这些具有优异活性和潜在临床应用前景但稳定性较差或缺乏靶向性的小分子化合物,将其与具有良好治疗效果或具有靶向性的多肽进行偶联,成为新型的多肽药物偶联物(peptide-drug conjugate,PDC),能够有效地增强小分子化合物的稳定性和靶向性。PDC药物的研发为肿瘤的诊断与治疗带来了新的希望。
硫酸软骨素(CS)是共价连接在蛋白质上形成蛋白聚糖的一类糖胺聚糖。硫酸软骨素广泛分布于动物组织的细胞外基质和细胞表面,发挥着重要生理功能。虽然硫酸软骨素的多糖骨架简单,但就硫酸化程度、硫酸基和两种差异向异构糖醛酸在链内的分布来说,存在较大的差异。硫酸软骨素的精细结构决定着其功能的特异性,以及与多种蛋白质分子的相互作用。
胎盘样硫酸软骨素A(pl-CSA)属于糖胺聚糖家族,其为附着至蛋白聚糖的、交替的氨基糖和己糖醛酸残基的直链聚合物,其糖基化模式与常规硫酸软骨素不同。早期研究指出pl-CSA是造成胎盘中疟原虫感染的红细胞隔离的原因;2015年Ali Salanti等人在《Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein》中指出,pl-CSA在多种癌细胞中表达,为癌症的治疗指明了新的方向。然而pl-CSA的特异性受体是未知的,目前没有文献报道能与pl-CSA特异性结合的受体、递送体系等。
发明内容
鉴于此,本发明提供了一种对靶向pl-CSA的的多肽药物偶联物及其制备方法和应用。所述靶向多肽药物偶联物的稳定性好,对pl-CSA不恰当表达相关的组织的靶向识别能力好,有望提高所负载药物对肿瘤等靶组织的靶向效应,可用于对pl-CSA的不恰当表达相关的疾病的诊断、治疗。
第一方面,本发明提供了一种胎盘样硫酸软骨素A靶向递送体系,所述靶向递送体系为多肽药物偶联物,包括小分子药物部分、多肽部分,以及分别与所述小分子药物部分与多肽部分相连接的连接子部分,其中,所述多肽部分所对应的多肽能特异性靶向pl-CSA,所述多肽的氨基酸序列选自SEQ ID NO:1-SEQ ID NO:3所示的氨基酸序列中的一种或多种。
本发明中,所述多肽部分是指如SEQ ID NO:1-SEQ ID NO:3所示的氨基酸序列中的一种或多种的多肽去掉-NH2或-COOH后的残留部分。
所述多肽可以是如SEQ ID NO:1、SEQ ID NO:2或如SEQ ID NO:3所示的一种序列,也可以如SEQ ID NO:1-SEQ ID NO:3所示序列的多种。
本发明中,所述小分子药物部分是指小分子药物去除不影响其药物活性的活性基团后的残留部分。
本发明中,所述连接子部分与所述小分子药物部分之间是通过化学键相连。连接所述连接子部分与多肽部分的化学键,可以是酰胺键(-NH-CO-)、或酯键(-O-CO-)等。
所述连接子部分与多肽部分之间是通过化学键相连。连接所述连接子部分与多肽部分的化学键,可以是酰胺键。
所述小分子药物可以是与预防、诊断或治疗与pl-CSA的不适当表达相关的疾病相关的药物。其中,所述小分子药物包括抗肿瘤药物、妊娠药物、荧光追踪剂和造影剂中的至少一种。
上述抗肿瘤药物、妊娠药物包括各种化学药物、多肽类药物、蛋白、疫苗和基因药物中的一种或多种。所述“化学药物”包括但不限于有机化合物;所述“基因药物”包括但不限于包裹、结合或共混有核酸片段的阳离子聚合物、多肽、聚氨基酸或转染试剂。其中,“多肽类药物、蛋白、疫苗和基因药物”可概称为“生物药物”。
本文中的“妊娠药物”是针对妊娠疾病而言,妊娠疾病是指妊娠生理期间发生的与妊娠有关的疾病,如胎儿宫内发育受阻、妊娠糖尿病和早产等。其中,妊娠药物包括治疗妊娠糖尿病、治疗妊娠综合征、治疗胎儿宫内生长迟缓、早产、治疗先兆子痫(也称“子痫前期”)和防止胎膜早破的上述各类化学药物、生物药物。
