CN102014968A - 选择疗法的方法 - Google Patents
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- CN102014968A CN102014968A CN2009801157799A CN200980115779A CN102014968A CN 102014968 A CN102014968 A CN 102014968A CN 2009801157799 A CN2009801157799 A CN 2009801157799A CN 200980115779 A CN200980115779 A CN 200980115779A CN 102014968 A CN102014968 A CN 102014968A
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Abstract
本发明涉及帮助确定用于罹患巴雷特食管的患者的疗法的方法,尤其是确定用于c不成功和又被诊断为异型增生的患者的疗法的方法。所述方法包括使用包含靶向以下物质的载体的成像剂:(a)Her2;(b)cMet;(c)鸟苷酸环化酶;或(d)IGF1R。所述成像剂在体外或优选在体内适用于放射性同位素或光学成像。
Description
发明领域
本发明涉及帮助确定用于罹患巴雷特食管(Barrett’s oesophagus)的患者的疗法的方法,尤其是确定用于一线疗法不成功且又被诊断为异型增生的患者的疗法的方法。所述方法包括使用包含靶向以下物质的载体的成像剂:(a)Her2;(b)cMet;(c)鸟苷酸环化酶;或(d)IGF1R。
本发明还提供所述成像剂和/或标记的载体在本发明方法中的用途。
发明背景
食道癌占所有已报告的癌症病例的不到5%,但在美国每年诊断大约30,000例新增所述病例,且存活率很低(参见以下)。可根据恶化的细胞类型将食道癌分为两大类:鳞状细胞癌和腺癌。巴雷特食管是与增加的发展为食道癌尤其是腺癌的风险有关的恶性前状态[Kiesslich等,Clin.Gastroenterol.Hepatol.,4,979-987(2006)]。慢性反流增加巴雷特食管风险,因此,指出胃食管反流(GERD)是食道癌的风险因子。
在美国和西欧食管腺癌比鳞状细胞癌更普遍。食道癌是可治疗的疾病,但很少被治愈。总体5年存活率在5%和30%之间。早期诊断食道癌提高患者的存活率。首要治疗包括单独手术或与辐射联合的化疗。用于治疗食道癌的化疗包括5-氟尿嘧啶和顺铂。缺乏明确的手术前分级法(staging)是主要的临床问题。
巴雷特食管中存在低度异型增生(dysplasia)(即异常组织生长)是发展为食道癌的危险因素,但目前对其的监视依赖组织病理学[Lim等,Endoscopy,39,581-7(2007)]。巴雷特食管中异型增生的诊断目前是经由每1-2cm随机四象限活组织检查(西雅图方案),该方案费时且花费大[DaCosta等,Best Pract.Res.Clin.Gastroenterol.,20(1),41-57(2006)]。在常规内镜检查期间通常不能观察到巴雷特食管中的异型增生[Endlicher等,Gut,48,314-319(2001)]。
US 6,035,229(Washington Research Foundation)阐述了在导管末端利用光源和成像探头用于检测巴雷特食管的***。该文献没有公开光学造影剂。
在检测高度异型增生的组织或恶性组织时用亚甲基蓝染料将巴雷特食管组织的体内染色与体外活检样品的染色进行了比较[Canto等,Endoscopy,33,391-400(2001)]。
Kiesslich等[Clin.Gastroenterol.Hepatol.,4,979-987(2006)]报道用荧光素来帮助用共聚焦激光显微内镜检测巴雷特上皮和相关肿瘤形成。
WO 2005/058371公开了用于在体内对食道癌和巴雷特食管成像的光学成像造影剂。所述造影剂对在巴雷特食管中异常表达的生物学靶标具有亲和力。WO 2005/058371的造影剂优选具有下式:
V-L-R
其中:
V为对在食道癌或巴雷特食管中异常表达的靶标具有亲和力的一个或多个载体部分;
L为接头部分或键;和
R为可在光学成像中检测的一个或多个报道子部分。
阐述了大量靶标,但所述靶标优选选自:E-钙黏着蛋白、CD44、P62/c-myc(HGF受体)、p53和EGFR/erB-2。陈述了所述载体(V)优选选自肽、拟肽部分、寡核苷酸、低聚糖、脂肪相关化合物和传统有机药物样小分子。报道子(R)优选与从电磁波谱的紫外到近红外部分的波长区域的光发生作用的染料。
巴雷特食管是特征为用柱状上皮取代鳞状食管上皮(化生)的病况。部分巴雷特食管患者将发展为食管腺癌,在该过程中的关键步骤是形成异型增生。因此,诊断为异型增生的患者视疾病的严重程度而定经受的疗法可包括抗反流药物、内镜黏膜消融和手术切除(图1;总结自“Guidelines for the Diagnosis and Management of Barrett’sColumnar-lined Oesophagus(对诊断和处理巴雷特内衬柱状上皮食管的指导方针”,英国胃肠病学会(UK Society ofGastroenterology),2005年8月;www.bsg.org.uk):
图1:对于处理巴雷特患者的当前指导方针
其中PPI=质子泵抑制剂
以每6个月一次的间隔跟踪经治疗的患者,来评估对疗法的响应。将响应者(即有证据表明该疗法有效的患者)看作低风险患者,同时对于无响应者考虑继续/另外治疗。由于开发了更多靶标特异性的疗法,因此需要有更好的疗法选择,尤其是对于那些对一线治疗无响应的巴雷特食管患者而言。
发明内容
本发明涉及帮助确定用于罹患巴雷特食管患者的疗法的方法。所述方法包括使用包含靶向以下物质的载体的成像剂:(a)Her2;(b)cMet;(c)鸟苷酸环化酶;或(d)IGF1R。所述方法为对一线治疗无响应的患者提供特定价值的疗法选择工具。预期在患病组织中显示强烈表达这些标记之一的患者将从靶向这些细胞蛋白的疗法中获益(图2)。
图2:在患者管理计划内怎样选择适合疗法
本发明提供cMet、Her2、IGF1-R和鸟苷酸环化酶c在巴雷特患者亚群中表达增加的证据。因此,用靶向这些蛋白的合适的成像剂鉴定所述患者,将使这些亚群受益于靶向cMet、Her2、IGF1-R或鸟苷酸环化酶c的药物疗法,同时使得能更有效地利用疗法资源。
发明详述
在第一方面,本发明提供用于帮助先前诊断为罹患巴雷特食管的个体患者确定最适合治疗过程的方法,所述方法包括:
(i)提供包含选择性靶向选自以下之一的蛋白标记的载体的成像剂:(a)Her2;(b)cMet;(c)鸟苷酸环化酶C;或(d)IGF1R,所述载体用成像部分标记,其中所述成像部分选自放射性同位素或光学报道子;
(ii)用步骤(i)的第一成像剂使所述患者的至少部分食管成像;
(iii)从步骤(ii)的成像确定在所述患者食管的一个或多个位置相对于背景是否增加了对所述成像剂的摄取;
(iv)当步骤(iii)的确定显示异常摄取时,通过在步骤(ii)中所用的成像剂的蛋白标记确定用于该患者的适合的靶向疗法:
(a)对于Her2,用靶向Her2的药物或疗法治疗;
(b)对于cMet,用靶向cMet的药物或疗法治疗;
(c)对于鸟苷酸环化酶C,用靶向鸟苷酸环化酶C的药物或疗法治疗;
(d)对于IGF1R,用靶向IGF1R的药物或疗法治疗;
