CN112999347A - 酞菁探针及其用途 - Google Patents
酞菁探针及其用途 Download PDFInfo
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- CN112999347A CN112999347A CN202110310088.7A CN202110310088A CN112999347A CN 112999347 A CN112999347 A CN 112999347A CN 202110310088 A CN202110310088 A CN 202110310088A CN 112999347 A CN112999347 A CN 112999347A
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- 239000000523 sample Substances 0.000 title claims description 204
- IEQIEDJGQAUEQZ-UHFFFAOYSA-N phthalocyanine Chemical compound N1C(N=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N3)=N2)=C(C=CC=C2)C2=C1N=C1C2=CC=CC=C2C4=N1 IEQIEDJGQAUEQZ-UHFFFAOYSA-N 0.000 title description 5
- 238000000034 method Methods 0.000 claims abstract description 64
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- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical group C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 claims description 9
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Abstract
Description
本申请是中国专利申请201580029000.7的分案申请,原申请的申请日是2015年6月2日,名称是“酞菁探针及其用途”。
相关申请的交叉参考
本申请要求如下申请文件的优先权:2014年6月2日提交的美国临时专利申请号62/006,790;2014年6月25目提交的美国临时专利申请号62/017,165;2014年10月21日提交的美国临时专利申请号62/066,807;和2014年11月19日提交的美国临时专利申请号62/082,052,为所有目的将全部这些文献的教导以其完整的形式并入本文作为参考。
发明背景
光动力疗法是使用光增敏剂和照射光破坏体内关注的细胞的治疗方法。当光增敏剂暴露于特定光波长时,它产生细胞毒性活性氧,其可以诱导邻近的细胞凋亡、坏死和域自体吞噬。
目前的光动力疗法依赖于使用抗体或其片段以使光增敏剂定位于靶细胞。然而,对于使用光动力疗法诱导受试者的靶细胞例如患病细胞中细胞凋亡的基于小分子缀合物的改进的光增敏剂探针存在需求。本发明满足了这种需求并且还提供了相关的优势。
发明概述
在一个实施方案中,本发明提供用于诱导细胞毒性、例如具有疾病或病症的受试者的细胞凋亡的方法。该方法包括:(a)对所述受试者施用治疗有效剂,其包含酞菁染料,例如与特异性地结合受试者的细胞的探针缀合的700DX;和(b)用适合的有效地诱导细胞死亡的用量的激发光照射所述细胞。与探针缀合的酞菁染料700DX是式Ia的化合物。
在一些方面,所述疾病或病症选自血管疾病、癌症、由细菌生物膜导致的感染、抗生素抗性伤口感染、光化性角化病、酒渣鼻、痤疮和银屑病。所述血管疾病可以是湿型年龄相关性黄斑变性。在一些情况中,所述癌症选自乳腺癌、结直肠癌、食管癌、支气管内癌、巴雷特食管中的高等级发育不良、肺癌、前列腺癌、宫颈癌、卵巢癌、胃癌、胰腺癌、肝癌、膀胱癌、脑癌、头颈癌、神经内分泌癌、皮肤癌及其组合。
在一些方面,所述受试者具有实体瘤或已经具有实体瘤。受试者的细胞可以在实体瘤中、受试者血液中或转移部位。
在一些情况中,适合的激发光具有660-740nm例如660nm、670nm、680nm、690nm、700nm、710nm、720nm、730nm或740nm的波长。
