CN102325788B - 癌症靶向肽及其在癌症治疗中的用途 - Google Patents
癌症靶向肽及其在癌症治疗中的用途 Download PDFInfo
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- CN102325788B CN102325788B CN201080008727.4A CN201080008727A CN102325788B CN 102325788 B CN102325788 B CN 102325788B CN 201080008727 A CN201080008727 A CN 201080008727A CN 102325788 B CN102325788 B CN 102325788B
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
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- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
本发明提供癌症靶向肽及其在癌症治疗中的用途。
Description
相关申请案
本申请要求2009年2月19日申请的美国临时申请案第61/153,725号的优先权,该案内容以全文引用的方式并入本文中。
背景技术
靶向药物递送将明显改进癌症疗法的功效。完成这一任务的关键是鉴别特异性靶向癌细胞的药剂。
发明概述
本发明是基于一个意外发现,即,许多肽,包括QNIYAGVPMISF(SEQ ID NO:1)、EATNSHGSRTMG(SEQ ID NO:2)、TVSWSTTGRIPL(SEQ ID NO:3)、QLEFYTQLAHLI(SEQ ID NO:4)和SMDPFLFQLLQL(SEQ ID NO:5),可特异性靶向乳腺癌细胞,由此便于将药物递送到乳腺肿瘤部位。
因此,本发明一方面特征在于乳腺癌靶向肽,其包括氨基酸序列SEQ ID NO:1-5中之一。这些肽中的任何肽都可与用于治疗乳腺癌的抗癌药物缀合。在一个实例中,将抗乳腺癌药物是封装于微粒(例如脂质体)中。示范性抗癌药物包括但不限于多柔比星(doxorubicin)、他莫昔芬(tamoxifen)、长春瑞宾(vinorelbine)、长春新碱(vincristine)、紫杉醇(paclitaxel)、勒托替康(lurtotecan)、多烯紫杉醇(docetaxel)、亚德利亚霉素(adriamycin)、表柔比星(epirubicin)、米托蒽醌(mitoxantrone)、丝裂霉素(mitomycin)、吉西他宾(gemcitabine)、顺铂(cisplatin)、奥沙利铂(oxaliplatin)、长春花碱(vinblastine)、5-FU、UFUR、阿那曲唑(anastrozole)、雷曲唑(letrozole)和依西美坦(exemestane)。
本发明另一方面特征在于一种通过对患有乳腺癌的个体(例如人类乳腺癌患者)给予有效量的含有上述乳腺癌靶向肽中之一和抗癌药物的缀合物进行靶向药物递送的方法。本文中使用的“有效量”是指用于将缀合物中所包括的每一活性剂递送到实体肿瘤部位,以使活性剂单独或与一种或一种以上其它活性剂组合对个体提供治疗作用的缀合物的量。本领域技术人员应认识到,有效量将视给药途径、赋形剂选择以及与其它活性剂的共使用而变化。
上述任一缀合物用于乳腺癌治疗或用于制造供治疗乳腺癌的药物的用途也在本发明的范围内。
有关本发明一个或一个以上实例的细节将陈述于以下描述中。本发明的其它特征或优势将由以下针对数个实施例的详细描述以及所附权利要求书而显而易见。
附图说明
首先将描述附图。
图1是绘示在噬菌体表面上表达的癌症靶向肽与乳腺肿瘤异种移植物的特异性结合活性的图。图面A:噬菌体克隆PC34,展示具有氨基酸序列SEQ ID NO:1的肽。图面B:噬菌体克隆PC65,展示具有氨基酸序列SEQ ID NO:2的肽。图面C:噬菌体克隆PC73,展示具有氨基酸序列SEQ ID NO:3的肽。图面D:噬菌体克隆PC83,展示具有氨基酸序列SEQ ID NO:4的肽。图面E:噬菌体克隆PC90,展示具有氨基酸序列SEQ ID NO:5的肽。图面F:对照噬菌体克隆PC34,展示对照肽。