(v)当步骤(iii)的确定为正常时,确定在步骤(iv)中确定的靶向疗法不适于该个体患者,要么给予所述患者不同疗法,要么用包含与步骤(ii)中采用的载体不同的载体的第二成像剂对所述患者重复步骤(iii)-(v)。
术语“先前诊断的”意即患者业已被诊断罹患巴雷特食管,或怀疑其罹患巴雷特食管。诊断应在临床症状加用一线内镜检查的典型证据基础上作出。目前这类一线内镜检查用白光进行,以便采集随机四象限活组织检查。这些活组织检查的组织学评估确认病的程度。
术语“成像剂”意即适于在哺乳动物体内成像的化合物,或用于在体外对采自哺乳动物身体的活检样品成像的化合物。优选哺乳动物为有生命的人对象。体内成像可为创伤性(例如在手术进行时发生或内镜)或非创伤性。优选的体内成像方法为内镜检查。
术语“选择性靶标”意即与背景组织和其它可能的靶标比较,载体对所述靶标具有更高的亲和力。载体能够以高亲和力(Ki值介于0-50nM之间,优选较低nM即小于1.0nM)结合该靶标。
术语Her2、cMet、鸟苷酸环化酶C和IGF1R具有其常规意义。
进一步说明如下:
Her2也被称为erbB-2。Her2为表皮生长因子受体家族成员。其为185kDa的细胞膜表面结合受体酪氨酸激酶,参与与细胞生长和分化有关的信号转导途径。
cMet受体为肝细胞生长因子/分散因子(HGF/SF)的高亲和力受体,其为主要由间充质细胞产生的二硫键连接的异源二聚体分子,主要作用于以内分泌方式和/或旁分泌方式作用于表达cMet的上皮细胞。
鸟苷酸环化酶C(GCC)为在控制下胃肠道上皮细胞流体分泌中起作用的鸟苷酸环化酶受体成员。其为123kDa的刷状缘膜蛋白,由GUCY2C基因(12p12)编码,由细胞外配体结合结构域、单跨膜区域和细胞质结构域组成。
***受体(IGF-1R,基因位点15q25)为155kDa的跨膜异四聚体,其在调节细胞存活、增殖以及细胞间粘着中起显著作用。其由两个细胞外α亚单位和两个跨膜β亚单位组成。α亚单位含有IGF-1的结合结构域,而β亚单位的细胞内部分含有用于自磷酸化并启动信号转导的酪氨酸激酶。IGF1-R与胰岛素受体具有60%序列同源性。同样地,其主要配体IGF-1与胰岛素具有50%同源性,但它们的下游信号转导途径不同。
适于在体内成像的放射性同位素可为金属或非金属,并为用于正电子发射型断层成像(PET)的正电子发射体或用于单光子发射计算机断面成像(SPECT)的γ-发射体。当成像部分为放射性金属离子(即射电金属)时,合适的射电金属可为:正电子发射体(对于PET成像而言),例如64Cu、48V、52Fe、55Co、94mTc或68Ga;或γ-发射体(对于SPECT成像而言),例如99mTc、111In、113mIn或67Ga。优选射电金属为99mTc、64Cu、68Ga和111In。最优选射电金属为γ-发射体,尤其是99mTc。当成像部分为γ-发射放射性卤素(对于SPECT成像而言)时,放射性卤素合适地选自123I、131I或77Br。优选γ-发射放射性卤素为123I。当成像部分为正电子-发射放射性非金属时,合适的这类正电子发射体包括:11C、13N、15O、17F、18F、75Br、76Br或124I。优选正电子-发射放射性非金属为11C、13N、18F和124I,尤其为11C和18F,最特别地为18F。
适于在体外对采自患者的活检样品成像的合适的放射性同位素为本领域已知,包括125I、3H和14C。
当成像部分具有光学性质时,报道子为能够在光学成像方法中直接或间接检测的任何部分。报道子可为光散射剂(例如有色或无色颗粒)、光吸收剂或光发射剂。更优选报道子为染料,例如发色团或荧光化合物。染料可为与从紫外光到近红外线波长的电磁波谱的光发生作用的任何染料。最优选报道子具有荧光性质。
优选的有机发色团型和荧光型报道子包括具有广泛离域电子***的基团,例如花青、部花青、吲哚菁、酞菁、萘菁、三苯基次甲基(triphenylmethines)、卟啉、吡咯(pyrilium)染料、硫代吡咯(thiapyrilium)染料、方酸(squarylium)染料、克酮酸(croconium)染料、azulenium染料、靛苯胺、苯并吩嗪(benzophenoxazinium)染料、苯并噻吩并噻嗪(benzothiaphenothiazinium)染料、蒽醌、萘醌、阴丹士林、邻苯二甲酰吖啶酮、三苯酚合苯醌(trisphenoquinones)、偶氮染料、分子内和分子间电荷传递染料和染料络合物、环庚三烯酮、四嗪、双(二硫杂环戊二烯(dithiolene))络合物、双(苯-二硫醇盐)(bis(benzene-dithiolate)络合物、碘苯胺(iodoaniline)染料、二(S,O-二硫杂环戊二烯)络合物。荧光蛋白例如绿色荧光蛋白(GFP)和改良的具有不同的吸收/发射性质的GFP也是有用的。在某些上下文中使用某些稀土金属(例如铕、钐、铽或镝)的络合物,如荧光纳米晶体(量子点)。
可使用的发色团的具体实例包括:荧光素、磺罗丹明101(德克萨斯红)、罗丹明B、罗丹明6G、罗丹明19、吲哚菁绿、花青染料Cy2、Cy3、Cy3.5、Cy5、Cy5.5、Cy7、Marina蓝、太平洋蓝、俄勒冈绿88、俄勒冈绿514、四甲基罗丹明和Alexa Fluor 350、Alexa Fluor 430、AlexaFluor 532、Alexa Fluor 546、Alexa Fluor 555、Alexa Fluor 568、AlexaFluor 594、Alexa Fluor 633、Alexa Fluor 647、Alexa Fluor 660、AlexaFluor 680、Alexa Fluor 700和Alexa Fluor 750。
特别优选的是在可见或近红外区(在400nm和3μm之间,特别是在600和1300nm之间)具有吸收最大值的染料。光学成像模式和测量技术包括但不限于:发光成像;内镜检查术;荧光内镜检查;光学相干断层扫描;透射成像(transmittance imaging);时间分辨透射成像;共焦成像;非线性显微镜;光声成像(photoacoustic imaging);声-光成像(acousto-optical imaging);光谱法;反射光谱;干涉测量法;相干干涉法;扩散光学断层扫描和荧光介导的扩散光学断层扫描(连续波、时域和频域***);和对光散射、吸收、偏振、发光、荧光寿命、量子产量及淬灭的测量。
对于步骤(iv)和(v)而言,相对于背景增加摄取表明存在步骤(i)中的蛋白标记(a)-(d),因为健康的背景食管组织(鳞状)不表达或低水平表达所述标记。这表明步骤(iv)的靶向疗法有价值。
适于与Her2结合的载体包括抗体曲妥珠单抗(Trastuzumab)(HerceptinTM,Genentech)和帕妥珠单抗(OmnitargTM,Genentech)。这些业已由Pal等综述[Rev.Endocr.Metab.Disord.,8,269-277(2007)]。也已阐述了对Her2具有特殊亲和力的Affibodies-参见例如Nilsson等[Curr.Opin.Drug Disc.Dev.,10,167-175(2007)]。
适于与cMet结合的载体包括17-30个氨基酸的环肽,其包含以下氨基酸序列(SEQ-1):
Cysa-X1-Cysc-X2-Gly-Pro-Pro-X3-Phe-Glu-Cysd-Trp-Cysb-Tyr-X4-X5-X6;
其中X1为Asn、His或Tyr;
X2为Gly、Ser、Thr或Asn;