具体地,所述妊娠药物选自硫酸高碘素、孕激素、米索前列醇、吲哚美辛、松弛肽、地高辛抗体、洋地黄抗体、生长激素样因子2、胰岛素生长因子2、ELABELA多肽中的一种或多种,但不限于此。其中,对于早产类的妊娠药物,可选自米索前列醇、米非司酮、前列甲酯、硫前列酮、三苯氧胺、来曲唑和甲氨蝶呤中的一种或多种。
其中,所述抗肿瘤的化学药物可列举阿霉素、表阿霉素、紫杉醇、去甲长春花碱、依托泊甙、顺铂、甲氨喋呤、姜黄素、5-氟尿嘧啶和灵菌红素,以及它们在药学上可接受的盐中的一种或多种,但不限于此。例如盐酸阿霉素为阿霉素在药学上可接受的盐,也具有一定的抗肿瘤活性。
在本发明一实施方式中,所述抗肿瘤药物为阿霉素、盐酸阿霉素、表阿霉素、盐酸表阿霉素或紫杉醇。
其中,所述抗肿瘤的多肽类药物可以选自曲普瑞林(Triptorelin)、ES-2多肽、蝎毒多肽、蜂毒肽、亮丙瑞林、布舍瑞林、大豆肽、豌豆肽、卵白肽、多粘菌素、乳酸杀菌素、乳酸链球菌肽、杆菌肽、放线菌素和争光霉素中的至少一种,但不限于此。
对于所述荧光追踪剂,可列举吲哚青绿、伊文思蓝、异硫蓝、专利蓝、亚甲蓝、香豆素6、IR780碘化物(11-氯-1,1'-二正丙基-3,3,3',3'-四甲基-10,12-三亚甲基吲哚三碳花青碘盐)和DiR碘化物中的一种或多种,但不限于此。
其中,所述造影剂包括X射线造影剂、磁共振成像造影剂和超声造影剂的至少一种。
对于X射线造影剂,可列举碘苯六醇、碘普罗胺、碘必乐、碘苯酯和硫酸钡中的一种或多种,但不限于此。对于磁共振成像造影剂,可列举锰的卟啉螯合物、Gd-DTPA及其线型、环型多胺多酸类螯合物,叶酸修饰的钆螯合物、含钆富勒烯造影剂等。对于超声造影剂,可选自液态氟碳类,例如全氟己烷(即十四氟己烷,C6F14)、全氟辛基溴化铵(PFOB)、全氟己烷(PFP)、全氟萘烷(PFD)等。
本发明第一方面提供的靶向pl-CSA的多肽药物偶联物中,带有能特异性靶向pl-CSA的多肽部分,可以提高药物对pl-CSA不恰当表达的组织的靶向性和富集程度,使药物能专属地到达肿瘤等靶组织,在其附近释放,提高药物的利用度,降低了药物对正常组织的毒副作用。药物在所述多肽药物偶联物中的稳定性好,延长体内循环时间。
第二方面,本发明提供了一种靶向pl-CSA的多肽药物偶联物的制备方法,包括以下步骤:
(1)将小分子药物与连接子反应,得到功能化的小分子药物;其中所述功能化的小分子药物上带有羧基或氨基;
(2)将所述功能化的小分子药物与靶向胎盘样硫酸软骨素A的多肽进行酰胺反应,得到靶向pl-CSA的多肽药物偶联物;其中,所述多肽的氨基酸序列选自SEQ ID NO:1-SEQID NO:3所示的氨基酸序列中的一种或多种;所述靶向多肽药物偶联物包括小分子药物部分、多肽部分,以及分别与所述小分子药物部分与多肽部分相连接的连接子部分。
本发明中,所得靶向多肽药物偶联物中的酰胺键在血液中具有很好的稳定性,可以有效的避免药物分子在进入细胞前的释放导致的副作用。
本发明中,用于靶向pl-CSA的多肽的序列如SEQ ID NO:1-SEQ ID NO:3所示。所述多肽是按照常规的多肽合成工艺进行,其中每个序列的最左端为N端,最右端为多肽的C端。
具体地,LKPSHEKKNDDNGKKLCKAC如SEQUENCE NO.1所示。
EDVKDINFDTKEKFLAGCLIVSFHEGKC如SEQUENCE NO.2所示。
GKKTQELKNIRTNSELLKEWIIAAFHEGKC如SEQUENCE NO.3所示。
值得注意的是,在构建所述功能化的小分子药物时,需注意不影响小分子药物的药物活性。当然,最终所得多肽药物偶联物,需仍具有药物活性。