图2是绘示游离多柔比星(FD)、封装于脂质体中的多柔比星(LD)和封装于缀合SP90的脂质体中的多柔比星(SP90-LD)的抗乳腺肿瘤活性的图。SP90是指在噬菌体克隆PC90上展示的肽(SEQ ID NO:5)。图面A:用FD、LD或SP90-LD处理的带有乳腺肿瘤的小鼠的肿瘤体积。图面B:用FD、LD或SP90-LD处理的带有乳腺肿瘤的小鼠的白细胞(WBC)计数。图面C:用FD、LD或SP90-LD处理的带有乳腺肿瘤的小鼠的体重。图面D:用FD、LD或SP90-LD处理的带有乳腺肿瘤的小鼠的体重变化。
图3是绘示用FD、LD或SP90-LD处理的带有乳腺肿瘤的小鼠的坏死/凋亡区的图。图面A:凋亡和坏死区。图面B:凝集素阳性区(指示存在肿瘤血管)。
图4是绘示肿瘤组织中多柔比星的分布的图。图面A:利用灌注法。图面B:不利用灌注法。
发明的详细描述
本发明涉及许多乳腺癌靶向肽,即,包括氨基酸序列SEQ ID NO:1-5中之一的肽。本文中使用的术语“肽”是指由最多100个氨基酸单体通过肽键连接而构成的聚合物。本文中所述的每一乳腺癌靶向肽都可包括最多50个(例如30个)氨基酸。这些肽可通过常规方法,即通过化学合成法或重组技术制备。
必要时,可对本文所述的任何乳腺癌靶向肽进行修饰以增加其稳定性。就本发明的实践来说,经化学方法修饰的肽或肽类似物包括以体内或体外稳定性和/或功效增加为特征的所述肽的任何功能性化学等效物。术语肽类似物也指本文所述肽的任何氨基酸衍生物。氨基酸类似物的制备程序包括但不限于侧链修饰、在肽合成期间并入非天然氨基酸和/或其衍生物和使用交联剂,以及对肽或其类似物施加构象限制的其它方法。侧链修饰的实例包括氨基修饰,例如通过与醛反应随后用NaBH4还原进行的还原烷基化;用乙酰亚胺甲酯酰胺化;用乙酸酐乙酰化;用氰酸酯将氨基氨甲酰化;用2,4,6,三硝基苯磺酸(TNBS)将氨基三硝基苯甲基化;用琥珀酸酐和四氢邻苯二甲酸酐将氨基烷基化;以及用5′-磷酸吡哆醛将赖氨酸吡哆醛化(pyridoxylation),随后用NABH4还原。精氨酸残基的胍基可通过与例如2,3-丁二酮、苯甲酰甲醛和乙二醛等试剂形成杂环缩合产物来进行修饰。羧基可通过形成o-酰基异脲使碳化二亚胺活化,随后衍生化成为例如相应的酰胺来加以修饰。硫氢基的修饰方法可例如为用碘乙酸或碘乙酰胺羧甲基化;用过甲酸氧化成磺基丙氨酸;与其它硫醇化合物形成混合二硫化物;与马来酰亚胺、马来酸酐或其它取代的马来酰亚胺反应;使用4-氯汞苯甲酸、4-氯汞苯磺酸、苯基氯化汞、2-氯汞-4-硝基苯酚和其它汞制剂形成汞衍生物;在碱性pH值下用氰酸酯氨甲酰化。色氨酸残基可通过例如用N-溴代琥珀酰亚胺氧化,或用2-羟基-5-硝基苯甲基溴或磺酰基卤化物将吲哚环烷基化来进行修饰。酪氨酸残基可通过用四硝基甲烷硝化形成3-硝基酪氨酸衍生物来改变。组氨酸残基咪唑环的修饰可通过用碘乙酸衍生物烷基化或用焦碳酸二乙酯N-乙酯基化(N-carbethoxylation)实现。在肽合成期间并入非天然氨基酸和衍生物的实例包括但不限于使用正亮氨酸、4-氨基丁酸、4-氨基-3-羟基-5-苯基戊酸、6-氨基己酸、叔丁基甘氨酸、正缬氨酸、苯基甘氨酸、鸟氨酸、肌氨酸、4-氨基-3-羟基-6-甲基庚酸、2-噻吩基丙氨酸和/或氨基酸的D-异构体。
如下文实例1-3中所示,本文所述的乳腺癌靶向肽在体内和体外特别结合于乳腺癌组织/细胞。因此,当这些肽与抗癌药物缀合时,其会将药物引导到乳腺癌部位,由此促进乳腺癌的治疗。本发明中使用的“缀合的”是指两个实体(此处为乳腺癌靶向肽和抗癌药物)以足以实现两个实体之间缔合的治疗益处的亲和力缔合。缀合可通过共价或非共价键合以及其它缔合形式实现,例如将一个实体截留于另一实体上或其内,或者将任一实体或两个实体截留于第三个实体(例如微胞)上或其内。
