CN116999570A - 一种肿瘤靶向的多肽药物偶联物及其应用 - Google Patents
一种肿瘤靶向的多肽药物偶联物及其应用 Download PDFInfo
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Abstract
本发明属于抗肿瘤药物开发领域，具体涉及肿瘤靶向的多肽药物偶联物的设计合成及其应用。所述的肿瘤靶向多肽药物偶联物结构包括：肿瘤靶向肽(靶向plectin‑1)，靶向/代谢调节功能基，连接子和细胞毒性抗肿瘤药物/放射性核素螯合基团；本发明提供的多肽偶联药物，将细胞毒性抗肿瘤药物/放射性核素螯合基团通过与多肽连接，***功能调节基团，改善多肽药物偶联物的肿瘤靶向能力和延长药物体内代谢，能够实现肿瘤组织部位的高浓度富集和长时间滞留，提高化疗药物/放射性核素的靶向性，使高剂量的化疗药物/放射性核素精确杀伤/诊断肿瘤细胞，从而实现更好更安全的治疗胰腺癌的功能。
Description
技术领域
本发明属于抗肿瘤药物开发领域，具体涉及肿瘤靶向的多肽药物偶联物及其应用。
背景技术
近年来，癌症已逐步发展成为全球人口疾病致死的最主要原因之一，在众多的恶性肿瘤中，胰腺癌(Pancreatic Cancer，PC)的死亡率-发病率之比最高，因此胰腺癌也有"癌症之王"之称。胰腺癌作为恶性程度最高的肿瘤之一，具有高度侵袭性和转移性，而且缺乏典型的早期症状，导致胰腺癌患者被诊断时已经处于晚期或发生转移。在美国，胰腺癌的5年生存率约为10％，主要原因在于在被诊断的患者中，只有不到20％患者被判定为胰腺癌早期可切除，而大约80％-85％的胰腺癌患者则已经发展为晚期，且手术切除并不能明显改善患者的预后，他们依然需要接受长期的全身性化疗以控制、改善病情。因此，更多针对于胰腺癌早期发现和提高良性与恶性肿瘤之间辨识度的诊断方法需要被积极开发出来以解决胰腺癌患者的临床需求。
临床上对于胰腺癌的治疗方法主要包括手术切除、放疗、化疗或者以上方法的联合疗法，而化学治疗手段应用最为广泛。尽管多种治疗方式正在被尝试和开发，却远远不能满足胰腺癌患者当前的临床需求，因此更多更有效的胰腺癌诊疗方法需要被探索和开发出来以解决这一困境。
Plectin-1是一种高分子量蛋白质(约500kDa)，包含一个中央棒状结构域，两侧是球形N端头部结构域和C端尾部结构域，头部结构域包括一个肌动蛋白结合结构域和一个plakin结构域，尾端由一个有着6个重复序列的plakin重复结构域、一个连接子子结构域和一个甘氨酸-丝氨酸-精氨酸结构域组成。Plectin-1广泛存在于多种癌症类型中，包括胰腺癌、乳腺癌、肺癌、***癌等，目前被较多应用于胰腺癌的研究中。Plectin-1充当细胞连接剂，连接并稳定细胞骨架蛋白(微管、微丝和中间丝)，对细胞的正常生理功能具有重要作用。它在胰腺癌细胞表面具有特异性异常定位，而在正常胰腺组织或者正常成纤维细胞中，定位于细胞核和细胞质中。Plectin-1靶向多肽序列KTLLPTP。
Dirk Bausc等人设计合成了基于Plectin-1的靶向分子t-PTP(KTLLPTP)，该多肽序列在分子水平能够很好的靶向结合Plectin-1。也有一些研究者利用该序列多肽尝试对基于Plectin-1的胰腺癌进行荧光成像诊断。然而，由于该序列多肽在动物体内的靶向性和代谢稳定性等因素限制其进一步的深入研究及应用。
发明内容
为了解决现有技术中的问题，本发明运用多肽药物偶联的策略，并通过化学合成方法制备了一系列基于plectin-1的多肽药物偶联物，其结构通式(I)为P-F-C-D，其中，
P为plectin-1靶向多肽，用于特异性识别并结合相应靶标；
F为功能性调节基团，用于改善整个偶联物分子的靶向性，延长偶联物分子体内循环时间，同时也可调节整个偶联物分子的水溶性、脂溶性等，以改善PK值；
C为连接子，用于连接靶向多肽-功能性调节基团部分和有效载荷部分；
D为有效载荷基团，包括化学抗肿瘤药物、放射性核素螯合基团或荧光基团，发挥肿瘤杀伤或者成像作用。
根据本发明具体实施方式的肿瘤靶向的多肽药物偶联物，通式(I)中的P单元为氨基酸序列为KTLLPTP(SEQ ID NO.1)，或在其基础上置换、缺失、***1-3个氨基酸的多肽序列或多肽衍生物。
根据本发明具体实施方式的肿瘤靶向的多肽药物偶联物，通式(I)中的F单元，所述功能性调节基团选自叶酸、RGD靶向肽、白蛋白靶向配体、plectin-1靶向肽(单体、二聚体)，所示结构如下：
根据本发明具体实施方式的肿瘤靶向的多肽药物偶联物，所述功能性调节基团选自如下所示结构：
根据本发明具体实施方式的肿瘤靶向的多肽药物偶联物，通式(I)中的所述连接子为连接可裂解连接子或不可裂解连接子；优选的，所述连接子以碳原子间通过共价键连接形成的不成环的链状为碳架；
根据本发明具体实施方式的肿瘤靶向的多肽药物偶联物，连接子选择以下结构中的一种：
根据本发明具体实施方式的肿瘤靶向的多肽药物偶联物，通式(I)中的D中，细胞毒性抗肿瘤药物包括紫杉醇和/或MMAE。
根据本发明具体实施方式的肿瘤靶向的多肽药物偶联物，通式(I)中的D中，荧光基团选自：
根据本发明具体实施方式的肿瘤靶向的多肽药物偶联物，通式(I)中放射性核素螯合基团选自以下结构中的任一种：
根据本发明具体实施方式的肿瘤靶向的多肽药物偶联物，其结构通式(I)为P-F-C-D，其中，
P为plectin-1靶向多肽，靶向多肽的氨基酸序列为KTLLPTP；
F为功能性调节基团，所述功能性调节基团选自叶酸、RGD靶向配体、白蛋白配体或plectin-1；
C为连接子，连接子选自以下结构中的一种；
D为有效载荷基团，有效载荷基团选自化学抗肿瘤药物或放射性核素螯合基团，优选为MMAT、DOTA-68Ga。
根据本发明具体实施方式的肿瘤靶向的多肽药物偶联物，所述多肽药物偶联物为以下结构中的任一种或多种：
以上结构中，连接子C部分可进行相应取代基，取代基可选自以下的非氢取代基：C3-10环烷基、C5-12芳基、C5-12杂芳基、羟基、卤素和C1-4烷氧基羰基的至少一个非氢取代基取代的C1-12烷基，C3-10环烷基，C1-12烷氧基，C5-12芳基，C5-12杂芳基，羟基和卤素，而且所述芳基和杂芳基是未取代的或被选自C1-4烷基、C1-4烷氧基、羟基和卤素的至少一个非氢取代基取代。
本文所用的“被取代”的基团是指其中至少一个氢原子被至少一个非氢原子基团替代的基团，前提是该基团必须满足化合价要求并且因该取代产生化学稳定的化合物。在本说明书中，除非特别描述为“未取代”，应理解所有取代基可以是取代或未取代的。
“烷基”是指直链和支链的饱和烃基，通常具有特定数目的碳原子(例如，1至12个碳原子)。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、正己基和正庚基。烷基可以通过任何环原子连接到母体基团或基质上，除非这样的连接会破坏化合价要求。同样，烷基或烯基可以包含至少一个非氢取代基，除非这样的取代会破坏化合价要求。