X3为Thr或Arg;
X4为Ala、Asp、Glu、Gly或Ser;
X5为Ser或Thr;
X6为Asp或Glu;和
Cysa-d各自为半胱氨酸残基,以便残基a和b以及c和d环化来形成两个单独的二硫键;
优选此类肽具有SEQ-2或SEQ-3:
(SEQ-2)
Ser-Cysa-X1-Cysc-X2-Gly-Pro-Pro-X3-Phe-Glu-Cysd-Trp-Cysb-Tyr-X4-X5-X6;
(SEQ-3)
Ala-Gly-Ser-Cysa-X1-Cysc-X2-Gly-Pro-Pro-X3-Phe-Glu-Cysd-Trp-Cysb-Tyr-X4-X5-X6-Gly-Thr。
尤其优选此类肽具有等于Arg的X3。最优选靶向c-Met的肽为:
Ala-Gly-Ser-Cysa-Tyr-Cysc-Ser-Gly-Pro-Pro-Arg-Phe-Glu-Cysd-Tr
p-Cysb-Tyr-Glu-Thr-Glu-Gly-Thr-Gly-Gly-Gly-Lys。
适于鸟苷酸环化酶C靶标的载体为本领域所知,其通常基于大肠杆菌(E.coli)热稳定内毒素(ST肽)的肽类似物。业已由Clemmons阐述了适于IGF1R靶标的载体[Nature Rev.Drug Disc.,6,821-833(2006)]。
在步骤(iv)中,合适的靶向疗法为分别对Her2、cMet、鸟苷酸环化酶C或IGF1R具有上游或下游作用的任何已知疗法。用细胞毒素药物化疗是可能的所述疗法,合适的所述细胞毒素药物包括:5-氟尿嘧啶、顺铂、博来霉素(bleomycin)、丝裂霉素(mitomycin)、多柔比星(doxorubicin)、甲氨蝶呤(methotrexate)、托泊替康(topotecan)、紫杉醇(paclitaxel)、长春瑞滨(vinorelbine)或多西他赛(docetaxel)。所述细胞毒素药物可联合使用,例如顺铂/5-氟尿嘧啶(5-FU);卡铂(carboplatin)/紫杉醇或顺铂/伊立替康(irinotecan)。细胞毒素药物也可与下述特定疗法联合使用。
当发现靶向Her2的成像剂摄取异常时,步骤(iv)中(a)的优选疗法包括用HerceptinTM(曲妥珠单抗)治疗,曲妥珠单抗为公认的具有已证实功效的靶向Her2的药物[UK National Cancer Research Institute Clinical Guidelines;Bohme“Anti-HER2 therapy:How to use Herceptinin clinical practice(抗-HER2疗法:在临床实践中如何使用Herceptin)”.Eur.J.Oncol.Nursing,4,30-36(2000)]。
当发现靶向cMet的成像剂摄取异常时,步骤(iv)中(b)的优选疗法为已知,包括用小分子抑制剂PHA665752治疗,其如Watson等[Neoplasia,8,949-955(2006)]所述。
当发现靶向GCC的成像剂摄取异常时,步骤(iv)中(c)的优选疗法包括在GCC作为直肠癌标记的情况下业已开发的疗法。因此,例如Waldman等阐述基于ST肽和热消融的靶向GCC疗法[“Opportunitiesfor near-infrared thermal ablation of colorectal metastases by guanylyl cyclase C-targeted gold nanoshells(通过靶向鸟苷酸环化酶C的金纳米壳用于近红外热消融结直肠转移的时机)”Future Oncology 2,705-716(2006)]。热消融作为用于巴雷特患者的可能治疗被广泛论述,因此也被认为是代表切实可行的疗法选择。
当发现靶向IGF1R的成像剂摄取异常时,步骤(iv)中(d)的优选疗法包括在癌症疗法中针对IGF1R作为靶标的已知治疗。这些在以下文献中阐述:Tao等[“Mechanisms of Disease:Signaling of the insulin-like growth factor 1 receptor pathway-Therapeutic perspectives in cancer(疾病机理:***1受体信号转导途径-癌症的治疗前景)”Nat.Clin.Pract.Oncol.4,591-602(2007)];Shao等[“Integrated molecular targeting of IGF1R and HER2 surface receptors and destruction of breast cancer cells using single wall carbon nanotubes(IGF1R和HER2表面受体的整合分子靶标并用单壁碳纳米管破坏乳腺癌细胞)”Nanotechnology,18,315101(2007)];Martins等[“Insulin-like growth factor I receptor pathway inhibition by ADW742,alone or in combination with imatinib,doxorubicin,or vincristine,is a novel therapeutic approachin Ewing tumor(由ADW742单独或与伊马替尼(imatinib)、多柔比星或长春新碱(vincristine)联合抑制***I受体途径为Ewing肿瘤的新治疗方法)”Clin.Cancer Res.12,3532-3540(2006)];Bohula等[“Targeting the type 1 insulin-like growth factor receptor as anti-cancer treatment(靶向***受体1型作为抗癌治疗)”Anti-Cancer Drugs 14,669-682(2003)]。由Wang等阐述了用激酶抑制剂或单克隆抗体的其它癌症治疗方法[Rec.Result.Cancer Res.,172,59-76(2007)]。
可通过常规患者给药途径递送步骤(iv)的靶向疗法,例如静脉内、经口或局部(例如通过喷雾到食管),其为本领域所知。调配用于更有效递送到食管的药物的方法为本领域所知[Batchelor,Pharmaceut.Res.,22(2),175-181(2005]和Collaud等,J.Control.Rel.,123,203-210(2007)],因此本发明步骤(iv)的治疗可任选经由所述调配物递送。
可通过常规患者给药途径递送步骤(i)的成像剂,例如静脉内或经口,其为本领域所知。当成像部分为放射性同位素时,成像剂优选经由静脉内途径给予,因为该方式可更小心地控制患者和操作者辐射剂量。当成像部分为光学报道子时,可使用静脉内或经口给予途径。如上所述,调配用于更有效递送到食管的药物的方法(其提供较长的局部食管接触时间)为本领域所知,因此本发明步骤(i)的光学成像剂可任选经由所述调配物递送。
步骤(v)的“不同疗法”为用于个体患者的新的治疗或治疗过程,即患者先前未曾接受过的治疗。“不同疗法”可选自步骤(iv)中(a)-(d)的其余靶向疗法选项之一,该疗法在步骤(v)中未确定它们是不合适的疗法。这可包括手术和姑息治疗。
优选方面
第一方面的方法优选用体内成像进行,因此报道子适于在体内成像。步骤(i)的蛋白标记优选选自Her2和cMet,最优选Her2。当标记为Her2时,优选疗法为HerceptinTM。步骤(iii)的异常摄取优选为摄取增加,因为希望与组织背景比较其提供摄取更多的成像剂,因而有利于“热点”检测。