其中,当所述功能化的小分子药物上带有羧基时,可利用其上的羧基与所述多肽的C端上的氨基(即,半胱氨酸上的氨基)来进行酰胺反应。当所述功能化的小分子药物上带有氨基时,可利用其上的氨基与所述多肽的N端上的羧基来进行酰胺反应。
进一步地,当制备带羧基的功能化的小分子药物时,所述连接子可以选自烷基烃二酸酐(分子式可表示为Cn+2H2nO3,n为大于1的整数)。优选为碳原子数为4-8的烷基烃二酸酐。
此时,所述小分子药物上需带有-NH2、-OH等活性基团。所得多肽药物偶联物可以表示为:小分子药物部分—A—多肽部分;其中A为连接子部分,A可以为-NH-CO-(CH2)n-CO-*或-O-CO-(CH2)n-CO-*、其中,A的*端与所述多肽部分连接。此时的多肽部分为如SEQ ID NO:1-SEQ ID NO:3所示的氨基酸序列中的一种或多种的多肽去掉-NH2后的部分。
此时,所述小分子药物部分是指小分子药物去除不影响其药物活性的活性基团后的残留部分。对于阿霉素及其药学上可接受的盐而言,所去掉的是-NH2或-NH2·HCl。
步骤(2)中,所述酰胺反应的方法为本领域的技术人员所熟知,通常需要加入缩合剂、催化剂(又可称为活化剂)。
具体地,步骤(2)中,所述酰胺反应的反应历程如下:将所述功能化的小分子药物与靶向胎盘样硫酸软骨素A的多肽、溶剂、缩合剂、催化剂相溶解,搅拌反应1-6h,得到靶向pl-CSA的多肽药物偶联物。
其中,所述缩合剂包括O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯(TBTU)、O-(N-丁二酰亚胺基)-二(二甲胺基)碳鎓四氟硼酸盐(TSTU)、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)和O-苯并三氮唑-四甲基脲六氟磷酸酯(HBTU)中的至少一种,但不限于此。
所述催化剂包括N,N-二异丙基乙胺(DIEA)、N-甲基吗啡啉、三乙基胺(TEA)中的任意一种,但不限于此。
所述溶剂包括N,N-二甲基甲酰胺(DMF)、丙酮、四氢呋喃(THF)中的至少一种,但不限于此。
进一步地,当所述功能化的小分子药物上带有羧基时,可以先将其与缩合剂、溶剂相混合,之后滴加催化剂,搅拌0.5-2h,然后加入靶向胎盘样硫酸软骨素A的多肽,继续搅拌1-4h,终止反应,收获反应液。
进一步地,当所述功能化的小分子药物上带有氨基时,可以先将所述靶向胎盘样硫酸软骨素A的多肽与缩合剂、溶剂相混合,之后滴加催化剂,搅拌0.5-2h,然后加入带有氨基的功能化的小分子药物,继续搅拌1-4h,终止反应,收获反应液。
优选地,在进行酰胺反应,获得反应液后;对所述反应液采用高效液相色谱来进行纯化。
本发明第二方面提供的多肽药物偶联物的制备方法简单易行,便于操作。制得的多肽药物偶联物对不恰当表达pl-CSA的组织的靶向性较强,其在靶组织的富集程度高。
第三方面,本发明提供了一种如本发明第一方面所述的靶向pl-CSA的多肽药物偶联物在制备预防、诊断或治疗与胎盘样硫酸软骨素A的不适当表达相关的疾病的药物中的应用。
所述与pl-CSA的表达或不适当表达相关的疾病包括妊娠疾病、肿瘤疾病、关节炎、关节病、多发性硬化、由神经损伤导致的病理病症(例如神经损伤后的愈合)、软骨和疤痕组织的病症(如风湿病、软骨修复或伤口愈合)、银屑病等,但不限于此。
进一步地,所述妊娠疾病包括先兆子痫(也称“子痫前期”)、胎儿宫内生长迟缓、胎膜早破、早产、妊娠糖尿病、妊娠综合征等,但不限于此。