在一个实例中,一种本文所述的乳腺癌靶向肽与抗癌药物直接或间接共价连接,通过常规方法形成治疗缀合物。所述药物可以是化疗剂,例如终止DNA结构单元合成的药物(例如甲氨喋呤(methotrexate)、氟尿嘧啶(fluorouracil)、羟基脲和巯基嘌呤)、直接破坏DNA的药物(例如顺铂、道诺霉素(daunorubicin)、多柔比星和依托泊苷(etoposide))、影响有丝分裂纺锤体合成或断裂的药物(例如长春花碱、长春新碱和紫杉醇)或中断血管生成的药物(例如抗VEGF抗体、血管抑素(angiostatin)、内皮抑素(endostatin)和肿瘤抑素(tumstatin))。或者,抗乳腺癌药物可以是放射治疗剂(例如90Y、125I、188Re、111In DTPA或131I标记的碘化钠)。
在另一实例中,乳腺癌靶向肽与封装抗乳腺癌药物的媒剂分子(即,微粒)连接,由此形成治疗缀合物。媒剂分子包括微胞、脂质体(例如阳离子型脂质体)、纳米粒子、微球或生物可降解聚合物。乳腺癌靶向肽可通过多种键(例如二硫键、酸不稳定性键、基于肽的键、氧基氨基键或肼键)系连于媒剂分子。封装于媒剂内的抗乳腺癌药物可与亲脂性分子缔合,这些亲脂性分子可帮助将成像分子/抗肿瘤药物递送到媒剂内部。
在一优选实例中,乳腺癌靶向肽与可封装欲递送到肿瘤部位的抗癌药物的脂质体连接。术语“脂质体”是指包含一个或一个以上同轴有序排列的脂质双层的小泡,其可封装水相。水相通常含有欲递送到肿瘤部位的化合物。在到达肿瘤部位后,脂质体与局部肿瘤细胞或肿瘤血管细胞的质膜融合,由此将化合物释放到细胞溶胶中。或者,脂质体通过胞吞作用或通过其它方式被肿瘤细胞或肿瘤血管细胞摄取作为运输小泡(例如内体或吞噬体()的内容物。一旦进入运输小泡中,脂质体就会降解或与小泡膜融合,并释放其内容物。脂质体膜的构造应使其在附近环境变为酸性时不稳定(例如参见PNAS 84:7851,1987;Biochemistry 28:908,1989)。当脂质体进入靶细胞时,其变得不稳定,并释放出其封装的内容物。这一不稳定作用称为融合诱导(fusogenesis)。二油酰基磷脂酰乙醇胺(Dioleoylphosphatidylethanolamine,DOPE)常用于促进这一过程。
多种方法可用于制备脂质体。例如参见,Szoka et al.,Ann.Rev.Biophys.Bioeng.9:467(1980);美国专利第4,186,183号、第4,217,344号、第4,235,871号、第4,261,975号、第4,485,054号、第4,501,728号、第4,774,085号、第4,837,028号、第4,235,871号、第4,261,975号、第4,485,054号、第4,501,728号、第4,774,085号、第4,837,028号、第4,946,787;PCT公开第WO 91/17424号;Deamer & Bangham,Biochim.Biophys.Acta443:629-634(1976);Fraley,et al.,PNAS76:3348-3352(1979);Hope et al.,Biochim.Biophys.Acta 812:55-65(1985);Mayer et al.,Biochim.Biophys.Acta 858:161-168(1986);Williams et al.,PNAS 85:242-246(1988);Liposomes(脂质体)(Ostro(ed.),1983,Chapter 1(第1章));Hope et al.,Chem.Phys.Lip.40:89(1986);Gregoriadis,Liposome Technology(脂质体技术)(1984);以及Lasic,Liposomes:from Physics to Applications(脂质体:物理学到应用)(1993))。适合的方法包括例如超声处理、挤压、高压/均质化、微射流、清洁剂透析、钙诱导的小脂质体小泡融合和醚融合法,所有这些方法都是本领域众所周知的。
本文所述的任何乳腺癌治疗缀合物都可与药学上可接受的载体混合,形成药物组合物。“可接受的”是指载体必须与组合物中的活性成分相容(且优选能够使活性成分稳定),并且对欲治疗的个体无害。适合的载剂包括微晶纤维素、甘露醇、葡萄糖、脱脂奶粉、聚乙烯吡咯烷酮和淀粉,或其组合。