在一些方面,所述探针选自配体、肽、小蛋白、小分子及其组合。在一些情况中,所述探针具有小于约50kDa的分子量。在另外的情况中,所述探针具有小于约10kDa的分子量。所述配体可以是EGF。所述肽可以选自YC-27、cRGDfK、血管活性肠肽、胃泌素释放肽、神经降压肽、AH111585、FPPRGD2、PK11195、SPARC、铃蟾肽、神经降压肽、物质P、生长抑素、胆囊收缩素、胰高血糖素样肽-1、神经肽Y、奥曲肽、DOTA-TOC、DOTA-TATE、毒蜥外泌肽-4、RGD、其类似物、其衍生物及其组合。在一些方面,所述肽选自soricidin、SOR-13和SOR-C27。在另外的方面,所述小分子选自VEGFR抑制剂、TNFR1抑制剂、生长因子受体抑制剂及其组合。在一些情况中,所述小分子VEGFR抑制剂选自帕唑帕尼、司马沙尼、阿昔替尼、卡博替尼、阿柏西普、布立尼布、tivozanib、雷莫芦单抗、莫替沙尼、伐他拉尼、西地尼布及其组合。或者,所述探针可以是选自DTPA-奥曲肽、[Gluc-Lys]-TOCA、半乳糖-RGD、AH111585、RGD-K5、FPPRGD2、RP-527、BZH3、[DTPA-Lys40]-毒蜥外泌肽-4和Tc-NT-X1的成员。在一些情况中,所述探针是肽配体、或其衍生物。
在一些方面,所述探针与放射性核素缀合或具有掺入其中的放射性核素。所述探针还可以与荧光团缀合。
在一些方面,步骤(a)的施用包括将治疗有效剂与探针缀合的酞菁染料700DX注入受试者血液。在一些方面,步骤(b)的照射包含使用含有近红外(NIR)光发射二极管的装置。本文所述的方法还可以包括对受试者施用抗癌药。与探针缀合的酞菁染料700DX是式Ia的化合物。
在另一个实施方案中,本发明提供用于治疗具有癌症的受试者的实体瘤的方法。该方法包括(a)给所述受试者施用治疗有效剂,其包含与实体瘤细胞特异性结合的与探针缀合的酞菁染料;和(b)用适合的激发光以有效地减小所述实体瘤尺寸的量照射所述细胞。
在一些方面,所述实体瘤选自乳腺肿瘤、结直肠肿瘤、肺肿瘤、前列腺肿瘤、卵巢肿瘤、胃肿瘤、胰腺肿瘤、肝肿瘤、膀胱肿瘤、脑瘤、神经内分泌瘤及其组合。
在一些方面,所述酞菁染料是700DX。在一些情况中,适合的激发光具有660-740nm例如660nm、670nm、680nm、690nm、700nm、710nm、720nm、730nm或740nm的波长。
在一些方面,其中所述探针选自配体、肽、小蛋白、小分子及其组合。在一些情况中,所述探针具有小于约50kDa的分子量。在另外的情况中,所述探针具有小于约10kDa的分子量。所述配体可以是EGF。所述肽可以选自YC-27、cRGDfK、血管活性肠肽、胃泌素释放肽、神经降压肽、AH111585、FPPRGD2、PK11195、SPARC、铃蟾肽、神经降压肽、物质P、生长抑素、胆囊收缩素、胰高血糖素样肽-1、神经肽Y、奥曲肽、DOTA-TOC、DOTA-TATE、毒蜥外泌肽-4、其类似物、其衍生物及其组合。在一些方面,所述肽选自soricidin、SOR-13和SOR-C27。在另外的方面,所述小分子选自VEGFR抑制剂、TNFR1抑制剂、生长因子受体抑制剂及其组合。在一些情况中,所述小分子VEGFR抑制剂选自帕唑帕尼、司马沙尼、阿昔替尼、卡博替尼、阿柏西普、布立尼布、tivozanib、雷莫芦单抗、莫替沙尼、伐他拉尼、西地尼布及其组合。或者,所述探针可以是选自DTPA-奥曲肽、[Gluc-Lys]-TOCA、半乳糖-RGD、AH111585、RGD-K5、FPPRGD2、RP-527、BZH3、[DTPA-Lys40]-毒蜥外泌肽-4和Tc-NT-X1的成员。在一些情况中,所述探针是肽配体、或其衍生物。
在另外一些方面,所述探针与放射性核素缀合。所述探针可以与荧光团缀合。
在一些方面,照射步骤(b)包含使用包含近红外(NIR)光发射二极管的装置。本文所述的方法还可以包括对所述受试者施用抗癌药。
在另一个实施方案中,本发明提供治疗有效组合物,其包含酞菁染料,例如与特异性地结合受试者的癌细胞的探针缀合的700DX,其中所述探针具有小于约50kDa的分子量。在一些方面,所述探针具有小于约10kDa的分子量。
与探针缀合的酞菁染料700DX是式Ia的化合物。在一些情况中,适合的激发光具有660-740nm例如660nm、670nm、680nm、690nm、700nm、710nm、720nm、730nm或740nm的波长。