“环烷基”是指饱和的单环和多环烃环，通常具有包括环的特定数目的碳原子(例如C3-10环烷基是指具有3、4、5、6、7、8、9或10个碳原子作为环成员的环烷基)。环烷基可以通过任何环原子连接到母体或基质，除非这样的连接会破坏化合价要求。同样，环烷基可以包含至少一个非氢取代基，除非这样的取代会破坏化合价要求。
“芳基”是指一价和二价芳族基团，分别包括5元和6元单环芳族基团，“杂芳基”是指一价和二价芳族基团，分别包括含有独立地选自氮、氧和硫的1至4个杂原子的5元和6元单环芳族基团。单环芳基和杂芳基的实例包括但不限于苯基、吡啶基、呋喃基、吡咯基、噻吩基、噻唑基、异噻唑基、咪唑基、***基、四唑基、吡唑基、噁唑基、异噁唑基、吡嗪基、哒嗪基、嘧啶基等。芳基和杂芳基还包括二环基团、三环基团等，包括稠合的上述5元和6元环。多环芳基和杂芳基的实例包括但不限于异喹啉基、萘基、联苯基、蒽基、芘基、咔唑基、苯并噁唑基、苯并二噁唑基、苯并噻唑基、苯并咪唑基、苯并噻吩基、喹啉基、吲哚基、苯并呋喃基、嘌呤基、吲哚嗪基等。芳基和杂芳基可以通过任何环原子连接到母体基团或基质，除非这样的连接会破坏化合价要求。同样，芳基和杂芳基可以包含至少一个非氢取代基，除非这样的取代会破坏化合价要求。芳基和杂芳基的非氢取代基还可以被另外的非氢取代基取代。
“羰基”是指一C(O)R’。本文所用“(O)”是指通过双键与原子如碳或硫连接的氧。
此处，“R”是指非氢取代基如低级烷基、低级烷氧基等。羰基的实例包括但不限于2-甲氧基氧代乙基、3-甲氧基氧代丙基等。羰基可以通过任何环原子连接到母体基团或基质，除非这样的连接会破坏化合价要求。同样，羰基可以包含至少一个非氢取代基，除非这样的取代会破坏化合价要求。
“烷氧基”是指烷基-O-。此处，烷基与以上定义的相同。烷氧基的实例包括但不限于甲氧基、乙氧基等。烷氧基可以通过任何环原子连接到母体基团或基质，除非这样的连接会破坏化合价要求。同样，烷氧基可以包含至少一个非氢取代基，除非这样的取代会破坏化合价要求。
“羟基”是指-OH，“卤素”是指氟、氯、溴和碘，“氧代”是指＝O。
本发明的肿瘤靶向多肽药物偶联物的制备方法，包括如下步骤：
步骤1、采用Fmoc固相合成策略合成Boc保护的plectin-1肿瘤靶向多肽。
步骤2、步骤1中的plectin-1肿瘤靶向多肽与功能性调节基团通过固相或液相缩合连接，得到P-F片段。
步骤3、将步骤2中得到的P-F片段，通过click或者缩合反应与带有连接子的化学毒性药物连接，或通过缩合反应与放射性核素螯合基团连接，HPLC纯化，得到P-F-C-D多肽药物偶联物。
本发明通过体外、体内抗肿瘤活性测试，获得了具有优良抗肿瘤效果的多肽偶联物，因此，本发明提供一种基于网格蛋白plectin-1的多肽药物偶联物(包括螯合物与放射性核素)在制备抗肿瘤诊疗药物方面的应用。其中，所述肿瘤优先选择胰腺癌，以及其它plectin-1异常表达的肿瘤。
本发明的另一方面提供包含上述肿瘤靶向多肽药物偶联物或其可药用盐作为活性成分的药物。
本发明的药物组合物除活性成分外还包含至少一种可药用载体。本发明所用“可药用载体”是指已知的可药用赋形剂，其可用于配制施用于对象的药用活性化合物，并且在使用条件下基本无毒且无刺激性。通过标准药学实践以及活性化合物的溶解性、化学特性和所选的施用途径确定赋形剂的准确量。
可以使用适合且生理可接受的辅剂(例如赋形剂、崩解剂、甜味剂、粘合剂、包衣剂、膨胀剂、润滑剂、光亮剂、调味剂等)将本发明的药物组合物配置为适当形式以用于期望的施用方法。
以肿瘤靶向多肽药物偶联物(P-F-C-D)为活性成分的药物组合物的制剂包括冻干粉针、注射液、片剂、脂质体、纳米制剂等多种形式。
本发明的有益效果：
本发明提供的肿瘤靶向(靶向plectin-1)多肽药物偶联物，将细胞毒药物(MMAE、紫杉醇)或者放射性核素通过与胰腺癌靶向多肽连接，既能够实现细胞毒药物在肿瘤组织部位的高浓度富集杀死肿瘤，又能够实现对肿瘤的PET显像诊断，实现对胰腺癌的诊疗一体化药物开发。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1为产物KTLLPTPG(无BOC)HRMS分析谱图。
图2为产物KTLLPTPG-EDA(Free BOC)HRMS分析谱图。
图3为PDC-1 HRMS分析谱图。
图4为PDC-2 HRMS分析谱图。
图5为PDC-3 HRMS分析谱图。
图6为PDC-4 HRMS分析谱图。
图7为PDC-5 HRMS分析谱图
图8为PDC-6 HRMS分析谱图
图9为PDC-7 HRMS分析谱图。
图10为PDC-8 HRMS分析谱图。
图11为PDC-9 HRMS分析谱图。
图12为PDC-10 HRMS分析谱图。
图13为PDC-11 HRMS分析谱图。
图14为PDC-12 HRMS分析谱图。
图15为PDC-15 HRMS分析谱图。
图16显示多肽-药物偶联物(荧光基团)在竞争和非竞争情况下对于PANC-1的标记水平，在靶向多肽的竞争下，多肽-药物偶联物(荧光基团，PDC-9)标记水平相较于无竞争状态明显下降。
图17显示多肽药物偶联物对于细胞来源胰腺癌荷瘤小鼠模型的肿瘤抑制活性，给药结束后，3个PDC给药组的平均肿瘤体积相较于空白对照组，差异具有统计学意义。
图18显示本发明制备的化合物对小鼠体重的影响，PDC-3给药组相较于其他2个给药组和空白对照组，体重有明显下降趋势。
图19显示放射性核素68Ga标记的PDC-12、PDC-14和PDC-16对胰腺癌荷瘤小鼠模型的PET/CT成像，结果显示，相较于68Ga-PDC-12和68Ga-PDC-14，68Ga-PDC-16尾静脉注射0.5h后在肿瘤部位有最好摄取和显像。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚，下面将对本发明的技术方案进行详细的描述。显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动的前提下所得到的所有其它实施方式，都属于本发明所保护的范围。
为使本发明的目的、技术方案和优点更加清楚，下面将对本发明的技术方案进行详细的描述。显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动的前提下所得到的所有其它实施方式，都属于本发明所保护的范围。
本发明的某些实施例中，可所用细胞包括：
人胰腺癌细胞：PANC-1；
人正常胰腺导管细胞；hTERT-HPNE；
上述细胞均可通过市售获得，例如购自中国科学院细胞库。
实施例1化学合成
(1)合成KTLLPTPG
合成方法如下：
洗肽方法：DMF 4×10mL×2min。
脱Fmoc保护基方法：20％哌啶+80％DMF 2×10mL×5min。
茚检：加入配置好的茚三酮、苯酚、吡啶，用量＝1滴：1滴：2滴，100℃加热30-90s，若有裸露氨基体系呈蓝色或淡棕色；若无裸露氨基，体系呈无色。
第一个氨基酸接入方法：3eq氨基酸+6eq DIEA，DMF 10mL。