为了能使用本文所述的任何缀合物进行肿瘤治疗,可经口服、经胃肠外、经局部、经直肠、经鼻、经口腔、经阴道、经由植入的储积器(reservoir)或经由吸入喷雾给予缀合物。本文中使用的术语“胃肠外”包括皮下、皮内、静脉内、肌肉内、关节内、动脉内、滑膜内、胸骨内、鞘内、病灶内和颅内注射或输注技术。
无菌可注射组合物,例如无菌可注射水性或油性悬浮液,可根据本领域已知的技术,使用适合的分散剂或润湿剂(例如吐温80(Tween80))或者悬浮剂配制。无菌可注射制剂也可以是在无毒胃肠外可接受的稀释剂或溶剂中制成的无菌可注射溶液或悬浮液,例如于1,3-丁二醇中的溶液。可使用的可接受的媒剂和溶剂是甘露醇、水、林格氏溶液(Ringer′s solution)和等渗氯化钠溶液。此外,还通常使用无菌不挥发性油作为溶剂或悬浮介质(例如合成单酸甘油酯或二酸甘油酯)。脂肪酸,例如油酸和其三酸甘油酯衍生物,以及天然的药学上可接受的油,例如橄榄油或蓖麻油,尤其是其聚氧乙基化形式,都可用于可注射制剂中。这些油溶液或悬浮液还可含有长链醇稀释剂或分散剂,或者羧甲基纤维或类似的分散剂。出于配配的目的,也可使用常用于制造药学上可接受的固体、液体或其它剂型的其它常用表面活性剂,例如吐温系列(Tweens)、斯盘系列(Spans),或者其它类似的乳化剂或生物利用率增强剂。
供口服给药的组合物可以是任何口服可接受的剂型,包括但不限于胶囊、片剂、乳剂和水性悬浮液、分散液和溶液。在口服片剂/胶囊的情况下,常用载体包括乳糖和玉米淀粉。通常还添加润滑剂,例如硬脂酸镁。对于口服给药的胶囊形式,适用的稀释剂包括乳糖和干玉米淀粉。当口服给予水性悬浮液或乳剂时,可将活性成分悬浮于或溶解于组合有乳化剂或悬浮剂的油相中。必要时,可以添加某些甜味剂、调味剂或着色剂。鼻用气雾剂或吸入组合物可根据药物配配领域中众所周知的技术来制备。对于直肠给药,也可以栓剂形式给药含噁二唑化合物的组合物。
无需进一步详细阐述,相信本领域技术人员可以根据上文的描述,最大限度地利用本发明。因此,以下具体实施例应解释为只是说明性的,且并非以任何方式限制本发明的剩余部分。本文引用的所有出版物都以引用的方式并入本文中。
实例1:在噬菌体粒子表面上表达的癌症靶向肽的结合
遵循Lo et al.,Mol.Cancer Ther 7:579-589(2008)和Lee et al.,Cancer Res.64:8002-8008(2004)中所述的程序,将BT483细胞(乳腺癌细胞)和人粘膜上皮细胞(正常细胞)接种于96孔板中。将这些细胞与用紫外线灭活的对照辅助噬菌体和下文所列的5种测试噬菌体中的一种一起孵育,所述5种噬菌体各自表达同样列于下文中的5种肽中的一种:
在数轮洗涤去除未结合的噬菌体粒子后,再将细胞与缀合辣根过氧化物酶(horseradish peroxidase,HRP)的抗M13单克隆抗体(Pharmacia,Uppsala,Sweden)一起孵育,随后与过氧化物酶的底物即二盐酸邻苯二胺(sigma,MO,USA);一起孵育。再次洗涤这些细胞,并在ELISA读取器中进行分析,以在490nm下测量各孔的光密度。OD490值指示测试噬菌体与乳腺癌细胞以及与正常细胞的结合活性。全部5种测试噬菌体呈现的与乳腺癌细胞的结合活性均明显高于与正常细胞的结合活性,这表明在这些噬菌体上表达的5种肽将靶向癌细胞,而非正常细胞。
此外,按如下利用流式细胞术测定5种测试噬菌体与乳腺癌细胞以及与正常细胞的结合活性。收获细胞,并将其悬浮于含有50mMEDTA的PBS中,随后与5种测试噬菌体中的一种一起孵育。洗涤后,将细胞与上文提到的抗M13抗体一起孵育,随后与缀合FITC的山羊抗小鼠IgG抗体一起孵育。再次洗涤细胞,并借助流式细胞仪(BectonDickinson)进行分析。由此得到的结果显示,测试噬菌体结合的癌细胞的百分比明显高于测试噬菌体结合的正常细胞,这表明全部5种在测试噬菌体上表达的肽均特异性结合于乳腺癌细胞。
实例2:测试噬菌体与癌症组织和正常器官的体内结合活性