在一些方面,其中所述探针选自配体、肽、小蛋白、小分子及其组合。所述配体可以是EGF。所述肽可以选自YC-27、cRGDfK、血管活性肠肽、胃泌素释放肽、神经降压肽、AH111585、FPPRGD2、PK11195、SPARC、铃蟾肽、神经降压肽、物质P、生长抑素、胆囊收缩素、胰高血糖素样肽-1、神经肽Y、奥曲肽、DOTA-TOC、DOTA-TATE、毒蜥外泌肽-4、其类似物、其衍生物及其组合。在一些方面,所述肽选自soricidin、SOR-13和SOR-C27。在另外的方面,所述小分子选自VEGFR抑制剂、TNFR1抑制剂、生长因子受体抑制剂及其组合。在一些情况中,所述小分子VEGFR抑制剂选自帕唑帕尼、司马沙尼、阿昔替尼、卡博替尼、阿柏西普、布立尼布、tivozanib、雷莫芦单抗、莫替沙尼、伐他拉尼、西地尼布及其组合。或者,所述探针可以是选自DTPA-奥曲肽、[Gluc-Lys]-TOCA、半乳糖-RGD、AH111585、RGD-K5、FPPRGD2、RP-527、BZH3、[DTPA-Lys40]-毒蜥外泌肽-4和Tc-NT-X1的成员。在一些情况中,所述探针是肽配体、或其衍生物。
在一些方面,所述探针与放射性核素缀合或具有掺入其中的放射性核素。所述探针可以与荧光团缀合。
本发明的其它目的、特征和优点对于本领域技术人员而言从如下详细描述和附图中显而易见。
附图简述
图1提供如Castano等人,Nat Rev Cancer,2006,6(7):535-545提供的光动力疗法的示意图。
图4A和4B显示1小时温育(图4A)和2.5小时温育(图4B)后700DX羧酸盐与蛋白质的结合,例如在人血清白蛋白(HSA)、牛血清白蛋白(BSA)和胎牛血清(FBS)中发现的那些蛋白质。在图4A中,标记溢入卵白蛋白泳道并且生成可见的标记阶梯。
图6A-D显示与700DX-EGF一起温育和照射(24J/cm2)后A431细胞的细胞存活率。图6A显示未照射的对照A431细胞。图6B显示照射的对照A431细胞。图6C显示与700DX-EGF一起温育、但未照射的的A431细胞。图6D显示照射后24小时时与700DX-EGF一起温育的A431细胞。上部小组代表细胞的相图(DIC图像)。下部小组代表细胞的荧光(在700nm)图像。
图7A-B显示与不同的700DX-缀合物的一起温育和照射(24J/cm2)后A431细胞的细胞存活率。图7A显示与700DX-帕木单抗一起温育并且照射的A431细胞。照射后62%的细胞坏死。图7B显示与700DX-EGF一起温育并且照射的A431细胞。36%处理的细胞坏死。上部小组代表细胞的相图(DIC图像)。下部小组代表细胞的荧光(在700nm)图像。
图8A-8B显示700DX在体内的清除和生物分布。图8A显示在施用所述染料后5分钟至24小时的时间点时施用700DX的裸鼠的一系列背面视图。图8B显示整个动物中总体荧光与图像俘获时间点的关系的示意图。
图9A-9B显示700DX在体内的清除和生物分布。图9A显示在施用所述染料后5分钟至24小时的时间点时施用700DX的裸鼠的一系列腹部视图。白色箭头表示肝的位置。图9B显示整个动物中总体荧光与图像俘获时间点的关系的示意图。
图10A-10C示例采集自施用700DX的裸鼠的器官中存在所述染料。在图10A中,非肝和肾的器官在700DX注射后24小时时几乎不显示信号。图10B显示通过肾的纵向切片(4nmole染料)。图10C显示在注射后24小时时不同器官中检测到的700DX水平的示意图。
图11A-11E显示接受任选标记的帕木单抗与和不与照射后的结果。图11A显示施用未标记的帕木单抗和无照射的细胞。图11B显示施用帕木单抗-700DX和无照射的细胞。图11C显示施用未标记的帕木单抗和照射的细胞。图11D显示施用帕木单抗-700DX和照射的细胞。左侧图像是DIC图像,中部图像是700nm图像,且右侧图像是合并的图像。图11E显示处理后的细胞数量和通过几种存活率和活力分析的%坏死的结果。
图12A-D显示700DX-EGF与和不与照射与阳性对照IRDye700DX-帕木单抗对坏死和细胞形态比较的效果。图12A显示对照品或无探针。图12B-12D显示细胞形态和施用700DX-帕木单抗(Pan-700DX)探针或700DX-EGF(EGF-700DX)探针并且照射10min(32J/cm2)的细胞中存在700DX。图12A显示未施用探针、但照射的阴性对照细胞。图12B显示施用EGF-700DX、但未照射的阴性对照细胞。图12C显示接受EGF-700DX和照射的细胞。图12D显示接受帕木单抗-700DX和照射的细胞。左侧图像代表DIC图像,且右侧图像代表700nm图像。
图13A-13G显示接受具有700nm图像的处理1、3、5或7的细胞形态,以便示例照射前如何有效地标记。
图14A-14D显示照射后2小时接受处理1(图14A)、3(图14B)、5(图14C)或7(图14D)的DIC图像。
图15A-15G显示用不同量(剂量)的EGF-700DX探针处理的细胞的半胱氨酸天冬氨酸蛋白酶3/7水平的FACS分析。图15A代表阴性对照(NC)。图15B显示用1μM EGF-700DX处理和照射的细胞。图15C显示用1μM EGF-700DX处理、但未照射的细胞。图15D显示用0.5μMEGF-700DX处理和照射的细胞。图15E显示用0.25μM EGF-700DX处理和照射的细胞。图15F显示用0.1μM EGF-700DX处理和照射的细胞。图15G提供半胱氨酸天冬氨酸蛋白酶3/7数据的示意图。