进一步地,所述肿瘤疾病包括胎盘绒毛癌、乳腺癌、胰腺癌、卵巢癌、子宫内膜癌、肝细胞癌、肺癌、结肠癌、前列腺癌、宫颈癌、睾丸癌、基底细胞皮肤癌、透明细胞肾细胞癌、头颈鳞状细胞癌、皮肤鳞状细胞癌、外阴角化鳞状细胞癌和外阴基底细胞癌、神经内分泌癌、肉瘤、造血系统癌和神经上皮组织的肿瘤中的一种或多种,但不限于此。
其中,所述肉瘤包括但不限于纤维肉瘤、去分化软骨和脂肪肉瘤、平滑肌肉瘤、脂肪肉瘤、粘液性脂肪肉瘤、子宫体平滑肌肉瘤、骨肉瘤、尤因肉瘤和横纹肌肉瘤、滑膜肉瘤、孤立性纤维瘤;所述造血系统癌包括但不限于慢性淋巴细胞白血病(CLL)、急性淋巴细胞白血病(ALL)、急性髓细胞白血病(AML)、B细胞、T细胞和大颗粒状淋巴瘤;所述神经上皮组织的肿瘤,包括但不限于星形细胞瘤(多形性黄色星形细胞瘤、纤维型星形细胞瘤、间变型星形细胞瘤、多形性胶质母细胞瘤)、少突神经胶质瘤、室管膜瘤、脉络丛肿瘤、少星形细胞瘤、神经胶质肉瘤、神经节神经胶质瘤、视网膜母细胞瘤、神经细胞瘤、神经母细胞瘤(嗅神经母细胞瘤和神经节母细胞瘤)、髓母细胞瘤和非典型畸胎样横纹肌样肿瘤。
综上,本发明的有益效果包括以下几个方面:
1、本发明提供的靶向pl-CSA的多肽药物偶联物中,表面带有的多肽部分是pl-CSA的特异性受体,可以有效提高该多肽药物偶联物对不恰当表达pl-CSA的组织的靶向性和富集程度,降低了药物对正常组织的毒副作用;且该多肽药物偶联物中目标投递物的稳定性高,在体内循环时间长;
2、所述靶向pl-CSA的多肽药物偶联物的制备方法简单易行,便于操作;
3、所述靶向pl-CSA的多肽药物偶联物的应用范围较广,可用于与不恰当表达pl-CSA相关的疾病的诊断、治疗,能够实现诊疗一体化。
附图说明
图1为实施例1中靶向胎盘样硫酸软骨素A的多肽药物偶联物的合成示意图;
图2为不同浓度的游离药物及不同浓度的实施例3中靶向多肽药物偶联物的抗瘤效果图。
具体实施方式
以下所述是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也视为本发明的保护范围。
图1为本发明实施例中靶向pl-CSA的多肽-药物偶联物的合成示意图。1为小分子药物,2为连接子,3为靶向pl-CSA的多肽,它们之间通过化学键而连接在一起,得到靶向pl-CSA的多肽-药物偶联物。所得的靶向pl-CSA的多肽-药物偶联物包括小分子药物部分1’、多肽部分3’,以及将小分子药物部分1’、多肽部分3’连接在一起的连接子部分2’,其中多肽部分3’是指靶向pl-CSA的多肽3去掉-NH2或-COOH后的部分,其整体结构与多肽3很接近。小分子药物部分1’是指小分子药物1去除不影响其药物活性的活性基团后的残留部分,其整体结构与小分子药物1很接近。而连接子部分2’可能与连接子2的结构类似,也可能相差较大,尤其是连接子2为环状二酸酐时。
以下结合具体的实施例来介绍靶向多肽药物偶联物的制备及应用。
实施例1
一种靶向胎盘样硫酸软骨素A(pl-CSA)的多肽-药物偶联物的制备:首先将盐酸阿霉素与丁二酸酐反应,在阿霉素分子上引入羧基;再将羧基化的阿霉素与多肽进行酰胺反应,使多肽片段的末端氨基与上述羧基化的阿霉素上的羧基反应,生成靶向多肽—药物偶联物。反应方程式如下:
具体地,包括以下步骤:
(1)化合物II的合成
50mL反应瓶中加入1.0g(1.72mmol)盐酸阿霉素,0.52g(5.2mmol)丁二酸酐,30mL四氢呋喃(THF),滴加0.66g(5.12mmol)的N,N-二异丙基乙胺(DIEA),27℃搅拌6h,蒸干溶剂得蜡状物,加水搅拌,有黄色固体析出,抽滤,水洗两次,干燥,得黄色固体1.15g,即,羧基化的阿霉素。
(2)化合物I的合成