在SCID小鼠的背外侧胁腹皮下(s.c.)注射1×107个BT483细胞,以诱导乳腺癌异种移植物。对带有约300mm3大小的异种移植瘤的小鼠静脉内(i.v.)给予上文实例1中提到的5种测试噬菌体中的一种(109pfu)或对照噬菌体。灌注后,从每只小鼠体内取出异种移植瘤和器官(即脑、心脏和肺),并均质化。遵循Lee et al.,Cancer Res.67:10958-10965(2007)以及Lo et al.,Mol.Cancer Ther 7:579-589(2008)中所述的方法,洗脱结合各组织样品的噬菌体,使用ER2738细菌细胞作为宿主回收,并滴定到IPTG/X-Gal琼脂板上。
如图1所示,肿瘤组织中噬菌体克隆PC34、PC65、PC73、PC82和PC90的回收率比包括脑、心脏和肺在内的正常器官中的回收率高得多,这表明全部5种噬菌体克隆都驻留于肿块中,而非正常器官中。更具体点而言,驻留于肿块中的噬菌体的浓度是驻留于正常器官中的噬菌体的3.0-588倍。对照噬菌体既不靶向肿瘤异种移植物,也不靶向正常器官。
实例3:肽SMDPFLFQLLQL(SEQ ID NO:5)的癌症靶向活性
表达肽SMDPFLFQLLQL(SEQ ID NO:5)的噬菌体克隆PC90的体外癌症靶向活性测试如下。从20名患有乳腺浸润性导管癌的患者获得新鲜乳腺癌组织样品。将每一组织样品切成4μm薄片,并固定于1%多聚甲醛中。随后,将组织样品切片与PC90或对照噬菌体一起孵育。用含1%吐温20的PBS(PBST0.1)洗涤后,遵循Lee et al.(2004)和Lo etal.所述的程序,将样品与抗M13小鼠单克隆抗体(AmershamBiosciences,Piscataway,NJ,USA)一起在室温下孵育1小时,再用PBST0.1洗涤,并使用不含生物素的超敏聚合物-HRP检测系统(Biogenex,San Ramon,CA,USA)测定各样品的免疫反应性。利用苏木精对附着有组织样品的载玻片进行复染色,用安快达(Aquatex)(Merck,Dannstadt,Germany)封片,并借助光学显微镜进行检查。遵循Hall et al.,J.Pathol.172:1-4(1994)中所述的方法,测定阳性染色的细胞的百分比。在本研究中发现PC90而不是对照噬菌体靶向组织样品中的肿瘤细胞。
利用肽竞争性分析确定PC90的癌症靶向活性,在所述分析中,将癌症组织样品与以下各物一起孵育:(1)合成肽(100ng/ml)SMDPFLFQLLQL(SEQ ID NO:5)(SP90)和PC90(109pfu);或(2)对照噬菌体(100ng/ml)RLLDTNRPLLPY(SEQ ID NO:6;参见Lee etal.,cancer Res.64:8002-8008,2004)和PC90。合成SP90和对照肽,并利用反相高效液相色谱法进行纯化。必要时,将得到的纯度超过95%的肽的N末端与FITC或生物素缀合。
由本研究得到的结果显示,SP90而非对照肽与PC90竞争结合组织样品中的癌细胞。
接下来,遵循上文实例2中所述的方法,在带有乳腺肿瘤的SCID小鼠中测试PC90的体内癌症靶向活性。结果显示,PC90粒子结合于肿瘤异种移植物中的癌细胞,但不结合包括脑、心脏和肺在内的正常器官。
共给予SP90以测试其阻断PC90结合肿瘤组织的能力。简而言之,将100μg上述SP90或对照肽与PC90共注射到带有乳腺肿瘤异种移植物的小鼠中。取出正常器官和肿瘤组织,并固定于鲍音液(Bouin′ssolution,Sigma,MO,USA)中。固定后,将样品包埋于石蜡块中,切成切片,并使切片脱蜡,再水合,且使用上文实例1中所述的小鼠抗M13单克隆抗体进行免疫染色。SP90显著抑制PC90与肿瘤组织的结合。更具体而言,100μg SP90抑制97%的PC90与肿瘤组织结合,而对照肽未呈现出任何抑制活性。
总的说来,上文论述的结果表明,无论合成形式还是在噬菌体表面上表达,肽SMDPFLFQLLQL(SEQ ID NO:5)都特异性靶向乳腺癌细胞。
实例4:用缀合肽SMDPFLFQLLQL的脂质体封装的多柔比星靶向治疗乳腺癌
制备缀合肽的封装多柔比星的脂质体