图16显示对于评价的染料和缀合的探针(IRDye 700DX羧酸盐(700DX)、EGF、RGD和IgG缀合物)单态氧产生的结果。
发明详述
I.前言
本发明涉及用于诱导具有疾病或病症的受试者的靶细胞死亡的组合物和方法,所述疾病或病症例如血管疾病、癌症、皮肤病、皮肤感染和因细菌生物膜导致的其它感染。更具体地,本发明涉及与探针(例如生物分子)缀合的的应用和照射以促进特定靶细胞凋亡和/或坏死。
II.定义
本文所用的下列术语具有属于它们的含义,另有指定的除外。
本文所用的术语“一个(a)”、“一个(an)”或“该(the)”不仅包括具有1的数值的方面,而且包括具有1以上数值的方面。例如,单数形式“一个(a)”、“一个(an)”或“该(the)”包括复数指示物,上下文中另有清楚描述的除外。因此,例如涉及的“一个细胞”包括多个这类细胞,且涉及的“该活性剂”包括本领域技术人员公知的一种或多种活性剂等。
术语“约”和“大约”通常应当是指测量值指定属性或精确度测定的量的可接受的误差程度。典型地,示例性的误差程度在指定值或数值范围的20百分比(%)内,优选10%内,且更优选5%内。或者且具体地在生物系统中,术语“约”和“大约”可以指数量级范围内的值,优选在指定值的5-倍内且更优选在2-倍内。本文给出的数值量是近似值,另有描述的除外,其含义是术语“约”或“大约”在未特别描述时是可以推断的。
术语“光动力疗法”或“PDT”包括用无毒性药物和光敏化照射处理细胞、组织或器官的非手术治疗,以便在原位生成细胞毒性的活性氧,其可以使细胞失活。例如,分子靶向的疗法可以使用靶向特异性光增敏剂,即基于近红外(NIR)酞菁染料与探针(例如生物分子)缀合的700DX,其通过特异性细胞表面蛋白特异性地结合靶细胞。对于大部分PDT应用,细胞毒性剂通过两种不同方法之一产生,所述方法称作I型或II型PDT途径。I型生成自由基且II型生成单态氧。自由基和单态氧导致组织被氧化破坏。
术语“细胞毒性”包括因细胞暴露于毒素导致的细胞死亡或其过程。
术语“细胞毒性剂”包括抑制或防止细胞功能和/或导致细胞死亡或破坏的物质。非限制性细胞毒性剂包括放射性同位素;化疗剂或化疗药(例如甲氨蝶呤、阿霉素、长春花生物碱类(长春新碱、长春碱、依托泊苷)、多柔比星、美法仑、丝裂霉素C、苯丁酸氮芥、柔红霉素或其它嵌入剂);生长抑制剂;酶及其片段,例如核水解酶;抗生素;毒素,例如小分子毒素或细菌、真菌、植物或动物来源的酶活性毒素,包括其片段和/或变体。
术语“癌症”包括哺乳动物中的生理学病症,其典型地被表征为不受调节的细胞生长。癌症的非限制性实例包括癌、淋巴瘤、母细胞瘤、肉瘤和白血病或淋巴样恶性肿瘤。这类癌症的更具体的实例包括鳞状细胞癌(例如上皮鳞状细胞癌)、肺癌包括小细胞肺癌、非小细胞肺癌(“NSCLC”)、肺腺癌和肺的鳞状癌、腹膜癌、肝细胞癌、胃癌或胃癌症包括胃肠道癌、胰腺癌、胶质母细胞瘤、宫颈癌、卵巢癌、肝癌、膀胱癌、肝细胞瘤、乳腺癌、结肠癌、直肠癌、结直肠癌、子宫内膜或子宫癌、唾液腺癌、肾或肾脏癌、前列腺癌、外阴癌、甲状腺癌、肝癌、肛门癌、阴茎癌和头颈癌。
术语“实体瘤”是指良性或恶性的异常细胞肿块且通常不合囊肿。实体瘤的非限制性实例包括神经胶质瘤、星形细胞瘤、髓母细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤、听神经瘤、少突神经胶质瘤、脑膜瘤(menangioma)、黑素瘤、神经母细胞瘤和视网膜母细胞瘤。
术语“700DX”或“IR700”是酞菁染料,其在与探针缀合时变成治疗有效剂。700DX染料可以具有NHS酯键以便能够与探针缀合。在一些情况中,所述探针具有伯胺(例如氮基基团),其中700DX的NHS酯和所述探针的氨基基团反应,形成酰胺键,其使所述探针连接至700DX,形成治疗有效剂。NHS酯700DX具有如下结构:
所述染料商购自LI-COR(Lincoln,NE)。氨基-反应性700DX是相对亲水性的染料且可以使用700DX的NHS酯使其与探针共价缀合。IRDye 700DX的其它变化形式公开在美国专利号7,005,518中(并入本文作为参考),并且它们也用于本发明。羧酸盐衍生物具有如下名称和结构硅酸盐(5-),双[N-[3-[(羟基-.κ.O)二甲基甲硅烷基]丙基]-3-磺基-N,N-双(3-磺丙基)-1-丙铵内盐(propanaminiumato)(4-)1[6-[[[3-[(29H,31H-酞菁-基-.κ.N29,.κ.N30,.κ.N31,.κ.N32)氧基]丙氧基]羰基]氨基]己酸(3-)]-,钠(1∶5)CAS登记号:[1623074-46-3]:
术语“酞菁染料”是指具有2个通过不饱和桥、例如聚甲炔连接的取代或未取代的含氮杂环的化合物。酞菁染料的非限制性实例、例如800CW描述在例如美国专利号6,995,274;7,504,089;7,597,878;8,227,621;8,303,936中,为所有目的将这些文献的公开内容以其完整的形式并入本文作为参考。
术语“红外荧光染料”、“IR荧光染料”或“IR染料”是指具有约600-1000nm近红外光谱中的吸收和发射波长的染料。红外荧光染料可以使用近红外(NIR)荧光成像系统检测。
术语“探针”或“生物分子”包括用于生物系统的天然或合成分子。优选的生物分子包括蛋白质、肽、小分子、配体、酶底物、激素、抗体、抗原、半抗原、抗生物素蛋白、链霉抗生物素、碳水化合物、寡糖、多糖、核酸、脱氧核酸、DNA片段、RNA片段、核苷酸三磷酸、环终止子三磷酸和PNA。
术语“缀合”、“偶合”或“标记”是指通过能够使所述部分与所述蛋白质共价结合的适合的交联剂使至少一种化学部分连接至蛋白质。
术语“连接基”包括能够以化学方式与不同物质(例如探针)上的官能团反应的化合物上的部分,形成键,例如共价键。参见,例如R.Haughland,The Handbook--A Guide toFluorescent Probes and Labeling Technologies,第9版,Molecular Probes,Inc.(1992)。典型地,所述连接基是亲电体或亲核体,其可以通过分别暴露于为亲核体或亲电体的相应官能团形成共价键。或者,所述连接基是光可活化的基团并且仅在用适当波长的光照射后变成具有化学反应性。典型地,带有所述连接基的染料与和该染料缀合的物质“所述探针”之间的缀合反应导致连接基的一个或多个原子并入新的键,其使所述染料连接至所述探针,形成治疗剂。
术语“连接基”包括使染料连接至探针的原子。
术语“治疗”是指治疗性治疗和预防性或防护性措施,其中目标在于预防或减缓(减轻)不期望的生理学改变或障碍,例如癌生长、发展或扩散。例如,有益或期望的临床结果包括、但不限于症状缓解、疾病程度减轻、疾病状态稳定(即不恶化)、疾病发展延迟或减慢、疾病状态改善和消退(无论是部分还是全部),无论是否可以检测到。“治疗”还可以指与如果不接受治疗预期的存活相比存活延长。需要治疗的那些包括已经具有病症或障碍的那些和倾向于具有或疑似具有该病症或障碍的那些或其中所述病症或障碍得到预防的那些。
术语“治疗有效量”是指单独或与另外的治疗剂(例如化疗剂)组合的足以在用该组合物治疗的受试者或细胞中实现期望的效果的组合物的用量。治疗剂或组合物(例如700DX-探针)的有效量可以依赖于几个因素,包括、但不限于待治疗的受试者或细胞、特定的治疗剂和治疗组合物的施用方式。例如,治疗有效量或浓度足以预防发展(例如转移)、延迟发展或导致疾病消退或能够减轻因所述疾病例如癌症导致的症状。例如,治疗有效量或浓度足以增加具有循环肿瘤细胞的患者的存活时间。
术语“受试者”、“患者”或“个体”典型地是指人,而且还指其它的动物,包括,例如其它灵长类、啮齿动物、犬类、猫科动物、马、羊、猪等。
III.实施方案的详细描述
A.与探针缀合的酞菁染料
本文公开了靶向光敏感药,例如700DX-探针。可以使用特异性地结合预定的靶细胞的任意的靶向部分,例如抗原、配体、蛋白质、肽、碳水化合物、核酸或小分子。所述探针可以小于抗体的分子量。在一些方面,所述探针小于约50kDa,例如约49kDa、45kDa、4-kDa、35kDa、30kDa、25kDa、20kDa、15kDa、10kDa、5kDa、1kDa或小于1kDa。所述探针可以是小于约10kDa,例如9kDa、8kDa、7kDa、6kDa、5kDa、4kDa、3kDa、2kDa、1kDa或小于1kDa。
B.探针
用于本发明的生物分子包括小分子量的蛋白质、配体、肽类、环肽类、小分子及其类似物,它们使细胞表面结合至靶细胞。在一些方面,所述生物分子是EGF、YC-27、cRGDfK、血管活性肠肽、胃泌素释放肽、AH111585、FPPRGD2、PK11195、SPARC、铃蟾肽、神经降压肽、物质P、生长抑素、胆囊收缩素、胰高血糖素样肽-1、神经肽Y、奥曲肽、DOTA-TOC、DOTA-TATE、毒蜥外泌肽-4、soricidin、SOR-13、SOR-C27、小分子VEGFR抑制剂例如帕唑帕尼、司马沙尼、阿昔替尼、卡博替尼、阿柏西普、布立尼布、tivozanib、雷莫芦单抗、莫替沙尼、伐他拉尼、西地尼布及其组合、小分子TNF1R抑制剂、生长因子受体抑制剂、DTPA-奥曲肽、[Gluc-Lys]-TOCA、半乳糖-RGD、AH111585、RGD-K5、FPPRGD2、RP-527、BZH3、[DTPA-Lys40]-毒蜥外泌肽-4、Tc-NT-X1、其类似物或其衍生物。