50mL反应瓶中加入0.22g(0.32mmol)化合物II,0.10g(0.31mmol)的O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯(TBTU),5mL的N,N-二甲基甲酰胺(DMF),氮气保护,滴加0.08g(0.62mmol)的N,N-二异丙基乙胺(DIEA),27℃搅拌1h后,加入0.10g如SEQUENCENO.1所示的多肽(序列为LKPSHEKKNDDNGKKLCKAC),27℃搅拌3h后,终止反应。使用MS-IT-TOF确定分子量,使用HPLC纯化粗产物,纯化后的产物即为靶向多肽—药物偶联物。
实施例2
一种靶向pl-CSA的多肽-药物偶联物的制备,首先将紫杉醇与丁二酸酐反应,在紫杉醇分子上引入羧基;再将羧基化的紫杉醇与多肽进行酰胺反应,使多肽片段的末端氨基与上述羧基化的紫杉醇上的羧基反应,生成多肽—药物偶联物。反应方程式如下:
具体地,其制备过程包括以下步骤:
(1)化合物III的合成
50mL反应瓶中加入1.0g(1.72mmol)紫杉醇,0.52g(5.2mmol)丁二酸酐,30mL四氢呋喃(THF),滴加0.66g(5.12mmol)N,N-二异丙基乙胺(DIEA),27℃搅拌6h,蒸干溶剂得蜡状物,加水搅拌,有黄色固体析出,抽滤,水洗两次,干燥,得黄色固体1.15g。
(2)化合物IV的合成
50mL反应瓶中加入0.22g(0.32mmol)化合物III,0.10g(0.31mmol)O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯(TBTU),5mL二甲基甲酰胺(DMF),氮气保护,滴加0.08g(0.62mmol)N,N-二异丙基乙胺(DIEA),27℃搅拌1h后,加入0.10g的如SEQUENCE NO.3的多肽(序列为GKKTQELKNIRTNSELLKEWIIAAFHEGKC),27℃搅拌3h后,终止反应。使用MS-IT-TOF确定分子量,使用HPLC纯化粗产物,纯化后的产物即为靶向多肽—药物偶联物。
实施例3
一种靶向pl-CSA的多肽-药物偶联物的制备方法,与实施例1不同之处在于:本实施例采用0.1g的如SEQUENCE NO.2的多肽(EDVKDINFDTKEKFLAGCLIVSFHEGKC)来替代实施例1中所用的多肽。
应用实施例1靶向多肽—药物偶联物的抗肿瘤作用研究
采用实施例3中的靶向多肽-药物偶联物,以绒毛膜癌系JEG3细胞为研究对象,利用MTT法评价本发明提供的靶向多肽-药物偶联物的抑瘤效果。具体如下:
收集对数期细胞,调整细胞悬液浓度,每孔加入100μL,铺板使待测细胞调密度至1000-10000每孔。于5%CO2,37℃下孵育,至细胞单层铺满孔底(96孔平底板),4小时以后分别加入7个浓度梯度(0,0.2,0.4,0.6,0.8,1,2)的游离阿霉素(Free DOX)和7个浓度梯度的靶向多肽-药物偶联物(DOX-plCSA),每孔100μL,设5个复孔(这里的浓度滴度是药物在每孔中的最终浓度,其中,Free DOX或DOX-plCSA的浓度为0时,加的是PBS缓冲液),继续孵育48小时,倒置显微镜下观察。每孔加入20μL的MTT溶液(5mg/mL,即0.5%MTT),继续培养4h。小心吸去孔内培养液,每孔加入150ul二甲基亚砜,置摇床上低速振荡5min,使结晶物充分溶解。在酶联免疫检测仪OD490nm处测量各孔的吸光值A。同时设置调零孔(培养基、MTT、二甲基亚砜),对照孔(细胞、相同浓度的药物溶解介质、培养液、MTT、二甲基亚砜)。
本实施例中增殖抑制率采用以下公式计算:
增殖抑制率=1-(实验孔A值-调零孔A值)/(对照孔A值-调零孔A值),其中每组的实际A值为减去凋零孔之后的结果。