其他氨基酸接入方法：3eq氨基酸+3eq HBTU(可根据不同情况选择不同缩合剂)+4eq HOBT+6eq DIEA，DMF 10mL，室温振荡1-4h。
切肽：1％TFA/DCM，振荡3h。
萃肽、HPLC制备：冰***10mL，水2×10mL萃取，收集水相。HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—80min乙腈20％—100％，流速：8ml/min。
先将(103mg，0.1mmol)二氯树脂在10mL DCM中溶胀30min，DCM洗3×10mL×2min，DMF洗3×10mL×2min，接入Fmoc-Gly-OH，洗肽，按DCM：MeOH：DIEA＝8.5mL：1mL：0.5mL封闭30min，洗肽，脱Fmoc，洗肽，茚检，随后按照(接入氨基酸→茚检→脱Fmoc→洗肽→茚检→接入下一个氨基酸顺序)依次接入PTPLLTK，切肽，萃肽，HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—80min乙腈20％—100％，流速：8ml/min，Rt＝45min，减压干燥得产物KTLLPTPG(WithBOC)(41mg，0.04mmol，产率：40％)。向前者加入20％TFA/DCM，室温搅拌2h，HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—80min乙腈20％—100％，流速：8ml/min，Rt＝20min，减压干燥得产物KTLLPTPG(Free BOC)(37.7mg，0.037mmol，产率：92％)HRMS(ESI):C38H67N9O11[M+H]2+calcd:413.7553,found:413.7553.Purity:99.03％.
产物KTLLPTPG(无BOC)HRMS分析谱图如图1所示：
(2)合成KTLLPTPG-EDA
合成方法如下：
将(25mg，0.0242mmol)KTLLPTPG(With BOC)，(3.3mg，0.029mmol)N-羟基丁二酰亚胺溶于1mL DCM中，随后加入(6mg，0.029mmol)DCC和(0.3mg，0.00242mmol)DMAP，(4.68mg，0.0363mmol)DIEA，室温下搅拌1h，随后加入(3mg，0.0484mmol)乙二胺，室温搅拌1h，减压浓缩，加入乙腈、水溶解，HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—80min乙腈20％—100％，流速：8ml/min，Rt＝30min，减压干燥得产物KTLLPTPG-EDA(With BOC)(16mg，0.015mmol，产率62％)。向前者加入20％TFA/DCM，室温搅拌2h，HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—80min乙腈20％—100％，流速：8ml/min，Rt＝20min，减压干燥得产物KTLLPTPG-EDA(FreeBOC)(14.9mg，0.014mmol，产率93％)HRMS(ESI):C40H73N11O10[M+H]2+calcd:434.7844,found:434.7845.Purity:96.10％。
产物KTLLPTPG-EDA(Free BOC)HRMS分析谱图如图2所示。
(3)合成PDC-1
合成方法如下：
将(50mg，0.06mmol)化合物1，(12mg，0.12mmol)丁二酸酐，(7mg，0.06mmol)DMAP加于反应瓶中，真空干燥2h，随后加入2mL DCM和1mL干燥吡啶，室温搅拌3h。加入15mL DCM，用1N HCl(3×15mL)洗涤有机相，合并有机相，饱和NaCl水溶液洗涤(3×10mL)，减压浓缩，得到SA-PTX(化合物2)，直接投入下一步。
将(9.6mg，0.01mmol)SA-PTX(化合物2)，(11mg，0.01mmol)KTLLPTPG-EDA(WithBOC)，(3mg，0.012mmol)BOP-Cl加入反应瓶中，随后加入1.5mL DCM，并加入(2mg，0.015mmol)DIEA，室温搅拌2h。减压浓缩，加入20％TFA/DCM，室温搅拌2h，减压浓缩，加入乙腈、水溶解，HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—80min乙腈20％—100％，流速：8ml/min，Rt＝30min，减压干燥得产物PDC-1(5.4mg，0.003mmol，产率30％)，HRMS(ESI):C91H126N12O26[M+H]2+calcd:902.4526,found:902.4527.Purity:99.05％。
PDC-1HRMS分析谱图如图3所示。
(4)合成PDC-2
合成方法如下：
将(720mg，1.95mmol)化合物3，(738mg，3.9mmol)氨基-聚乙二醇-丙酸叔丁酯溶于15mL DMF中，随后在0℃下加入(1.12g，5.85mmol)EDCI，(790mg，5.85mmol)HOBT和(755mg，5.85mmol)DIEA，室温下搅拌4h。减压浓缩，萃取(水30mL，乙酸乙酯3×50mL)，水洗2×70mL，饱和NaCl水溶液2×70mL，无水Na2SO4干燥，减压浓缩，柱层析纯化，石油醚：乙酸乙酯＝1：4—1：10。得化合物4(705mg，0.99mmol，产率50.8％)。将(20mg，0.028mmol)化合物4溶于2mL20％TFA/DCM，室温搅拌3h，DCM 3×3mL，直接投入下一步反应。
将(32mg，0.084mmol)HATU加入上述产物中，3mL DMF溶解，加入(11mg，0.084mmol)DIEA，0℃下搅拌20min，随后加入(60mg，0.056mmol)KTLLPTPG-EDA(With BOC)，室温搅拌3h。减压浓缩，加入2mL 5％DBU/DCM，室温搅拌2h，DCM 3×3mL，得Dimer-KTLLPTPG(化合物5)，直接投入下一步反应。
将(2mg，0.00209mmol)SA-PTX(化合物2)，(1mg，0.00209mmol)HATU溶于1mL DMF中，加入(1mg，0.0077mmol)DIEA，0℃搅拌20min，随后加于(5.2mg，0.00209mmol)Dimer-KTLLPTPG(化合物5)中，室温搅拌2h，减压浓缩，加入2mL 20％TFA/DCM，室温搅拌3h，DCM 3×3mL。加入乙腈、水溶解，HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—80min乙腈20％—100％，流速：8ml/min，Rt＝23min，减压干燥得产物PDC-2(1mg，0.00033mmol，产率15.78％)。HRMS(ESI):C146H222N26O42[M+H]2+calcd:1506.8120,found:1506.8099.Purity:>99.00％.