1.配体
表皮生长因子或EGF是在表皮和上皮组织生长、增殖和分化中具有作用的53-氨基酸肽。它结合其关联受体EGF受体。例如,Uniprot登记号P01133或GenBank登记号NP_001171601、NP_001171602和NP_001954中举出了人EGF肽。人EGF mRNA(编码)序列在GenBank登记号NM_001178130、NM_001178131和NM_001963中举出。本领域技术人员知晓EGF也称作前表皮生长因子和尿抑胃素,并且被裂解成表皮生长因子肽。在一些方面,用于本发明的EGF肽配体具有SEQ ID NO:1的氨基酸序列(NSDSECPLSHDGYCLHDGVCMYIEALDKYACNCVVGYIGERCQYRDLKWWELR)。
2.肽类
用于本发明的探针包括环肽类。可以通过各种方法使肽类环化,例如形成二硫化物、硫化物且尤其是N-和C-末端或氨基酸侧链的羧基与氨基官能团之间的内酰胺键。
环化可以通过本领域中已知的任意方法得到,例如通过酰胺键形成,通过在链(-CO-NH或-NH-CO键)上的不同位置上并入Glu、Asp、Lys、Orn、二氨基丁(Dab)酸、二-氨基丙(Dap)酸。还可以通过并入式H-N(CH2)n-COOH)-C(R)H-COOH或H-N((CH2)n-NH2)-C(R)H-COOH的修饰的氨基酸得到骨架与骨架的环化,其中n=1-4,且另外其中R是任意的天然或天然氨基酸的侧链。还可以通过经并入2个Cys残基形成S-S键得到环化。可以通过形成式-(CH2)n-S-CH2-CO-的关联键得到额外的侧链与侧链环化,其中n=1或2,例如,其通过能够通过Cys或高Cys和其游离SH基团与例如溴乙酰化的Lys、Orn、Dab或Dap反应进行。
术语“包含RGD的肽”或“RGD肽”在本文中可以互换使用且是指包含RGD序列的肽,也称作RGD基元。术语“RGD素拟态”是指化合物,特别是非肽类的化合物,它们模拟具有RGD基元的肽类。
包含RGD的肽可以是直链的或环肽,其由4-100个、优选5-50个、5-30个、5-20个或更优选5-10个氨基酸残基组成。在一些方面,RGD肽由4、5、6、7、9或25个、最优选5个氨基酸残基组成。术语“氨基酸”包括20种天然存在的氨基酸以及非天然氨基酸。非天然氨基酸的非限制性实例包括4-氨基丁酸(Abu)、2-氨基己二酸、二氨基丙(Dap)酸、羟赖氨酸、高丝氨酸、高缬氨酸、高亮氨酸、异亮氨酸(Nle)、正缬氨酸(Nva)、鸟氨酸(Orn)、TIC、萘丙氨酸(NaI)、Phe的环-甲基化衍生物、Phe的卤代衍生物或O-甲基-Tyr。或者,氨基酸包括修饰的氨基酸,例如在体内翻译后出现的修饰物,例如,羟脯氨酸、磷酸丝氨酸和磷酸苏氨酸;D-修饰物;所述肽键的N-烷基化物,优选N-甲基化物;Lys的氨基末端基团或游离氨基基团的酰化物或烷基化物;Asp或Glu的羧基末端基团或游离羧基基团的酯化物或酰胺化物;和Ser或Tyr的羟基基团的酯化物或醚化物。此外,氨基酸是指D-氨基酸和L-氨基酸。
VEGF受体抑制剂包括、但不限于VG3F(参见,例如Goncalves等人,J Pept Sci,14(6):767-72,2008)、VEGF-P3(NC)和VEGF-P3(CYC)(参见,例如Vicari等人,JBiol Chem,286:13612-13625,2011)。
肿瘤坏死因子受体1(TNFR1)的抑制剂的实例包括、但不限于抗体或及其片段,例如ATROSAB(参见,例如Richter等人,PloSOne,8(8):e72156,2013和Zettlitz等人,MAbs,2(6):639-647,2010)、IZI-06.1(参见,例如Kontermann等人,J Immunother,31(3):225-34,2008)、公开在美国专利申请公开号2012/0107330和2012/0213787中的抗-TNFR1拮抗剂或多肽类;小肽类,例如WP9QY(YCWSQYLCY)(SEQ ID NO:2);参见,例如Lohman和Isakson,TheFaseb Journal,28(1),增刊669.8)。
TNFR1-选择性拮抗剂可以是TNF-α突变体,例如R1antTNF或PEG-R1antTNF(分别参见,例如Shibata等人,Cytokine,44(2):229-233,2008和Kitagaki等人,J AltherosclerThromb,19(1):36-46,2012)。