如Lee et al.(2007)、Lo et al.和Lee et al.(2004)中所述,制备缀合肽的含多柔比星脂质体。简而言之,将肽与NHS-PEG-DSPE[N-羟基琥珀酰亚胺基-羧基-聚乙二醇(MW,3400)衍生的二硬脂酰基磷脂酰乙醇胺](NOF Corporation,Japan)按1∶1.5摩尔比偶联。完成反应,并通过使用TNBS(三硝基苯磺酸盐)(Sigma,MO,USA)定量未反应的氨基来确定。按每10μmol磷脂1毫克药物的比率,用脂质体封装多柔比星。在脂质双层的转变温度下共孵育后,接着将肽基-PEG-DSPE与封装多柔比星的脂质体缀合。如借助Kirpotin et al.,Biochemstry 36:66-75(1997)中所述的方法所测定,由此得到的每一缀合肽的脂质体含有约500个肽分子。遵循此方法,制备缀合SP90的封装多柔比星的脂质体(SP-LD)以及缀合对照肽的封装多柔比星的脂质体(CP-LD)。
由SP-LD介导的多柔比星体外胞吞作用
在37℃下,将BT483细胞与SP-LD或CP-LD一起孵育5分钟。随后用PBS洗涤细胞、固定,并在电子显微镜下检查,以检测细胞内体中脂质体的内化情况。结果表明,在与SP-LD一起孵育的细胞中,发现脂质体内化到约90%的细胞内体中,而在与CP-LD一起孵育的细胞中,只有约51%的细胞内体被发现呈脂质体阳性。这表明,SP-LD介导乳腺癌细胞对脂质体的胞吞作用。
用SP-LD处理乳腺肿瘤
在SCID小鼠(4-6周龄)的背外侧胁腹皮下注射1×107个BT483细胞,以诱导产生乳腺癌异种移植物。利用下述公式确定这些小鼠体内的肿瘤体积:长度×(宽度)2×0.52。将带有约50-100mm3大小的异种移植瘤的小鼠随机分为4组,每一组按如下经尾静脉给药进行处理。
第1组:用含有缀合SP90的多柔比星的脂质体(SP90-LD)处理,每周一次持续3周,其中多柔比星剂量为3mg/kg,
第2组:用含多柔比星脂质体(LD)处理,每周一次持续3周,其中多柔比星剂量为3mg/kg,
第3组:用游离多柔比星(FD)处理,每周一次持续3周,其中多柔比星剂量为3mg/kg,且
第4组:用盐水处理,每周一次持续3周(空白对照组)。
测量小鼠体重和肿瘤大小,一周两次。遵循上述公式计算肿瘤体积。
如图2的图面A所示,第2组小鼠(用LD处理)的平均肿瘤体积比第1组小鼠(用SP90-LD处理)的大约2.2倍(n=6,P<0.01)。第3组小鼠(用FD处理)和对照小鼠的平均肿瘤体积分别比第2组小鼠的大8.3倍和15.4倍(n=6,P<0.005)。
最后一次处理后三天(即第17天),按如下测定经处理小鼠的总白细胞(WBC)数量。从每只小鼠的下颌静脉抽取血液,并小心地与15%EDTA溶液混合以防凝固。随后,将血液与含2%乙酸和1%龙胆紫(Gentian violet)(Sigma-Aldrich,Saint Louis,MO,USA)的红细胞裂解缓冲液混合,并在室温下孵育。使用血细胞计数器计算WBC的数量。
经SP90-LD处理的小鼠的WBC总数为4.8×103个/mm3,类似于对照小鼠(5.0×103个/mm3)和经FD处理的小鼠(5.6×103个/mm3),但比经LD处理的小鼠(2.6×103个/mm3)高得多。参见图2的图面B。这一数据表明,SP-90-LD的毒性低于LD。
由本研究获得的结果还表明,在第1、2和4组中未观察到显著体重减轻,这表明与盐水和LD一样,SP90-LD也不会引起体重减轻。参见图2的图面C和图面D。
按如下,利用苏木精-伊红染色(H&E staining)检查经处理小鼠体内肿瘤组织的组织病理学。在37℃下,将冷冻并切片的肿瘤组织与末端脱氧核苷酸转移酶介导的dUTP切口末端标记反应混合物(RocheDiagnostics,Switzerland)一起孵育1小时,以检测坏死/凋亡区。用含DAPI的封片剂(Vector Laboratories)对附着有组织样品的载玻片进行复染色。随后,在荧光显微镜下观察载玻片,并用MetaMorph软件(Molecular Devices,PA,USA)进行分析。很明显,在经SP90-LD处理的小鼠的整个切片中都存在散布的坏死/凋亡区,而在经LD处理的小鼠中,发现较少坏死/凋亡区。经FD处理的小鼠和对照小鼠显示出甚至更少的坏死/凋亡区。参见图3的图面A。这些结果表明,SP90-LD在诱导肿瘤细胞坏死/凋亡方面比LD和FD更有效。