PDC-2HRMS分析谱图如图4所示。
(5)合成PDC-3
合成方法如下：
将(1g，2.635mmol)化合物7，(325mg，2.899mmol)化合物6和(1.099g，2.899mmol)HBTU，(391mg，2.899mmol)HOBT溶于20mL DMF，随后加入(374mg，2.899mmol)DIEA，室温搅拌6h，减压浓缩。乙腈/水溶解，HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—90min乙腈10％—100％，流速：8ml/min，Rt＝25min，减压干燥得化合物8(1.16g，2.4505mmol，产率93％)。
将(500mg，1.05mmol)化合物8，(384mg，3.15mmol)化合物9溶于10mL DMF中，随后加入(30mg，0.231mmol)DIEA，室温搅拌5h。减压浓缩，加入40mL乙酸乙酯，过滤，乙酸乙酯洗3×30mL，得化合物10(637mg，0.9975mmol，产率95％)。
将(300mg，0.4697mmol)化合物10，(321mg，0.4473mmol)化合物11和(25mg，0.1878mmol)HOBT溶于6mL DMF，随后加入(883mg，11.18mmol)吡啶，搅拌过夜。减压浓缩，乙腈/水溶解，HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—80min乙腈20％—100％，流速：8ml/min，Rt＝40min，减压干燥得化合物12(283mg，0.2325mmol，产率52％)。
将(10mg，0.0082mmol)化合物12，(7.3mg，0.0082mmol)KTLLPTPG-N3(化合物13)，(1mg，0.0041mmol)CuSO4·5H2O和(3.3mg，0.0164mmol)抗坏血酸钠加于反应瓶中，随后加入DMF：H2O＝0.75mL：0.25mL，室温搅拌过夜，减压浓缩，HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—80min乙腈20％—100％，流速：8ml/min，Rt＝27min，减压干燥得产物PDC-3(5.7mg，0.0027mmol，产率：32.9％)。HRMS(ESI):C104H171N23O23[M+H]2+calcd:1056.1532,found:1056.1533.Purity:96.50％.
PDC-3HRMS分析谱图如图5所示。
(6)合成PDC-4
合成方法如下：
将(100mg，0.217mmol)化合物14，(75mg，0.2387mmol)化合物15，(50mg，0.2604mmol)HBTU和(35mg，0.2604mmol)HOBT溶于6mL DMF中，加入(42mg，0.3255mmol)DIEA，室温搅拌6h，萃取(水15mL，乙酸乙酯3×20mL，收集有机相，水50mL洗一次，饱和NaCl水溶液50mL洗一次，无水Na2SO4干燥)，减压浓缩，柱层析纯化：二氯甲烷：甲醇＝30：1—10：1，得产物(134mg，0.1844mmol，产率84.97％)，取(60mg，0.0825mmol)该产物，加入20％TFA/DCM 2mL，室温搅拌3h，DCM×3，得化合物16，直接投入下一步反应。
向(47mg，0.0825mmol)化合物16加入(102mg，0.09075mmol)KTLLPTPG-NHS(化合物17)，DMF 3mL溶解，随后加入(22mg，0.165mmol)DIEA，室温搅拌4h。减压浓缩，乙腈/水溶解，HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—70min乙腈30％—100％，流速：8ml/min，Rt＝40min，减压干燥得化合物18(56mg，0.0354mmol，产率43％)。
取(25mg，0.0158mmol)化合物18，加入5％DBU/DCM 1mL，室温搅拌1h，DCM×3，加入(20mg，0.01738mmol)KTLLPTPG-NHS(化合物17)，DMF 1.5mL，(4mg，0.0316mmol)DIEA，室温搅拌4h，减压浓缩，直接投入下一步反应。向前者加入(2mg，0.01422mmol)叠氮乙胺，(4mg，0.02133mmol)HBTU和(3mg，0.02133mmol)HOBT，加入1mL DMF，(4mg，0.02844mmol)DIEA，室温搅拌过夜，减压浓缩，加入乙腈/水HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—70min乙腈30％—100％，流速：8ml/min，Rt＝40min，减压干燥得化合物19(8.5mg，0.0035mmol，产率24.6％)。
将(8.5mg，0.0035mmol)化合物19加于2mL 30％TFA/DCM中，室温搅拌3h，DCM×3，直接投入下一步反应。加入(4.5mg，0.0035mmol)HA-Val-Cit-PABC-MMAE，(0.5mg，0.00175mmol)CuSO4·5H2O和(1.5mg，0.007mmol)抗坏血酸钠，H2O：DMF＝0.25mL：0.75mL。室温搅拌过夜，减压浓缩，HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—90min乙腈10％—100％，流速：8ml/min，Rt＝34.5min，，冻干得产物(6.8mg，0.0021mmol，产率60％)。HRMS(ESI):C157H265N35O38[M+H]2+calcd:1625.4993,found:1625.5014.Purity:>99.00％.
PDC-4HRMS分析谱图如图6所示。
(7)合成PDC-5
合成方法如下：
将(20mg，0.238mmol)化合物20，(87mg，0.2856mmol)化合物9溶于2mL DMF中，加入(37mg，0.2856mmol)DIEA，室温搅拌5h。减压浓缩，柱层析纯化，石油醚：乙酸乙酯＝20：1—10：1，得产物(50mg，0.2015mmol，产率84.7％)。取(20mg，0.0803mmol)该产物，加入(52mg，0.073mmol)MMAE，(5mg，0.0365mmol)HOBT，1mL DMF溶解，加入(144mg，1.825mmol)吡啶，室温搅拌过夜，减压浓缩，柱层析纯化，二氯甲烷：甲醇＝25：1—5：1，得化合物21(42mg，0.0507mmol，产率69.5％)。
将(10mg，0.012mmol)化合物21和(11mg，0.012mmol)KTLLPTPG-N3(化合物13)，(1.5mg，0.006mmol)CuSO4·H2O与(5mg，0.024mmol)抗坏血酸钠加于反应瓶中，加入DMF：H2O＝0.75mL：0.25mL，室温搅拌过夜，减压浓缩，HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—80min乙腈20％—100％，流速：8ml/min，Rt＝25min，减压干燥得产物PDC-5(6.5mg，0.0037mmol，产率30.8％)。HRMS(ESI):C85H144N18O19[M+H]2+calcd:861.5500,found:861.5510.Purity:98.96％.