其中,各实验组对JEG3细胞的增殖抑制率的结果如图2所示,其中,*表示与PBS组比较P<0.05;**表示与PBS组比较P<0.01。
图2的实验结果显示:偶联物DOX-plCSA与游离的阿霉素(Free DOX)相比,具有很强的抑瘤效果。DOX-plCSA的半数抑制率IC50=0.42μg/mL,Free DOX的半数抑制率IC50=0.8μg/mL。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对本发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
SEQUENCE LISTING
<110> 中国科学院深圳先进技术研究院
<120> 靶向胎盘样硫酸软骨素A的多肽药物偶联物及其制备方法和应用
<130> 2017
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Claims (10)
1.一种靶向胎盘样硫酸软骨素A的多肽药物偶联物的制备方法,包括以下步骤:
(1)将小分子药物与连接子反应,得到功能化的小分子药物;其中所述功能化的小分子药物上带有羧基或氨基;
(2)将所述功能化的小分子药物与靶向胎盘样硫酸软骨素A的多肽进行酰胺反应,得到多肽药物偶联物;其中,所述多肽的氨基酸序列选自SEQ ID NO:1-SEQ ID NO:3所示的氨基酸序列中的一种或多种;所述多肽药物偶联物包括小分子药物部分、多肽部分,以及分别与所述小分子药物部分与多肽部分相连接的连接子部分。
2.如权利要求1所述的制备方法,其特征在于,当所述功能化的小分子药物上带有羧基时,所述连接子包括烷基烃二酸酐,所述连接子的分子式可表示为Cn+2H2nO3,n为大于1的整数。
3.如权利要求2所述的制备方法,其特征在于,所述连接子为碳原子数为4-8的烷基烃二酸酐。
4.如权利要求2所述的制备方法,其特征在于,所述多肽药物偶联物可以表示为:小分子药物部分—A—多肽部分;其中A为连接子部分,A可以为-NH-CO-(CH2)n-CO-*或-O-CO-(CH2)n-CO-*、其中,A的*端与所述多肽部分连接;
其中,所述多肽部分为如SEQ ID NO:1-SEQ ID NO:3所示的氨基酸序列中的一种或多种的多肽去掉-NH2后的残留部分;所述小分子药物部分是指小分子药物去除不影响其药物活性的活性基团后的残留部分。
5.如权利要求2所述的制备方法,其特征在于,当所述功能化的小分子药物上带有羧基时,所述酰胺反应的历程如下:先将带有羧基的功能化的小分子药物与缩合剂、溶剂相混合,之后滴加催化剂,搅拌0.5-2h,然后加入所述多肽,继续搅拌1-4h。
6.如权利要求1-5任一项所述的制备方法,其特征在于,所述小分子药物包括抗肿瘤药物、妊娠药物、荧光追踪剂和造影剂中的至少一种。
7.一种靶向胎盘样硫酸软骨素A的多肽药物偶联物,其特征在于,包括小分子药物部分、多肽部分,以及分别与所述小分子药物部分与多肽部分相连接的连接子部分,其中,所述多肽部分所对应的多肽能特异性靶向胎盘样硫酸软骨素A,所述多肽部分为如SEQ IDNO:1-SEQ ID NO:3所示的氨基酸序列中的一种或多种多肽去掉氨基或羧基后的部分;所述小分子药物部分是指小分子药物去除不影响其药物活性的活性基团后的残留部分。
8.如权利要求7所述的多肽药物偶联物,其特征在于,所述连接子部分为-NH-CO-(CH2)n-CO-*或-O-CO-(CH2)n-CO-*、其中,A的*端与所述多肽部分连接;
其中,所述多肽部分为如SEQ ID NO:1-SEQ ID NO:3所示的氨基酸序列中的一种或多种的多肽去掉-NH2后的残留部分。