对于体外和体内两种成像方法而言,都优选成像部分为光学报道子,更优选荧光近红外染料。光学报道子还优选为生物相容的,即适于在体内光学成像。术语“生物相容”意即无毒并因此适于给予哺乳动物体(尤其是人体)而在给予时无有害反应或疼痛或不适。所述NIR染料在红色光到近红外波长600-1200nm处适当地具有其吸收最大值。NIR染料优选花青染料。
其中:
每一个X′独立选自:-C(CH3)2、-S-、-O-或-C[(CH2)aCH3][(CH2)bM]-,其中a为0-5的整数值,b为1-5的整数值,而M为G基团或选自SO3M1或H;
每一个Y′独立代表1-4个选自以下的基团:H、-CH2NH2、-SO3M1、-CH2COOM1、-NCS、F和G基团,其中Y′基团位于芳环的任何位置;
Q′独立选自:H、SO3M1、NH2、COOM1、铵、酯基、苄基和G基团;
M1为H或Bc;其中Bc为生物相容的阳离子;
1为1-3的整数;
m为1-5的整数;
其中X′、Y′和Q′中至少一个包含G基团;
G为适于经由共价键将染料与载体连接的活性基团或官能团。
术语“生物相容的阳离子”(Bc)意即带正电的反荷离子,其与带负电的离子化基团形成盐,其中所述带正电的反荷离子亦为无毒性,因此适于给予哺乳动物体,尤其是人体。合适的生物相容的阳离子实例包括:碱金属钠或钾;碱土金属钙和镁;和铵离子。优选生物相容的阳离子为钠和钾,最优选钠。
G基团与载体的互补基团反应,在花青染料荧光团和载体之间形成共价连接。G可为能与肽的互补官能团反应的活性基团,或作为另一选择,可包括能与载体的活性基团反应的官能团。活性基团和官能团实例包括:活性酯;异硫氰酸酯;马来酰亚胺;卤代乙酰胺;酰卤;肼;乙烯基砜;二氯三嗪;亚磷酰胺;羟基;氨基;巯基;羰基;羧酸和硫代磷酸酯。优选G为活性酯。
术语“活化酯”或“活性酯”意即与羧酸相关的酯衍生物,将其设计为更好的离去基团,因此使得其更加易于与亲核试剂例如胺反应。合适的活性酯实例为:N-羟基丁二酰亚胺(NHS)、磺基丁二酰亚胺基酯、五氟苯酚、五氟硫代苯酚、对硝基苯酚、羟基苯并***和PyBOP(即六氟磷酸苯并***-1-基-氧基三吡咯烷子基)。优选活性酯为N-羟基丁二酰亚胺或五氟苯酚酯,尤其为N-羟基丁二酰亚胺酯。
更优选的花青染料具有式Ia:
其中:
Y1和Y2独立为-O-、-S-、-NR6-或-CR7R8-,选择它们以使Y1和Y2中至少一个为-CR7R8-;
R1和R2独立为H、-SO3M1或Ra;
R3为H、C1-5烷基、C1-6羧基烷基或Ra基团;
R4-R6独立为C1-5烷基、C1-6羧基烷基或Ra;
R7为H或C1-3烷基;
R8为Ra或C1-6羧基烷基;
Ra独立为C1-4磺基烷基;
其中M1如式I中所定义;
前提条件为式Ia花青染料包含至少一个Ra基团和来自R1、R2和Ra基团的总共1-6个磺酸取代基。
术语“磺酸取代基”意即式-SO3M1的取代基,其中M1如上所定义。优选式Ia染料具有3-6个磺酸取代基。-SO3M1取代基被共价键合到碳原子,所述碳原子可为芳基(例如R1或R2基团)或烷基(即Ra基团)。在式Ia中,Ra基团优选具有式-(CH2)kSO3M1,其中M1如上所定义,k为1-4的整数值。k优选3或4。
特别优选花青染料具有式Ib:
其中:
R9和R10独立为H或SO3M1,R9和R10中至少一个为SO3M1;
R11和R12独立为C1-4烷基或C1-6羧基烷基;
R13、R14、R15和R16独立为Rb基团;
其中Rb为C1-4烷基、C1-6羧基烷基或-(CH2)qSO3M1,其中q为3或4整数值;
其中M1如对于式I和Ia所定义;
前提条件为花青染料的R9、R10和Rb基团具有总共1-4个SO3M1取代基。
选择优选的式Ib花青染料,以便为了促进与载体结合存在至少一个C1-6羧基烷基。
优选的各个式Ib花青染料概述于表1中:
表1:各个花青染料的化学结构
其中Rf=-(CH2)5COOH。
尤其优选的花青染料具有式Ic:
其中:
Rc独立为Ra基团或C1-6羧基烷基;
R17-R20独立为C1-5烷基或Rc基团,选择它们以使R17=R18=Rc或R19=R20=Rd,其中Rd为C1-2烷基;
Ra和M1如上对于式I所定义。
尤其优选的式Ib和Ic花青染料为Cy5**和Alea647,且Cy5**是理想的花青染料。
其中:
Y1为式Ya或Yb的基团
R21-R24和R29-R33独立选自:H、-SO3M1、卤素(Hal)、Rg或C3-12芳基;
R25为H、C1-4烷基、C1-6羧基烷基、C3-12芳基磺酰基、Cl,或R25与R26、R34、R35或R36之一一起可任选形成5-或6-元的不饱和脂环、不饱和杂脂环或芳环;
R26和R36独立为Rg基团;
R27和R28独立为C1-4烷基、C1-4磺基烷基或C1-6羟基烷基,或可任选与R29和/或R30之一或二者一起形成5-或6-元含N杂环或杂芳环;
X为-CR34R35-、-O-、-S-、-Se-、-NR36-或-CH=CH-,其中R34-R36独立为Rg基团;
Rg为C1-4烷基、C1-4磺基烷基、C1-6羧基烷基或C1-6羟基烷基;
W为1或2;
J为生物相容的阴离子;
其中M1如对于式I所定义;
前提条件为BzpM包含至少一个选自R21-R36基团的磺酸取代基。
术语“生物相容的阴离子”(J)意即带负电的反荷离子,其与带正电的离子化基团(在这种情况下为吲哚啉基团)形成盐,其中所述带负电子的反荷离子也无毒性,因此适于给予哺乳动物体,尤其是人体。反荷离子(J-)代表以摩尔当量存在的阴离子,因此平衡BzpM染料上的正离子。阴离子(J)适当地带有单个或多个电荷,只要存在平衡电荷的量即可。适当地从无机酸或有机酸获得阴离子。合适的阴离子实例包括:卤离子,例如氯离子或溴离子;硫酸根;硝酸根;柠檬酸根;乙酸根;磷酸根和硼酸根。优选阴离子为氯离子。
式II的苯并吡咯染料(BzpM)为荧光染料或发色团,其能够在光学成像程序中用绿色到近红外波长(500-1200nm,优选550-1000nm,更优选600-800nm)的光直接或间接检测。优选BzpM具有荧光性质。
本发明合适的成像剂为其中BzpM具有式IIa或IIb的那些:
其中X、w、J和R21-R33如对于式II所定义。
当R25与R26/R34-R36之一一起形成5-或6-元不饱和脂环、不饱和杂脂环或芳环时,合适的所述芳环包括:苯基、呋喃、噻唑、吡啶基、吡咯或吡唑环。合适的不饱和环至少包含连接R25的C=C。
当R27和/或R28与R29和/或R30之一或二者一起形成5-或6-元含N杂环或杂芳环时,合适的所述环包括:噻唑、吡啶基、吡咯或吡唑环或其部分氢化的变体。优选吡啶基或二氢吡啶基。
优选在式II BzpM的R25、R26、R34、R35或R36位置连接载体,更优选在R26、R34、R35或R36位置,最优选在R26、R34或R35位置。为了便于连接,相关R25、R26、R34、R35或R36取代基优选C1-6羧基烷基,更优选C3-6羧基烷基。
苯并吡咯染料(BzpM)优选具有至少2个磺酸取代基,更优选2-6个磺酸取代基,最优选2-4个磺酸取代基。优选至少一个磺酸取代基为C1-4磺基烷基。所述磺基烷基优选位于R26、R27、R28、R34、R35或R36位置;更优选位于R26、R27、R28、R34或R35位置;最优选位于R26位置并同时位于式II的R27和R28之一或二者位置。式II的磺基烷基优选具有式-(CH2)kSO3M1,其中M1为H或Bc,k为1-4的整数值,Bc为生物相容的阳离子(如上所定义)。k优选3或4。