PDC-5HRMS分析谱图如图7所示：
(8)合成PDC-6
合成方法如下：
将(200mg，1.64mmol)叠氮乙胺盐酸盐，(922mg，1.968mmol)化合物22和(808mg，5.985mmol)HBTU溶于15mL DMF中，随后加入(211mg，1.64mmol)DIEA，室温下搅拌4h，加入水20mL，乙酸乙酯3×40mL萃取，饱和NaCl 100mL洗，无水NaSO4干燥，柱层析纯化，二氯甲烷：甲醇＝40：1，得产物(748mg，1.394mmol，产率85％)。取(100mg，0.1863mmol)该产物，加入20％TFA/DCM 3mL，室温搅拌2h，DCM×3，加入(59mg，0.2019mmol)Boc-NH-PEG3-COOH，(141mg，0.3726mmol)HBTU，6mL DMF，(48mg，0.3726mmol)DIEA，室温搅拌2h，减压浓缩，柱层析纯化，二氯甲烷：甲醇＝20：1，得化合物23。
取(74mg，0.1mmol)化合物23，5％DBU/DCM 2mL，室温搅拌1h，DCM×3，加入(65mg，0.11mmol)化合物24，(76mg，0.2mmol)HBTU，(27mg，0.2mmol)HOBT，DMF 3mL，(26mg，0.2mmol)DIEA，室温搅拌2h，减压浓缩，柱层析纯化，二氯甲烷：甲醇＝20：1，得化合物25。
取(30mg，0.0275mmol)化合物25，20％TFA/DCM 2mL，室温搅拌2h，DCM×3，加入(34mg，0.03025mmol)KTLLPTPG-NHS(化合物17)，DMF 2mL，(11mg，0.0825mmol)DIEA，室温搅拌2h，减压浓缩，HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—80min乙腈20％—100％，流速：8ml/min，Rt＝40min。得化合物26(24mg，0.0126mmol，产率45.8％)。取(11mg，0.00576mmol)化合物26，加入20％TFA/DCM，室温搅拌2h，DCM×3，直接投入下一步反应，加入(7mg，0.00576mmol)HA-Val-Cit-PABC-MMAE，(0.75mg，0.003mmol)CuSO4·5H2O，(2.5mg，0.01152mmol)抗坏血酸钠，DMF：H2O＝0.75mL：0.25mL，室温搅拌过夜，减压浓缩，HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—80min乙腈20％—100％，流速：8ml/min，Rt＝35min，冻干得产物PDC-6(6mg，0.00207mmol，产率36％)。HRMS(ESI):C140H227IN28O33[M+H]2+calcd:1478.8048,found:1478.8069.Purity:95.34％.
PDC-6HRMS分析谱图如图8所示。
(9)合成PDC-7
合成方法如下：
将(187mg，0.4mmol)化合物27，(49mg，0.4mmol)叠氮乙胺盐酸盐，(303mg，0.7994mmol)HBTU，(108mg，0.8mmol)HOBT加于反应瓶中，随后加入15mL DMF，加入(103mg，0.8mmol)DIEA，室温搅拌4h，减压浓缩，柱层析纯化，石油醚：乙酸乙酯＝1：2，得产物直接投入下一步。取(100mg，0.1863mmol)该产物，加入20％TFA/DCM 3mL，室温搅拌2h，DCM×3，加入(66mg，0.2049mmol)Boc-NH-PEG3-COOH，(141mg，0.3726mmol)HBTU，(50mg，0.3726mmol)HOBT，加入6mL DMF溶解，随后加入(48mg，0.3726mmol)DIEA，室温搅拌2h，减压浓缩，柱层析纯化，二氯甲烷：甲醇＝20：1，得化合物28(120mg，0.1621mmol，产率87％)。
将(120mg，0.1621mmol)化合物28加于20％TFA/DCM 2mL，室温搅拌2h，DCM×3，直接投入下一步反应。向前者加入(273mg，0.2432mmol)KTLLPTPG-NHS，DMF 3mL溶解，随后加入(104mg，0.8105mmol)DIEA，室温搅拌4h，减压浓缩，加入5％ DBU/DCM 3mL，室温搅拌1h，DCM×3。乙腈/水溶解，HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—70min乙腈30％—100％，流速：8mL/min，Rt＝40min，减压干燥得化合物29(152mg，0.107mmol，产率66％)。
将(15mg，0.0108mmol)化合物29，(6.5mg，0.0119mmol)FA-NHS(化合物30)加于1mLDMF中，加入(2.8mg，0.0216mmol)DIEA，室温下搅拌2h。减压浓缩，HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—80min乙腈20％—100％，流速：8mL/min，Rt＝33min，减压干燥得化合物31。取(5.6mg，0.00303mmol)化合物31并加入20％TFA/DCM，室温搅拌2h，DCM×3，直接加入(3.7mg，0.00303mmol)HA-Val-Cit-PABC-MMAE，(0.5mg，0.0015mmol)CuSO4·5H2O和(1.2mg，0.00606mmol)抗坏血酸钠，DMF：H2O＝0.75mL：0.25mL，室温搅拌过夜，减压浓缩，HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—90min乙腈10％—100％，流速：8mL/min，Rt＝33min，减压干燥得产物PDC-7(2mg，0.0007mmol，产率23％)。HRMS(ESI):C138H217N33O33[M+H]2+calcd:1433.3247,found:1433.3231.Purity:95.34％.
PDC-7HRMS分析谱图如图9所示。
(10)合成PDC-8
合成方法如下：
将(100mg，0.229mmol)化合物32，(283mg，0.2519mmol)KTLLPTPG-NHS(化合物17)溶于5mL DMF中，随后加入(59mg，0.458mmol)DIEA，室温下搅拌2h，减压浓缩，得化合物33，加入5％DBU/DCM 3mL，室温搅拌1h，DCM×3，HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—70min乙腈30％—100％，流速：8mL/min，Rt＝40min，减压干燥获得产物，投入下一步反应。取(30mg，0.0245mmol)该产物，(2.8mg，0.0245mmol)戊二酸酐，溶于2mL DCM中，加入(5mg，0.049mmol)TEA，室温搅拌1h，得化合物34，直接投入下一步反应，向化合物34中加入(5.5mg，0.02646mmol)DCC，(3mg，0.02646mmol)NHS，(1.5mg，0.01102mmol)DMAP，室温搅拌6h，减压浓缩，直接加入(11mg，0.01804mmol)化合物35，室温搅拌4h，减压浓缩，HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—80min乙腈20％-—100％，流速：8mL/min，Rt＝30min，减压干燥得产物(10mg，0.0052mmol，产率28.8％)。向(10mg，0.0052mmol)该产物中加入20％TFA/DCM 2mL，室温搅拌2h，DCM×3，加入(6.3mg，0.0052mmol)HA-Val-Cit-PABC-MMAE，(0.65mg，0.0026mmol)CuSO4·5H2O和(2mg，0.0104mmol)抗坏血酸钠，DMF：H2O＝0.75mL：0.25mL，室温搅拌过夜。减压浓缩，HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—80min乙腈20％—100％，流速：8mL/min，Rt＝16min，减压干燥得产物PDC-8(5mg，0.0017mmol，产率32.7％)。HRMS(ESI):C142H228N34O33[M+H]3+calcd:980.2475,found:980.2478.Purity:96.13％.