9.如权利要求8所述的多肽药物偶联物,其特征在于,所述小分子药物包括抗肿瘤药物、妊娠药物、荧光追踪剂和造影剂中的至少一种。
10.如权利要求1-6任一项所述的制备方法制得的或如权利要求7-9任一项所述的多肽药物偶联物在制备预防、诊断或治疗与胎盘样硫酸软骨素A的不适当表达相关的疾病的药物中的应用。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113956331A (zh) * | 2020-07-21 | 2022-01-21 | 深圳先进技术研究院 | 异位子宫内膜识别多肽及其衍生物和应用 |
CN113952467A (zh) * | 2020-07-21 | 2022-01-21 | 深圳先进技术研究院 | 一种子宫内膜异位症分子诊疗制剂及其制备方法和应用 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102459646A (zh) * | 2009-05-15 | 2012-05-16 | 环太平洋生物技术有限公司 | 胃癌的检测标志物 |
CN102516385A (zh) * | 2012-02-07 | 2012-06-27 | 江苏大学 | 一种神经生长因子-紫杉醇偶联物及其制法和用途 |
CN104136041A (zh) * | 2012-02-09 | 2014-11-05 | Var2制药有限公司 | 靶向硫酸软骨素聚糖 |
CN104306983A (zh) * | 2014-10-31 | 2015-01-28 | 山东大学 | 氧化还原敏感的透明质酸-多烯紫杉醇共轭物及制备方法 |
-
2017
- 2017-09-28 CN CN201710906586.1A patent/CN109568597B/zh active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102459646A (zh) * | 2009-05-15 | 2012-05-16 | 环太平洋生物技术有限公司 | 胃癌的检测标志物 |
CN102516385A (zh) * | 2012-02-07 | 2012-06-27 | 江苏大学 | 一种神经生长因子-紫杉醇偶联物及其制法和用途 |
CN104136041A (zh) * | 2012-02-09 | 2014-11-05 | Var2制药有限公司 | 靶向硫酸软骨素聚糖 |
CN104306983A (zh) * | 2014-10-31 | 2015-01-28 | 山东大学 | 氧化还原敏感的透明质酸-多烯紫杉醇共轭物及制备方法 |
Non-Patent Citations (1)
Title |
---|
邵志敏 等: "《乳腺癌 基础与临床的转化 上》", 30 September 2016 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113956331A (zh) * | 2020-07-21 | 2022-01-21 | 深圳先进技术研究院 | 异位子宫内膜识别多肽及其衍生物和应用 |
CN113952467A (zh) * | 2020-07-21 | 2022-01-21 | 深圳先进技术研究院 | 一种子宫内膜异位症分子诊疗制剂及其制备方法和应用 |
WO2022016751A1 (zh) * | 2020-07-21 | 2022-01-27 | 深圳先进技术研究院 | 一种子宫内膜异位症分子诊疗制剂及其制备方法和应用 |
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