此外,检查SP90-LD对肿瘤血管形成的影响。从经处理小鼠体内取出肿瘤组织,用4%多聚甲醛固定,并用石蜡包埋。通过依次用缀合生物素的番茄(Lycopersicon esculentum;西红柿)凝集素(Vector,CA,USA)和缀合链菌抗生物素的若丹明(Pierce,IL,USA)染色,来检测肿瘤组织中的血管。在经SP90-LD处理的小鼠中,肿瘤血管数量明显少于经LD处理的小鼠。参看图3的图面B。经FD处理的小鼠和对照小鼠显示较高的肿瘤血管密度。这些结果证实,SP90-LD在抑制肿瘤血管生成方面比LD和FD更有效。
最后,检查经处理小鼠中多柔比星的定位。简而言之,对3组带有乳腺癌异种移植物(约300mm3)的SCID小鼠经其尾静脉注射2mg/kg剂量的SP90-LD、LD或FD。在所选时间点,将每组三只小鼠麻醉,并处死。经由下颌穿刺收集血液样品,并由这些样品制备血浆样品。灌注后,取出肿瘤异种移植物和正常器官(即脑、心脏和肺),并均质化。参见Mayer et al.,J.Pharmacol.Exp.Ther.280:1406-1414(1997)。在λex 485/20nm和λem 645/40nm下,利用荧光光谱测定法来分析这些组织样品(Synergy HT Multi-Detection Microplate Reader(辛纳吉HT多功能酶标仪),BioTek Instruments,Winooski,VT 05404USA)。将由此得到的数据针对从未经多柔比星处理的小鼠得到的数据进行标准化。遵循与上文所述相同的方案,使用含有一系列预定量的多柔比星的对照匀浆制备标准多柔比星曲线。根据标准曲线测定组织样品中多柔比星的量(μg)。多柔比星组织浓度是指每毫升血浆或每克组织中多柔比星的量。
此外,通过使用带有装备546/12nm激发滤光片和590nm发射滤光片组的100W HBO汞灯源的蔡司艾克沃特200M倒置显微镜(ZeissAxiovert 200M inverted microscope)检测多柔比星的自发荧光,来检查其组织定位。在FLUAR 10x/0.50NA透镜下观察组织切片,并使用鲁普科技公司(Roper Scientific)的库斯那普HQ CCD摄像机(CoolSnapHQ CCD camera)捕获图像。
由本研究得到的结果显示于图4的图面A和B中,其表明经SP90-LD处理的小鼠中平均肿瘤内多柔比星浓度分别比经FD处理的小鼠、经LD处理的小鼠以及经缀合对照肽的LD(C-LD)处理的小鼠中的浓度高12.0倍、2.2倍和2.6倍。此外,在经SP90-LD处理的小鼠的肿瘤组织的较大区域中检测到多柔比星,而在经LD、FD或C-LD处理的小鼠的肿瘤组织中只在有限区域中检测到。
总而言之,发现SP90可有效促进多柔比星向肿瘤组织的靶向递送,从而引起肿瘤细胞坏死/凋亡。
其它实施例
本说明书中揭示的所有特征都可组合成任何组合。本说明书中揭示的每一特征都可被用于相同、等效或类似目的的替代性特征替代。因此,除非另作明确规定,否则所揭示的每一特征只是一系列通用的等效或类似特征的一个实例。
根据上文描述,本领域技术人员易于确定本发明的基本特征,且在不背离本发明的精神和范围的情况下,可对本发明进行各种改变和修改,以使其适用于各种应用和条件。因此,其它实施例也在权利要求书的范围内。
Claims (7)
1.乳腺癌靶向肽,其由SMDPFLFQLLQL(SEQ ID NO:5)组成。
2.抗癌缀合物,其包含根据权利要求1所述的肽和抗癌药物。
3.根据权利要求2所述的缀合物,其中所述肽与封装所述抗癌药物的微粒缔合。
4.根据权利要求3所述的缀合物,其中所述微粒是脂质体。
5.根据权利要求2-4中任一权利要求所述的缀合物,其中所述抗癌药物选自:多柔比星、他莫昔芬、长春瑞宾、长春新碱、紫杉醇、勒托替康、多烯紫杉醇、亚德利亚霉素、表柔比星、米托蒽醌、丝裂霉素、吉西他宾、顺铂、奥沙利铂、长春花碱、5-FU、UFUR、阿那曲唑、雷曲唑和依西美坦。
6.根据权利要求2-5中任一权利要求所述的抗癌缀合物在制备用于治疗乳腺癌的药物中的用途。
7.核酸,其由编码根据权利要求1所述的肽的核苷酸序列组成。