在式II中,w优选1。R25优选H或C1-4羧基烷基,最优选H。X优选-CR34R35-或-NR36-,最优选-CR34R35。
优选的BzpM染料具有式III:
其中Y1、R21-R24、R26、R34、R35和J如对于式II所定义。合适的式III染料具有式IIIa或IIIb:
优选的式III、IIIa和IIIb的R21-R24和R26-R33基团如上对于式IIa和IIb所述。在式III、IIIa和IIIb中,优选选择R34和R35以使其中一个为Rj基团,另一个为Rk基团。Rj为C1-2烷基,最优选甲基。Rk为C1-4烷基、C1-6羧基烷基或C1-4磺基烷基,优选C3-6羧基烷基或-(CH2)kSO3M1,其中选择k为3或4。
优选式III染料具有C1-6羧基烷基取代基,以使其易于与载体共价连接。
在式II或III中,当R27和/或R28与R29和/或R30之一或二者一起形成5-或6-元含N杂环或杂芳基环时,优选所述环为吡啶基或二氢吡啶基。优选其中R28基团与R30环化的所述Y1基具有式Yc:
优选其中R27和R28基团二者都被环化的所述Y1基具有式Yd:
其中:
R27、R29和R31-R33如上所定义;
每一X1独立为H或C1-4烷基。
在式Yc中,优选:
每一X1为CH3;
R29=R31=H;
R32为H;
R33为CH3或-C(CH3)3,更优选-C(CH3)3。
在式Yd中,优选:
R29=H;
R32为H;
R33优选为CH3或-C(CH3)3,更优选-C(CH3)3。
优选式II的-NR27R28基团为:
(i)以开链形式,即R27/R28基团不与R29/R30之一或二者环化,优选所述R27和R28基团独立选自C1-4烷基或C1-4磺基烷基,最优选乙基或C3-4磺基烷基;或
(ii)环化得到式Yc或Yd的环化Y1取代基,更优选式Yc。
最优选开链形式(i)。
尤其优选的式III染料具有式IIIc、IIId或IIIe:
其中:
M1和J如上所定义;
R37和R38独立选自C1-4烷基或C1-4磺基烷基;
R39为H或C1-4烷基;
R40为C1-4烷基、C1-4磺基烷基或C1-6羧基烷基;
R41为C1-4磺基烷基或C1-6羧基烷基;
R42为C1-4烷基、C1-4磺基烷基或C1-6羧基烷基;
X2、X3和X4独立为H或C1-4烷基。
优选选择式IIId、IIIe和IIIf染料以使R40-R42中的一个或多个为C1-4磺基烷基。
优选的特定的式IIId染料为DY-631和DY-633:
优选的特定的式IIIe染料为DY-652:
当患者先前业已被诊断罹患巴雷特食管异型增生时,预期第一方面的方法特别有用,尤其是用于高度异型增生的患者(其处于发展为癌症的高风险中,在目前指导方针下优选完全除去有病的组织)。优选步骤(v)的不同疗法选自以下:用质子泵抑制剂化疗、内镜黏膜消融或手术切除。
所述方法还特别用于患者业已对一线疗法无响应时-即用于“无反应者”。通常由跟踪内镜检查(参见图1)来确定缺乏响应。在这种情况下一线疗法通常为以下的一种或多种:抗反流药物、内镜黏膜消融和手术切除,由此所述方法旨在发现最合适的二线疗法。
优选步骤(i)的成像剂作为药物组合物提供。所述组合物包含成像剂与生物相容的载体,呈适于给予哺乳动物的形式。“生物相容的载体”为流体,尤其是液体,成像剂可悬浮于或溶解于其中,以便组合物在生理学上可耐受,即可将其给予哺乳动物体而无毒性或无过度不适作用。生物相容的载体适当地为可注射液态载体,例如无菌、无热原注射用水;水溶液剂,例如盐水(可将其有利地平衡以使最终注射产物为等渗);一种或多种张力调节物质的水溶液(例如等离子体阳离子与生物相容的反荷离子的盐)、糖(例如葡萄糖或蔗糖)、糖醇(例如山梨醇或甘露醇)、二元醇类(例如丙三醇)或其它非离子多元醇物质(例如聚乙二醇、丙二醇等)。优选生物相容的载体为无热原注射用水或等渗盐。
成像剂和生物相容的载体各自在合适的小瓶或容器中提供,所述容器包括使得可以保持无菌完整性和/或放射性安全性的密封容器加上任选的惰性顶部空间气体(例如氮气或氩气),同时允许由注射器或插管加入及取出溶液。优选所述容器为隔膜密封的小瓶,其中用外封盖(通常为铝)卷边紧合在不透气的瓶塞上。瓶塞适合用皮下注射针一次或多次穿过(例如卷曲隔膜密封瓶塞(crimped-on septum seal closure))而同时保持无菌完整性。所述容器具有另外的优点:若需要瓶塞可承受真空(例如以改变顶部空间气体或使溶液脱气);和承受压力变化,例如减压而不让外部大气压气体(例如氧气、水汽)进入。优选多剂量容器包含含有多个患者剂量的单个容量瓶(例如10-30cm3体积),由此可在制剂的有效期期间的不同时间间隔将单患者剂量抽取到临床级注射器中以适合临床环境。设计预填充的注射器含有单人次剂量或“单位剂量”,因此,优选适于临床使用的一次性注射器或其它注射器。优选本发明药物组合物具有适于单个患者的剂量,并提供在合适的注射器或容器中,其如上所述。
药物组合物可任选含有另外的赋形剂,例如抗微生物防腐剂、pH调节剂、填充剂、稳定剂或渗透压调节剂。术语“抗微生物防腐剂”意即抑制可能有害的微生物体(例如细菌、酵母菌或霉菌)生长的物质。抗微生物防腐剂也可表现出某种杀细菌特性,这视所采用的剂量而定。本发明抗微生物防腐剂的主要作用是抑制任何所述微生物在药物组合物中生长。然而,抗微生物防腐剂也可任选用于抑制可能有害的微生物体在用于给药前制备所述组合物的试剂盒的一种或多种组分中生长。合适的抗微生物防腐剂包括:对羟基苯甲酸酯,即对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯或对羟基苯甲酸丁酯或其混合物;苯甲醇;苯酚;甲酚;溴棕三甲铵和硫柳汞。优选抗微生物防腐剂为对羟基苯甲酸酯。
术语“pH调节剂”意即用于确保组合物的pH在给予的人或哺乳动物的可接受限制内(大约pH 4.0-10.5)的化合物或化合物的混合物。合适的所述pH调节剂包括可药用缓冲剂,例如tricine、磷酸盐或TRIS[即三(羟基甲基)氨基甲烷]和可药用碱,例如碳酸钠、碳酸氢钠或其混合物。当组合物以试剂盒形式采用时,可任选以分开小瓶或容器提供pH调节剂,以使试剂盒使用者可将调节pH作为多步骤程序的一部分。
术语“填充剂(filler)”意即药用填充剂(bulking agent),其可在生产和冷冻干燥期间促进物质处理。合适的填充剂包括无机盐(例如氯化钠)和水溶性糖或糖醇(例如蔗糖、麦芽糖、甘露醇或海藻糖)。
可在无菌制备(即洁净室)条件下制备药物组合物,以提供所需的无菌无热原的产物。优选关键组分无菌,尤其是所涉及试剂加仪器上那些与成像剂接触的部分(例如小瓶)。可通过本领域已知方法对组分及试剂灭菌,所述方法包括:无菌过滤、用例如γ-辐射终端灭菌、高压灭菌、干热灭菌或化学处理(例如用环氧乙烷)。优选事先对某些组分灭菌,以使只需要进行最少量的操作。然而,作为预防措施优选包括至少无菌过滤步骤为制备药物组合物中的最终步骤。
还可从试剂盒制备药物组合物。
第一方面的方法优选进一步包括以下步骤:
(vi)当开始如步骤(iv)的(a)-(d)中所定义的靶向疗法时,使用步骤(ii)的成像剂以监测所述已开始的疗法的效力。
在该方式中,由于成像剂靶向与所述疗法/化疗相同的蛋白标记,那么预期其最适于确定是否持续存在靶标的异常表达,并因此最适于确定所述疗法的效力的客观测量。