PDC-8HRMS分析谱图如图10所示。
(11)合成PDC-9
合成方法如下：
将(10mg，0.0093mmol)KTLLPTPG-EDA(With BOC)和(3.6mg，0.0093mmol)FITC(36)溶于1mL DMF中，随后加入(1.2mg，0.0093mmol)DIEA，室温搅拌2h，减压浓缩，加入20％TFA/DCM 1mL，室温搅拌2h，DCM×3，HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—90min乙腈10％—100％，流速：8mL/min，Rt＝28min，减压干燥得产物(6mg，0.0048mmol，产率51.6％)。HRMS(ESI):C61H84N12O15S[M+H]2+calcd:629.3023,found:629.3027.Purity:99.12％.
PDC-9HRMS分析谱图如图11所示。
(12)合成PDC-10
合成方法如下：
洗肽方法：DMF 4×10mL×2min。
脱Fmoc保护基方法：3％DBU+3％哌啶+94％DMF 1×5min，1×15min。
脱Dde保护基方法：2％水合肼/DMF 3×3min。
茚检：加入配置好的茚三酮、苯酚、吡啶，用量＝1滴：1滴：2滴，100℃加热30-90s，若有裸露氨基体系呈蓝色或淡棕色；若无裸露氨基，体系呈无色。
接入下一个氨基酸方法：3eq氨基酸+3eq HBTU(可根据不同情况选择不同缩合剂)+4eq HOBT+6eq DIEA，DMF 10mL，室温振荡1-4h。
接入FA-NHS(化合物30)方法：3eq FA-NHS(化合物30)+3eq HBTU+4eq HOBT+6eqDIEA，DMF 10mL，室温振荡1-4h。
接入FITC(化合物36)方法：1eq FITC(化合物36)+3eq DIEA，DMF 10mL，室温振荡1-4h。
切肽：95％TFA/H2O，振荡3h。
萃肽、HPLC制备：冰***10mL，水2×10mL萃取，收集水相。HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—80min乙腈20％—100％，流速：8ml/min。
先将(217mg，0.1mmol)氨基树脂在10mL DCM中溶胀30min，DCM洗2×10mL×2min，DMF洗3×10mL×2min，茚检(体系应呈无色)，脱Fmoc，DMF洗，4×10mL×2min，茚检(体系应呈蓝色)，接入Fmoc-Lys(Dde)-OH，洗肽，茚检，脱Fmoc，洗肽，茚检，随后按照(接入氨基酸→茚检→脱Fmoc→洗肽→茚检→接入下一个氨基酸顺序)依次接入PTPLLTK，洗肽，脱Dde，洗肽，茚检，接入Fmoc-Lys(Dde)-OH，洗肽，茚检，脱Fmoc，接入FA-NHS(化合物30)，洗肽，茚检，脱Dde，接入FITC(化合物36)，洗肽，茚检。切肽，萃肽，HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—80min乙腈20％—100％，流速：8ml/min，Rt＝26min，减压干燥得产物PDC-10(55mg，0.03mmol，产率：30％)。HRMS(ESI):C38H67N9O11[M+H]2+calcd:918.9316C88H117N21O21S,found:918.9301.Purity:96.11％.
产物PDC-10HRMS分析谱图如图12所示。
(13)合成PDC-11
合成方法如下：
洗肽方法：DMF 4×10mL×2min。
脱Fmoc保护基方法：3％DBU+3％哌啶+94％DMF 1×5min，1×15min。
脱Dde保护基方法：2％水合肼/DMF 3×3min。
茚检：加入配置好的茚三酮、苯酚、吡啶，用量＝1滴：1滴：2滴，100℃加热30-90s，若有裸露氨基体系呈蓝色或淡棕色；若无裸露氨基，体系呈无色。
接入下一个氨基酸方法：3eq氨基酸+3eq HBTU(可根据不同情况选择不同缩合剂)+4eq HOBT+6eq DIEA，DMF 10mL，室温振荡1-4h。
接入化合物24方法：3eq(化合物24)+3eq HBTU+4eq HOBT+6eq DIEA，DMF 10mL，室温振荡1-4h。
接入FITC(化合物36)方法：1eq FITC(化合物36)+3eq DIEA，DMF 10mL，室温振荡1-4h。
切肽：95％TFA/H2O，振荡3h。
萃肽、HPLC制备：冰***10mL，水2×10mL萃取，收集水相。HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—80min乙腈20％—100％，流速：8ml/min。
先将(217mg，0.1mmol)氨基树脂在10mL DCM中溶胀30min，DCM洗2×10mL×2min，DMF洗3×10mL×2min，茚检(体系应呈无色)，脱Fmoc，DMF洗，4×10mL×2min，茚检(体系应呈蓝色)，接入Fmoc-Lys(Dde)-OH，洗肽，茚检，脱Fmoc，洗肽，茚检，随后按照(接入氨基酸→茚检→脱Fmoc→洗肽→茚检→接入下一个氨基酸顺序)依次接入PTPLLTK，洗肽，脱Dde，洗肽，茚检，接入Fmoc-Lys(Dde)-OH，洗肽，茚检，脱Fmoc，接入化合物24，洗肽，茚检，脱Dde，接入ACP，洗肽，茚检，脱Fmoc，接入FITC(化合物36)，洗肽，茚检。切肽，萃肽，HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—80min乙腈20％—100％，流速：8ml/min，Rt＝28.5min，减压干燥得产物PDC-11(73mg，0.036mmol，产率：40％)。HRMS(ESI):C38H67N9O11[M+H]2+calcd:1020.9557C96H138IN17O22S,found:1020.9554.Purity:98.69％.
产物PDC-11HRMS分析谱图如图13所示。
(14)合成PDC-12
合成方法如下：
将(5mg，0.0125mmol)NOTA-NHS(化合物37)，(13mg，0.0119mmol)KTLLPTPG-EDA(With BOC)溶于0.5mL DMF中，随后加入(3mg，0.0238mmol)DIEA，室温搅拌2h，减压浓缩，加入20％TFA/DCM，室温搅拌2h，DCM×3，HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—80min乙腈20％—100％，流速：8ml/min，Rt＝20min，(4mg，0.00347mmol，产率29.16％)。HRMS(ESI):C52H92N14O15[M+H]2+calcd:577.3506,found:577.3508.Purity:87.20％.