YC-27是前列腺特异性膜抗原-特异性(PSMA-特异性)小分子。PSMA还称作谷氨酸羧肽酶I或谷氨酸羧肽酶II。参见,例如美国专利申请公开号2012/0009121,Chen等人,Biochem Biophys ResCommun,390(3):624-629,2009和Kovar等人,Protaste Cancer,2014,论文ID 104248,第10页。
血管活性肠肽(VIP)是位于CNS、消化道、呼吸道和泌尿生殖道、外分泌腺、甲状腺和肾上腺的神经元细胞体中的脑/肠激素。人VIP肽在例如Uniprot登记号P01282或GenBank登记号NP_003372和NP_919416中举出。人VIP mRNA(编码)序列在GenBank登记号NM_003381和NM_194435中举出。本领域技术人员知晓VIP也称作作用于血管的肠多肽,且所述肽可以被裂解成3条链,例如肠肽PHV-42(肽组氨酸缬氨酸42)、肠肽PHM-27(肽组氨酸甲硫酰胺27)和27个氨基酸长度的血管活性肠肽。在一些方面,用于本发明的血管活性肠肽具有SEQ IDNO:3(HSDAVFTDNYTRLRKQMAVKKYLNSILN)的氨基酸序列。VIP类似物包括[Lys15,Arg16,Leu27]-VIP/GRF、RO 25-1553和18F-标记的-Arg15-Arg21-VIP。
胃泌素释放肽或GRP是在从148-氨基酸前蛋白原裂解信号肽后与10-氨基酸神经介素C一起生成的神经肽。胃泌素释放肽调节胃肠道和中枢神经系统的大量功能,包括刺激胃泌素释放。人GRP肽在例如Uniprot登记号P07492或GenBank登记号NP_001012530中举出。人GRP mRNA(编码)序列在GenBank登记号NM_001012512中举出。
神经降压肽或NTS是13个氨基酸的神经肽,其在裂解神经降压肽/神经介素N前体后生成。神经降压肽控制中枢神经系统的大量功能,包括平滑肌收缩。人神经降压肽在例如Uniprot登记号P30990或GenBank登记号NP_006174中举出。人神经降压肽mRNA(编码)序列在GenBank登记号NM_006183中举出。
AH111585或fluciclatide是包含RGD(精氨酸-甘氨酸.天冬氨酸)三-肽的小环肽。它特别地结合αVβ3和αVβ5整合蛋白。
西仑吉肽是小环RGD肽(例如αVβ3和αVβ5整合蛋白的环(RGDfV)抑制剂。西仑吉肽的化学结构是环(Arg-Gly-Asp-D-Phe-Val)或环(L-精氨酰基甘氨酸酰基-L-α-天冬酰基-D-苯丙氨酰基-N-甲基-L-缬氨酰基)。
环(RGDfK)或c(RGDfK)是具有环(Arg-Gly-Asp-D-Phe-Lys)氨基酸结构或化学结构2-[(2S,5R,8S,11S)-8-(4-氨基丁基)-5-苄基-11-[3-(二氨基亚甲基氨基)丙基]-3,6,9,12,15-五氧代-1,4,7,10,13-五氮杂环十五-2-基]乙酸的环五肽。
FPPRGD2是聚乙二醇化二聚化RGD(精氨酸-甘氨酸-天冬氨酸)肽,其重复通过谷氨酸连接的环五肽(Phe-Pro-Pro-Arg-Gly-Asp)单元。所述肽特异性地结合αVβ3整合蛋白。
铃蟾肽是具有SEQ ID NO:4(Pyr-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2)举出的氨基酸序列的14-氨基酸肽。铃蟾肽的类似物包括[Gly-Gly-Gly]-铃蟾肽和d-Tyr6,βAla11,Phe13,NIe1414]-铃蟾肽。
所述小分子PK-11195是选择性地结合外周苯二氮杂受体的异喹啉甲酰胺。PK-11195可以作为GABA-A拮抗剂起作用。本领域技术人员知晓PK-11195也称作1-(2-氯苯基)-N-甲基-N-(1-甲基丙基)-1-异喹啉甲酰胺。
物质P是属于速激肽神经肽家族的十一肽。人前速激肽-1前蛋白在例如Uniprot登记号P20366或GenBank登记号NP_003173、NP_054702、NP_054703和NP_054704中举出。人前速激肽-1 mRNA(编码)序列在GenBank登记号NM_003182、NM_013996、NM_013997和NM_013998中举出。本领域技术人员知晓前速激肽-1被裂解成5肽类,包括物质P、神经激肽A、神经激肽L、物质K和神经肽K。物质P的氨基酸序列在SEQ ID NO:5(RPKPQQFFGLM)中举出。
分泌的酸性和富含半胱氨酸的蛋白质(SPARC)(也称作骨结合素和BM-40是无结构基质细胞32-kDa糖蛋白。该蛋白质可以用于鉴定浸润的乳腺癌、表达缺氧和酸性标记的癌细胞例如HIF2α和胚胎-软骨细胞表达的基因1、肝细胞癌、胃癌、前列腺癌的骨转移、癌组织缺氧和酸度、膀胱癌和肺癌。人SPARC前蛋白在例如Uniprot登记号P09486或GenBank登记号NP_003109中举出。人SPARC mRNA(编码)序列在GenBank登记号NM_003118中举出。SPARC蛋白质可以被裂解成具有在SEQ ID NO:6(CFGIKQKDIDKDLVI)中举出的氨基酸片列的SPARC肽。