用于本发明方法的合适的载体在文献中已知,或在某些情况下可市购-其如上所述。业已阐述用于放射性药物成像的ST肽的合成及其在用111In和99mTc进行放射性标记中与螯合剂的缀合[Cuthbertson等,Tet.Lett.,42.9257-59(2001);Wolfe等,J.Nucl.Med.,43,392-399(2002);Giblin等,Bioconj.Chem.,15,872-880(2004)]。业已由Engfeldt等[Eur.J.Nucl.Med.Mol.Imaging,34,722-733(2007);Cancer Res.,67,2178-2186(2007);Bioconj.Chem.,18,549-558和1956-1964(2007)]阐述用于Her2成像的放射性标记的Affibodies。
当成像部分包含氟的放射性同位素(例如18F)时,该放射性原子可经由用18F-氟化物与具有良好离去基团的合适前体(例如烷基溴、甲磺酸烷基酯或对甲苯磺酸烷基酯)反应直接标记来进行。还可通过胺前体与烷化剂例如18F(CH2)3OMs(其中Ms为甲磺酸根)的N-烷基化以得到N-(CH2)3 18F来引入18F,或通过羟基与18F(CH2)3OMs或18F(CH2)3Br的O-烷基化来引入18F。亦可通过N-卤代乙酰基与18F(CH2)3OH试剂烷基化得到-NH(CO)CH2O(CH2)3 18F衍生物来引入18F。对于芳基***来说,18F-氟化物亲核取代芳基重氮盐、芳基硝基化合物或芳基季铵盐是得到芳基-18F衍生物的可能途径。对于18F-标记的和123I-标记的衍生物的合成途径的其它详细资料由Bolton,J.Lab.Comp.Radiopharm.,45,485-528(2002)阐述。
可通过常规方法使光学报道子与载体缀合-参见Achilefu[Technol.Cancer.Res.Treat.,3,393-409(2004)],Li等[Org.Lett.,8(17),3623-26(2006)和Bullok等,[J.Med.Chem.,48,5404-5407(2005)]。花青染料与靶向c-Met的肽的缀合亦如实施例7所述提供(参见以下)。
在第二方面,本发明提供如第一方面所定义的标记载体在制备用于第一方面方法中的成像剂中的用途。载体和成像剂的优选方面如第一方面所述。
在第三方面,本发明提供如第一方面所定义的成像剂在第一方面的方法中的用途。载体和成像剂的优选方面如第一方面所述。
成像剂可任选经由试剂盒提供,其如本领域所知。
本发明由以下实施例来阐明。实施例1提供本发明的组织微阵列方法。实施例2表明cMet水平在正常组织中很低,在化生异型增生直至低于癌组织程度的组织中显著提高。不能将这种表达特性与疾病进展相联系,因为cMet在所有巴雷特患者中都高度表达,而不管是否进展到较高风险阶段(异型增生或腺癌)。然而,实施例2显示对cMet成像是cMet-靶向疗法是否合适的良好的指示剂。
实施例3表明在鳞状组织中Her2表达很少,在巴雷特组织和高度异型增生中出现强染色,在低度异型增生中弱染色,而在腺癌样本中染色强度不定。尤其令人感兴趣的是在邻近低度异型增生(LGD)、高度异型增生(HGD)或癌的巴雷特患者组织中Her2表达较高。随着邻近病灶的严重程度加深染色强度增大,这指出在Her2和疾病进展之间可能有相关性。实施例3显示对Her2成像是Her2-靶向疗法是否合适的良好指示剂。
实施例4表明在鳞状组织中IGF1-R显示很低或无染色,且在巴雷特、异型增生和腺癌阶段表达增加。实施例4显示对IGF1-R成像是IGF1-R-靶向疗法是否合适的良好指示剂。
实施例5显示尽管可在鳞状组织中检测鸟苷酸环化酶,在后来阶段表达增加,对于低度异型增生和癌达到90-100%。实施例3显示对GCC成像是GCC-靶向疗法是否合适的良好指示剂。
实施例6提供靶向c-Met的肽(化合物1)的合成。实施例7提供用花青染料标记实施例6的肽的方法。
缩写
使用常规单个字母或3个字母的氨基酸缩写。
Acm:乙酰氨甲基
ACN:乙腈
Boc:叔丁氧基羰基
DCM:二氯甲烷
DMSO:二甲亚砜
HPLC:高效液相色谱
NHS:N-羟基-丁二酰亚胺
NMM:N-甲基吗啉
NMP:1-甲基-2-吡咯烷酮
Pbf:2,2,4,6,7-五甲基二氢苯并呋喃-5-磺酰基
tBu:叔丁基
TFA:三氟乙酸
TIS:三异丙基硅烷
Trt:三苯甲基
实施例1:组织微阵列
从巴雷特食管患者采集新鲜活检组织样本,该样本具有一系列组织学。总共有107个样本,包含:20例胃对照(gastric control);7例鳞状细胞对照;20例巴雷特化生;20例低度异型增生;20例高度异型增生;和20例腺癌。在以上组织样本中实施组织微阵列,其中每一个中心部分具有厚度不等的~0.6mm直径。
由Camp等阐述组织微阵列方案[“Validation of tissue microarray technology in breast carcinoma(组织微阵列技术在乳腺癌中的验证)”.Lab.Invest.80,1943-1949(2000)]。全部切片来自自其获得核心的同一石蜡块。所有组织皆来自患者活检,没有对患者的食管异型增生/腺癌特地进行化疗。
测定了以下生物标记的表达:Her2、(b)cMet、(c)鸟苷酸环化酶或(d)IGF1R,结果阐述于实施例2-5中。
化生指组织特性的异常变化(在食管化生中,正常的鳞状上皮被柱状上皮取代),而异型增生指异常组织生长(在食管异型增生中,化生柱状上皮开始失去控制的增殖)。
实施例2:cMet表达
C-met作为肝细胞生长因子(HGF)受体起作用。在免疫组织化学分析中使用以下抗体:
R&D Systems抗-人HGF R(c-Met)羊抗体(AF276)1∶25(用于TMA和全剖面染色);
Novocastra c-Met(HGF R)小鼠单克隆(8F11)(非特异性染色)。
以与实施例1相似的方式进行免疫组织化学分析,给出(表1)所示结果:
表1
实施例3:Her2表达
使用CONFIRMTM抗-HER-2/neu(Ventana Medical Systems Inc,Tucson,AZ,USA)抗体。
与HER2/neu蛋白的COOH末端亲和的30mg/mL兔单克隆抗体克隆4B5 IgG1。结果如表2所示:
表2
其中:Adj=相邻
实施例4:IGF1-R表达
胰岛素-相关生长因子1受体(IGF1-R)为具有酪氨酸激酶活性的细胞受体,其亦具有促有丝***及致肿瘤特性。所用抗体为Chemicon小鼠抗-***-1受体单克隆(MAB1120)。
结果如表3所示:
表3
实施例5:鸟苷酸环化酶C表达
GC-C为肠上皮细胞特异性表达的表面受体。所用抗体为AbgentGUCY2C兔多克隆(AP7136a)1∶50。
结果如表4所示:
表4
实施例6:合成靶向c-Met的肽(化合物1)
步骤(a):合成受保护的前体线性肽
所述前体线性肽具有以下结构:
Ac-Ala-Gly-Ser-Cys-Tyr-Cys(Acm)-Ser-Gly-Pro-Pro-Arg-Phe-Glu-Cys(Acm)-Trp-Cys-Tyr-Glu-Thr-Glu-Gly-Thr-Gly-Gly-Gly-Lys-NH2