产物PDC-12HRMS分析谱图如图14所示。
(15)合成PDC-13
合成方法如下：
将(5mg，0.011mmol)化合物38，(13.5mg，0.0121mmol)KTLLPTPG-NHS(化合物17)溶于0.5mL DMF中，随后加入(2.8mg，0.022mmol)DIEA，室温搅拌2h，减压浓缩，加入20％TFA/DCM，室温搅拌2h，DCM×3，HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—80min乙腈20％—100％，流速：8ml/min，Rt＝25min，(4.5mg，0.0036mmol，产率32.5％)。
(16)合成PDC-14
合成方法如下：
将(5mg，0.01mmol)化合物39，(12.5mg，0.011mmol)KTLLPTPG-NHS(化合物17)溶于0.5mL DMF中，随后加入(2.6mg，0.02mmol)DIEA，室温搅拌2h，减压浓缩，加入20％TFA/DCM，室温搅拌2h，DCM×3，HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—80min乙腈20％—100％，流速：8ml/min，Rt＝22.5min，(4mg，0.0031mmol，产率31％)。
(17)合成PDC-15
合成方法如下：
将(720mg，1.95mmol)化合物3，(738mg，3.9mmol)氨基-聚乙二醇-丙酸叔丁酯溶于15mL DMF中，随后在0℃下加入(1.12g，5.85mmol)EDCI，(790mg，5.85mmol)HOBT和(755mg，5.85mmol)DIEA，室温下搅拌4h。减压浓缩，萃取(水30mL，乙酸乙酯3×50mL)，水洗2×70mL，饱和NaCl水溶液2×70mL，无水Na2SO4干燥，减压浓缩，柱层析纯化，石油醚：乙酸乙酯＝1：4—1：10。得产物(705mg，0.99mmol，产率50.8％)。将(20mg，0.028mmol)该产物溶于2mL20％TFA/DCM，室温搅拌3h，DCM 3×3mL，直接投入下一步反应。
将(32mg，0.084mmol)HATU加入上述产物中，3mL DMF溶解，加入(11mg，0.084mmol)DIEA，0℃下搅拌20min，随后加入(60mg，0.056mmol)KTLLPTPG-EDA(With BOC)，室温搅拌3h。减压浓缩，加入2mL 5％DBU/DCM，室温搅拌2h，DCM 3×3mL，得Dimer-KTLLPTPG(化合物5)，直接投入下一步反应。
将(5mg，0.012mmol)NOTA-NHS(化合物37)，(27mg，0.011mmol)Dimer-KTLLPTPG(化合物5)中溶于1mL DMF中，加入(3mg，0.024mmol)DIEA，室温搅拌2h，减压浓缩，加入2mL20％TFA/DCM，室温搅拌3h，DCM 3×3mL。加入乙腈、水溶解，HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—90min乙腈10％—100％，流速：8ml/min，Rt＝25min，减压干燥得产物PDC-15(5.6mg，0.0024mmol，产率22％)。HRMS(ESI):C107H188N28O31[M+H]2+calcd:1181.7070,found:1181.7072.Purity:>99.00％.
PDC-15HRMS分析谱图如图15所示。
(18)合成PDC-16
合成方法如下：
洗肽方法：DMF 4×10mL×2min。
脱Fmoc保护基方法：3％DBU+3％哌啶+94％DMF 1×5min，1×15min。
脱Dde保护基方法：2％水合肼/DMF 3×3min。
茚检：加入配置好的茚三酮、苯酚、吡啶，用量＝1滴：1滴：2滴，100℃加热30-90s，若有裸露氨基体系呈蓝色或淡棕色；若无裸露氨基，体系呈无色。
接入下一个氨基酸方法：3eq氨基酸+3eq HBTU(可根据不同情况选择不同缩合剂)+4eq HOBT+6eq DIEA，DMF 10mL，室温振荡1-4h。
接入DOTA(化合物40)方法：3eqDOTA(化合物30)+3eq HBTU+4eq HOBT+6eq DIEA，DMF 10mL，室温振荡1-4h。
接入FA-NHS(化合物30)方法：3eq FA-NHS(化合物30)+3eq HBTU+4eq HOBT+6eqDIEA，DMF 10mL，室温振荡1-4h。
接入FITC(化合物36)方法：1eq FITC(化合物36)+3eq DIEA，DMF 10mL，室温振荡1-4h。
切肽：95％TFA/H2O，振荡3h。
萃肽、HPLC制备：冰***10mL，水2×10mL萃取，收集水相。HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—80min乙腈20％—100％，流速：8mL/min。
先将(217mg，0.1mmol)氨基树脂在10mL DCM中溶胀30min，DCM洗2×10mL×2min，DMF洗3×10mL×2min，茚检(体系应呈无色)，脱Fmoc，DMF洗，4×10mL×2min，茚检(体系应呈蓝色)，接入Fmoc-Lys(Dde)-OH，洗肽，茚检，脱Fmoc，洗肽，茚检，随后按照(接入氨基酸→茚检→脱Fmoc→洗肽→茚检→接入下一个氨基酸顺序)依次接入GPTPLLTK，洗肽，脱Dde，洗肽，茚检，接入Fmoc-Lys(Dde)-OH，洗肽，茚检，脱Fmoc，接入DOTA(化合物40)，洗肽，茚检，脱Dde，接入FA-NHS(化合物30)，洗肽，茚检。切肽，萃肽，HPLC制备：0.1％TFA乙腈/0.1％TFA水，0—95min乙腈5％—100％，流速：8mL/min，Rt＝22.5min，减压干燥得产物PDC-16(115mg，0.061mmol，产率：61％)。LCMS(ESI):C85H135N25O24[M+H]2+found:946.5Rt＝2.77min.Purity:97.81％.