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- 2009-12-31 TW TW098146442A patent/TWI373345B/zh not_active IP Right Cessation
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2010
- 2010-02-19 BR BRPI1008290A patent/BRPI1008290A2/pt not_active Application Discontinuation
- 2010-02-19 SG SG2011057023A patent/SG173593A1/en unknown
- 2010-02-19 CN CN201080008727.4A patent/CN102325788B/zh not_active Expired - Fee Related
- 2010-02-19 EP EP10744326A patent/EP2398820A4/en not_active Withdrawn
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- 2010-02-19 WO PCT/US2010/024647 patent/WO2010096604A2/en active Application Filing
- 2010-02-19 AU AU2010215974A patent/AU2010215974A1/en not_active Abandoned
- 2010-02-19 US US13/201,749 patent/US8674070B2/en active Active
- 2010-02-19 KR KR1020117021184A patent/KR20120014891A/ko not_active Application Discontinuation
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- 2010-02-19 JP JP2011551230A patent/JP5753100B2/ja not_active Expired - Fee Related
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TWI373345B (en) | 2012-10-01 |
US20120039988A1 (en) | 2012-02-16 |
KR20120014891A (ko) | 2012-02-20 |
EP2698376A1 (en) | 2014-02-19 |
WO2010096603A2 (en) | 2010-08-26 |
WO2010096604A3 (en) | 2011-01-06 |
WO2010096604A2 (en) | 2010-08-26 |
EP2398820A2 (en) | 2011-12-28 |
TW201031424A (en) | 2010-09-01 |
US8835605B2 (en) | 2014-09-16 |
EP2398820A4 (en) | 2012-11-07 |
JP5753100B2 (ja) | 2015-07-22 |
CN102325788A (zh) | 2012-01-18 |
SG173593A1 (en) | 2011-09-29 |
MY169807A (en) | 2019-05-16 |
US20120093721A1 (en) | 2012-04-19 |
WO2010096603A3 (en) | 2011-02-17 |
BRPI1008290A2 (pt) | 2016-03-15 |
EP2698376B1 (en) | 2016-02-17 |
US8674070B2 (en) | 2014-03-18 |
JP2012518410A (ja) | 2012-08-16 |
AU2010215974A1 (en) | 2011-09-01 |
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