在Applied Biosystems 433A肽合成仪上用0.1mmol Rink Amide Novagel树脂为原料使用Fmoc化学装配肽基树脂H-Ala-Gly-Ser(tBu)-Cys(Trt)-Tyr(tBu)-Cys(Acm)-Ser(tBu)-Gly-Pro-Pro-Arg(Pbf)-Phe-Glu(OtBu)-Cys(Acm)-Trp(B oc)-Cys(Trt)-Tyr(tBu)-Glu(OtBu)-Thr(ψMe,Mepro)-Glu(OtBu)-Gly-Thr(tBu)-Gly-Gly-Gly-Lys(Boc)-聚合物。在偶联步骤中施用过量的1mmol预活化的氨基酸(用HBTU)。将Glu-Thr假脯氨酸(Novabiochem 05-20-1122)结合到序列中。将树脂转移到氮鼓泡器仪器中,用溶于DCM(5mL)中的乙酸酐(1mmol)和NMM(1mmol)溶液处理60分钟。通过过滤除去酸酐溶液,用DCM洗涤树脂并在氮气流中干燥。
在含有2.5%TIS、2.5%4-硫甲酚和2.5%水的TFA(10mL)中经2小时30分钟同时从树脂中除掉侧链保护基并解离肽。过滤除掉树脂,真空下除去TFA,将***加到残留物中。用***洗涤形成的沉淀,风干得到264mg的粗肽。
由制备型HPLC(梯度:20-30%B,经40分钟,其中A=H2O/0.1%TFA和B=ACN/0.1%TFA,流速:10mL/分钟,柱:PhenomenexLuna 5μC18(2)250x 21.20mm,检测:UV 214nm,产物保留时间:30min)纯化该粗肽,得到100mg的纯化合物1线性前体。通过分析型HPLC分析纯产物(梯度:10-40%B,经10分钟,其中A=H2O/0.1%TFA和B=ACN/0.1%TFA,流速:0.3mL/分钟,柱:PhenomenexLuna 3μC18(2)50x2mm,检测:UV 214nm,产物保留时间:6.54分钟)。用电喷雾质谱法进行其它产物的表征(MH2 2+计算值:1464.6,MH2 2+实测值:1465.1)。
步骤(b):形成单环Cys4-16二硫桥
Cys4-16;
Ac-Ala-Gly-Ser-Cys-Tyr-Cys(Acm)-Ser-Gly-Pro-Pro-Arg-Phe-Glu-Cys(Acm)-Trp-Cys-Tyr-Glu-Thr-Glu-Gly-Thr-Gly-Gly-Gly-Lys-NH2。
将步骤(a)的线性前体(100mg)溶于5%DMSO/水(200mL)中,用氨水将该溶液调整到pH 6。将反应混合物搅拌5天。然后用TFA将溶液调整到pH 2,通过真空蒸发除掉大部分溶剂。将残留物(40mL)分部分注射到制备性HPLC柱进行产物纯化。
由制备型HPLC(梯度:0%B,经10分钟,然后0-40%B,经40分钟,其中A=H2O/0.1%TFA和B=ACN/0.1%TFA,流速:10mL/分钟,柱:Phenomenex Luna 5μC18(2)250x 21.20mm,检测:UV 214nm,产物保留时间:44分钟)纯化该残留物,得到72mg的纯化合物1单环前体。
通过分析型HPLC(梯度:10-40%B,经10分钟,其中A=H2O/0.1%TFA和B=ACN/0.1%TFA,流速0.3mL/分钟,柱:PhenomenexLuna 3μC18(2)50x2mm,检测:UV 214nm,产物保留时间:5.37分钟(P1);5.61分钟(P2);6.05分钟(P3))分析纯产物(为异构体P1-P3的混合物)。用电喷雾质谱法进行其它产物的表征(MH2 2+计算值:1463.6,MH2 2+实测值:1464.1(P1);1464.4(P2);1464.3(P3))。
步骤(c):形成第二个Cys6-14二硫桥(化合物1)
将步骤(b)的单环前体(72mg)在氮气氛下溶于75%AcOH/水(72mL)中。依次序加入1M HCl(7.2mL)和0.05M I2/AcOH(4.8mL),将该混合物搅拌45分钟。加入1M抗坏血酸(1mL),得到无色混合物。真空下蒸发掉大部分溶剂。用水/0.1%TFA(4mL)稀释残留物(18mL),用制备型HPLC纯化产物。
通过制备型HPLC(梯度:0%B,经10分钟,然后20-30%B,经40分钟,其中A=H2O/0.1%TFA和B=ACN/0.1%TFA,流速10mL/分钟,柱:Phenomenex Luna 5μC18(2)250x21.20mm,检测:UV 214nm,产物保留时间:43-53分钟)纯化该残留物,得到52mg的纯化合物1。
通过分析型HPLC分析该纯产物(梯度:10-40%B,经10分钟,其中A=H2O/0.1%TFA和B=ACN/0.1%TFA,流速:0.3mL/分钟,柱:Phenomenex Luna 3μC18(2)50x2mm,检测:UV 214nm,产物保留时间:6.54分钟)。用电喷雾质谱法进行其它产物的表征(MH2 2+计算值:1391.5,MH2 2+实测值:1392.5)。
实施例7:花青染料与化合物1缀合
将化合物1(实施例6;10mg)、NMM(4μL)和Cy5NHS酯(5.7mg;GE Healthcare PA15104)溶解于NMP(1mL)中,将反应混合物搅拌7小时。然后用5%乙腈/水(8mL)稀释反应混合物,用制备型HPLC纯化产物。
通过制备型HPLC(梯度:5-50%B,经40分钟,其中A=H2O/0.1%HCOOH和B=ACN/0.1%HCOOH,流速10mL/分钟,柱:Phenomenex Luna 5μC18(2)250x21.20mm,检测:UV 214nm,产物保留时间:35.5分钟)纯化该粗肽,得到8.1mg的纯染料-缀合的产物。通过分析型HPLC分析纯产物(梯度:5-50%B,经10分钟,其中A=H2O/0.1%HCOOH和B=乙腈/0.1%HCOOH,流速:0.3mL/分钟,柱:Phenomenex Luna 3μC18(2)50x2mm,检测:UV 214nm,产物保留时间:8.15分钟)。用电喷雾质谱法进行其它产物的表征(MH2 2+计算值:1710.6,MH2 2+实测值:1711.0)。
Claims (16)
1.用于帮助先前诊断为罹患巴雷特食管的个体患者确定最适合治疗过程的方法,所述方法包括:
(i)提供包含选择性靶向选自以下之一的蛋白标记的载体的成像剂:(a)Her2;(b)cMet;(c)鸟苷酸环化酶C;或(d)IGF1R,所述载体用成像部分标记,其中所述成像部分选自放射性同位素或光学报道子;
(ii)用步骤(i)的第一成像剂使所述患者的至少部分食管成像;
(iii)从步骤(ii)的成像确定在所述患者食管的一个或多个位置相对于背景是否增加了对所述成像剂的摄取;
(iv)当步骤(iii)的确定显示异常摄取时,通过在步骤(ii)中所用的成像剂的蛋白标记确定用于该患者的适合的靶向疗法:
(a)对于Her2,用靶向Her2的药物或疗法治疗;
(b)对于cMet,用靶向cMet的药物或疗法治疗;
(c)对于鸟苷酸环化酶C,用靶向鸟苷酸环化酶C的药物或疗法治疗;
(d)对于IGF1R,用靶向IGF1R的药物或疗法治疗;
(v)当步骤(iii)的确定为正常时,确定在步骤(iv)中确定的靶向疗法不适于该个体患者,要么给予所述患者不同疗法,要么用包含与步骤(ii)中采用的载体不同的载体的第二成像剂对所述患者重复步骤(iii)-(v)。
2.权利要求1的方法,其中所述蛋白标记选自Her2和cMet。
3.权利要求2的方法,其中所述蛋白标记为Her2。
4.权利要求1-3中任一项的方法,其中所述成像部分为适于人体PET外部成像的放射性同位素,或为适于人体SPECT外部成像的放射性同位素。
5.权利要求1-3中任一项的方法,其中所述成像部分为光学报道子。