实施例2体外实验：测试各多肽药物偶联物对肿瘤细胞的活性以及成像
1)活性实验
分别将PANC-1(人胰腺癌细胞)、hTERT-HPNE(人正常胰腺导管细胞)细胞按3.0×103个细胞/100μL/孔，接种到96孔板中，放置培养箱中，过夜后加药，设置不同的药物浓度，将原液加入到完全培养基中稀释100倍后作用于细胞，培养箱中放置48h，每孔加入10μLCCK-8溶液，设置空白对照组(只含CCK-8溶液和完全培养基)，培养箱中孵育1h，FlexStation III Services型酶联检测仪在450nm测定吸光度值，同一实验至少重复3次。
计算出本发明化合物对所测试癌细胞的抑制作用。
各化合物在不同浓度下对于癌细胞和正常细胞的抑制效果及IC50值(半数抑制浓度)如表1所示。
表1各化合物对于PANC-1、hTERT-HPNE的IC50值
| IC50/nM | PDC-1 | PDC-2 | PDC-3 | PDC-4 | PDC-5 | PDC-6 | PDC-7 | PDC-8 | PTX | MMAE |
| PANC-1 | ＞50000 | 4667±577.4 | 171.3±14.01 | 3087±580.1 | 2583±591.8 | 170±19.92 | 999.3±1.155 | 168.7±34.21 | 10.67±1.155 | 3.333±1.528 |
| HPNE | / | / | 274.3±44.28 | 1514±538.5 | 1365±188.4 | 401.5±82.31 | 5433±416.3 | 1523±336.3 | / | 10.67±3.512 |
如表1所示：PTX、MMAE作为细胞毒药物，缺乏对于正常细胞和癌细胞的选择性。而本发明中的PDC分子，以PTX为细胞毒性药物的PDC-1、PDC-2对于PANC-1细胞的抗增殖活性相较于单独的PTX明显下降：两者化合物IC50值：PDC-1：＞50μM；PDC-2：4667±577.4nM。这说明靶向多肽与细胞毒性药物偶联后，整个偶联物分子进入细胞的方式已经发生了改变：由细胞毒性药物以自由扩散进入细胞的方式转变为通过受体-配体识别进入细胞的方式。同时因为可裂解连接子的加入，细胞毒性药物在细胞内的释放程度也会受相应的发挥切割作用的水解酶的影响。因此在相同的给药摩尔浓度下，靶向多肽-药物偶联物相较于单独的化学药物，活性会有所下降。
以MMAE为细胞毒性药物，Val-Cit-PABC为连接子的PDC-3-PDC-8对于PANC-1细胞的抑制活性基本都保持在纳摩尔浓度，各化合物IC50值：PDC-3：171.3±14.01nM；PDC-4：3087±580.1nM；PDC-6：170±19.92nM；PDC-7：999.3±1.155nM；PDC-8：168.7±34.21nM，这说明MMAE在细胞内得到了较好的释放。而PDC-5连接子换成了脂肪链炔醇，对组织蛋白酶B(特异性识别并切割Val-Cit-PABC)的敏感性降低，因此MMAE在细胞内的释放效率下降，在以多肽单体为靶向部分的基础上，PDC-5的体外抗肿瘤活性明显低于PDC-3。但这些化合物，在PANC-1与hTERT-HPNE之间缺乏选择性。
具有双特异性配体的PDC-6、PDC-7、PDC-8在PANC-1与hTERT-HPNE细胞之间表现出了较好的选择性，分别以靶向多肽和白蛋白配体、靶向多肽和叶酸、靶向多肽和整合素配体为双特异性配体，各自对于PANC-1的IC50值分别为：PDC-6：170±19.92nM；PDC-7：999.3±1.155nM；PDC-8：168.7±34.21nM；对于hTERT-HPNE的IC50值分别为：PDC-6：401.5±82.31nM；PDC-7：5433±416.3nM；PDC-8：1523±336.3nM。
2)荧光成像
按2×105个细胞/皿，接种细胞到激光共聚焦专用小皿，加入1.5mL完全培养基，培养箱放置过夜后，竞争组先加入plectin-1靶向肽在5μM浓度下作用2h，随后去掉培养基，与加药组同时加入PDC-9，在1μM浓度下于37℃、5％CO2条件下孵育4h，随后PBS洗(3×1mL×2min)，室温下多聚甲醛固定10min，PBS洗(2×2min)，室温下DAPI作用5min，PBS洗(3×2min)，加入完全培养基。随后用Zeiss LSM800，German进行激光共聚焦成像如图16所示。
实施例3测试多肽-药物偶联物的体内抗肿瘤活性
以免疫缺陷小鼠作为癌细胞移植对象，小鼠在7-8周龄开始接种PANC-1细胞。具体操作流程如下：
准备好细胞，加入PBS∶基质胶＝2∶1，混匀，放置于冰中，按1.0×107个细胞/150μL/只，接种于小鼠腋窝皮下，在第20天，肿瘤平均体积达到70～90mm3，分5个组，3个给药组(PDC-3，PDC-6，PDC-7)，1个阳性对照组(PTX)，1个空白对照组，并于该天开始给药。腹腔注射，给药剂量：给药组(PDC-3，PDC-6，PDC-7)：0.3mg/kg。PTX阳性对照组：8mg/kg。空白对照组：200μL生理盐水/只。
每2天记录1次肿瘤体积和小鼠体重，肿瘤体积计算方法：V(mm3)＝(L×W2/2)，L：长径；W：短径。待空白对照组平均肿瘤体积达到1200mm3左右，处死小鼠，取瘤并称瘤重。
各优势化合物肿瘤抑制效果及对小鼠体重的影响如图17、图18所示。
实施例4多肽-药物偶联物对细胞来源胰腺癌荷瘤小鼠模型的PET/CT成像
按体积比V(0.25M醋酸钠溶液)∶V(0.05M盐酸溶液)＝1∶4混合两种溶液，取8mL该缓冲液淋洗锗镓发生器，得到68Ga盐酸-醋酸钠缓冲液。平行取3份2mL该缓冲溶液，分别加入20微克PDC-12、14和16，将反应混合物加热至100℃，保持10min。随后将反应后溶液通过C18柱，将游离离子去除，然后用70％乙醇溶液冲洗C18柱。得到标记好的68Ga-PDC-12、68Ga-PDC-14和68Ga-PDC-16。将标记好的68Ga-PDC-12、68Ga-PDC-14和68Ga-PDC-16用生理盐水稀释，将小鼠分成3组，组内每只小鼠注射100μCi，在0.5h进行PET/CT扫描成像，用PET/CT图像处理软件进行重建，得到现象图如图19所示。相比于68Ga-PDC-12和68Ga-PDC-14，68Ga-PDC-16在肿瘤部位有良好的摄取和显像。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本发明揭露的技术范围内，可轻易想到变化或替换，都应涵盖在本发明的保护范围之内。因此，本发明的保护范围应以所述权利要求的保护范围为准。
Claims (9)
1.一种肿瘤靶向的多肽药物偶联物，其特征在于，其结构如式(I)所示：P-F-C-D，其中，
P为肿瘤靶向多肽，以特异性识别肿瘤特异性靶点plectin-1；
F为功能性调节基团；
C为连接子；
D为有效载荷基团，包括细胞毒性抗肿瘤药物、放射性核素螯合基团或荧光基团。
2.根据权利要求1所述的肿瘤靶向的多肽药物偶联物，其特征在于，肿瘤靶向多肽的氨基酸序列如SEQ ID NO.1所示，或
在SEQ ID NO.1上置换、缺失、***1～3个氨基酸的多肽序列或多肽衍生物。
3.根据权利要求1所述的肿瘤靶向的多肽药物偶联物，其特征在于，所述功能性调节基团选自叶酸、RGD环肽、4-碘苯基末端基团、伊文斯蓝、plectin-1靶向肽中的一种或多种。
4.根据权利要求1所述的肿瘤靶向的多肽药物偶联物，其特征在于，所述连接子为连接可裂解连接子或不可裂解连接子；优选的，所述连接子以碳原子间通过共价键连接形成的不成环的链状为碳架；优选的，所述连接子选自如下所示结构中的一种：
5.根据权利要求1所述的肿瘤靶向的多肽药物偶联物，其特征在于，细胞毒性抗肿瘤药物包括紫杉醇和/或MMAE。
6.根据权利要求1所述的肿瘤靶向的多肽药物偶联物，其特征在于，所述荧光基团选自：
7.根据权利要求1所述的肿瘤靶向的多肽药物偶联物，其特征在于，所述放射性核素螯合基团选自以下结构中的一种：
8.根据权利要求1所述的多肽药物偶联物，其特征在于，所述多肽药物偶联物为以下结构中的任一种或多种：
9.权利要求1-8任一项所述的肿瘤靶向的多肽药物偶联物在制备抗癌药物中的应用。
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