6.权利要求5的方法,其中所述光学报道子为在红光-近红外波长600-1200nm处具有最大吸收的染料。
7.权利要求5或6的方法,其中所述光学报道子为生物相容的。
8.权利要求1-7中任一项的方法,其中所述患者先前被诊断为罹患巴雷特食管异型增生。
9.权利要求1-8中任一项的方法,其中所述患者业已对以下一种或多种一线疗法无响应:抗反流药物、内镜黏膜消融和手术切除。
10.权利要求1-9中任一项的方法,其中步骤(v)的不同疗法选自:用质子泵抑制剂化疗、内镜黏膜消融或手术切除。
11.权利要求1-9中任一项的方法,其中步骤(v)的不同疗法选自步骤(iv)的靶向疗法选项(a)-(d)中余者之一,所述选项在步骤(v)中未被确定为不合适。
12.权利要求1-11中任一项的方法,其中步骤(i)的成像剂以药物组合物来提供。
13.权利要求1-12中任一项的方法,所述方法进一步包括以下步骤:
(vi)当开始步骤(iv)中的(a)-(d)所定义的靶向疗法时,使用步骤(ii)的成像剂来监测所述开始的疗法的功效。
14.如权利要求1-7中任一项的步骤(i)中所定义的标记载体在制备用于权利要求1-13中任一项的方法的成像剂中的用途。
15.如权利要求1-7项中任一项的步骤(i)中所定义的成像剂在权利要求1-13中任一项的方法中的用途。
16.权利要求15的用途,其中所述成像剂经由试剂盒制备。
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Cited By (3)
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CN103874482A (zh) * | 2011-10-07 | 2014-06-18 | 国立大学法人鸟取大学 | 脂质体复合物 |
CN103998929A (zh) * | 2011-12-20 | 2014-08-20 | 通用电气健康护理有限公司 | 选择患者的方法 |
CN110290833A (zh) * | 2017-02-09 | 2019-09-27 | 肿瘤贝塔股份有限公司 | 用于施加辐射的模型、用于制作所述模型的方法以及所述模型的用途 |
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EP2402370A1 (en) * | 2010-06-29 | 2012-01-04 | Pierre Fabre Médicament | Novel antibody for the diagnosis and/or prognosis of cancer |
GB201013808D0 (en) * | 2010-08-18 | 2010-09-29 | Ge Healthcare Ltd | Peptide radiotracer compositions |
DE102010042517A1 (de) * | 2010-10-15 | 2012-04-19 | Siemens Aktiengesellschaft | Verbessertes SPECT-Verfahren |
RU2013122649A (ru) * | 2010-12-01 | 2015-01-10 | ДжиИ ХЕЛТКЕР ЛИМИТЕД | Способ радиоактивного коньюгирования |
AU2012212075A1 (en) | 2011-02-02 | 2013-07-18 | Amgen Inc. | Methods and compositons relating to inhibition of IGF-1R |
GB201103696D0 (en) * | 2011-03-04 | 2011-04-20 | Ge Healthcare Ltd | Technetium labelled peptides |
GB201106004D0 (en) | 2011-04-08 | 2011-05-25 | Univ Edinburgh | Optical imaging probes |
GB201314936D0 (en) | 2013-08-21 | 2013-10-02 | Ge Healthcare Ltd | Radiolabelling method |
GB201322456D0 (en) | 2013-12-18 | 2014-02-05 | Ge Healthcare Ltd | Radiotracer compositions and methods |
BR112016021383A2 (pt) | 2014-03-24 | 2017-10-03 | Genentech Inc | Método para identificar um paciente com câncer que é susceptível ou menos susceptível a responder ao tratamento com um antagonista de cmet, método para identificar um paciente apresentando câncer previamente tratado, método para determinar a expressão do biomarcador hgf, antagonista anti-c-met e seu uso, kit de diagnóstico e seu método de preparo |
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EP1679082A1 (en) | 2005-01-07 | 2006-07-12 | Schering AG | Use of cyanine dyes for the diagnosis of proliferative diseases |
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Cited By (6)
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CN103874482A (zh) * | 2011-10-07 | 2014-06-18 | 国立大学法人鸟取大学 | 脂质体复合物 |
CN103874482B (zh) * | 2011-10-07 | 2016-08-24 | 国立大学法人鸟取大学 | 脂质体复合物 |
CN103998929A (zh) * | 2011-12-20 | 2014-08-20 | 通用电气健康护理有限公司 | 选择患者的方法 |
CN109316609A (zh) * | 2011-12-20 | 2019-02-12 | 通用电气健康护理有限公司 | 选择患者的方法 |
CN109316609B (zh) * | 2011-12-20 | 2022-03-18 | 通用电气健康护理有限公司 | 选择患者的方法 |
CN110290833A (zh) * | 2017-02-09 | 2019-09-27 | 肿瘤贝塔股份有限公司 | 用于施加辐射的模型、用于制作所述模型的方法以及所述模型的用途 |
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