生长抑素是可以调节内分泌系统的肽激素。所述肽可以是环十四肽。生长抑素肽通过前蛋白原交替裂解成14-氨基酸肽和28-氨基酸肽生成。人生长抑素前蛋白在例如Uniprot登记号P61278或GenBank登记号NP_001039中举出。人生长抑素mRNA(编码)在GenBank登记号NM_001048中举出。本领域技术人员知晓生长抑素也称作促生长素释放抑制因子、生长激素-抑制激素、GHIH、生长激素释放抑制因子、SRIF、生长激素释放抑制激素、SRIH、生长抑素-28或生长抑素-14。生长抑素类似物包括、但不限于奥曲肽、兰瑞肽、伐普肽、八肽BIM 23014(SR兰瑞肽)、奥曲肽的缓释形式(善龙LAR)、SOM230(Novartis,Basel)、BIM23244(Biomeasure,Milford,MA)。放射性标记的生长抑素肽类例如125I-或123I-[Tyr3]奥曲肽、111In-DTPA-[d=Phe1]奥曲肽(奥曲肽)、111In-DOTA-兰瑞肽、99mTc-P829、90Y-DOTA-Tyr3-奥曲肽(90Y-DOTATOC)和DOTA-[1-NaI3]-(DOTANOC)也用于本发明。
胆囊收缩素是通过胃肠道系统调节脂肪和蛋白质消化的肽激素。胆囊收缩素肽类由胆囊收缩素前蛋白、前胆囊收缩素原交替裂解生成。胆囊收缩素肽类包括胆囊收缩素-58、胆囊收缩素-58desnono肽、胆囊收缩素-39、胆囊收缩素-33、胆囊收缩素-25、胆囊收缩素-18、胆囊收缩素-12、胆囊收缩素-8、胆囊收缩素-7、胆囊收缩素-5。人胆囊收缩素前蛋白在例如Uniprot登记号P06307或GenBank登记号NP_000720中举出。人胆囊收缩素mRNA(编码)序列在GenBank登记号NM_000729中举出。在一些方面,胆囊收缩素肽是111In-DTPA-[A-Asp26,Nle28,31]CCK。
胰高血糖素样肽-1或GLP-1是在肠上皮内分泌细胞中合成的肽激素。GLP-1通过胰高血糖素原交替裂解生成并且以作为GLP-1(跨越氨基酸7-36)酰胺和GLP-1(跨越氨基酸7-37)的两种形式被发现。
神经肽Y或NPY是36-氨基酸神经肽,其作为神经递质在脑和自主神经系统中起作用。人神经肽Y在例如Uniprot登记号P01303或GenBank登记号NP_000896中举出。人神经肽YmRNA(编码)在GenBank登记号NM_000905中举出。NPY可以包括NPY类似物,包括Y1和Y2拮抗剂。
依度曲肽、DOTA0-Phe1-Tyr3或DOTA-TOC是可以选择性地结合生长抑素受体的小分子。
DOTA-TATE、DOTATATE或DOTA-octerotate是酸DOTA和(Tyr3)-octreotate的酰胺。DOTA-TATE可以选择性地结合生长抑素受体。
毒蜥外泌肽-4是作为胰高血糖素样肽(GLP)受体激动剂起作用的肽激素。毒蜥外泌肽-4可以促进胰岛素分泌。合成毒蜥外泌肽-4包括其为39-氨基酸肽的艾塞那肽。毒蜥外泌肽-4的氨基酸序列在SEQ ID NO:8(HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2)中举出。
Soricidin是54-氨基酸肽。SOR-C13和SOR-C27来源于soricidin的C-末端。它们是钙离子流入通道、TRPV通道的高亲和性拮抗剂。SOR-C13和SOR-C27可以靶向结肠、前列腺和甲状腺的肿瘤以及白血病和淋巴瘤。SOR-C13的氨基酸序列在SEQ ID NO:9(KEFLHPSKVDLPR)中举出。SOR-C13的氨基酸序列在SEQ ID NO:10(EGKLSSNDTEGGLCKEFLHPSKVDLPR)中举出。soricidin的氨基酸序列在SEQ ID NO:11(DCSQDCAACSILARPAELNTETCILECEGKLSSNDTEGGLCKEFLHPSKVDLPR)中举出。
3.小分子
小分子VEGF受体抑制剂的非限制性实例包括帕唑帕尼(GW786034B;GlaxoSmithKline);GW654652(GlaxoSmithKline);司马沙尼(SU5416;Sugen);阿昔替尼(Pfizer);卡博替尼(COMTRIQTM,XL184;Exelixis);阿柏西普(Sanofi-Aventis);布立尼布(BMS-582664;Bristol-Myers Squibb),tivozanib(AV-651;AVEOPharmaceuticals);雷莫芦单抗(CYRAMZATM;Eli Lilly and Company);莫替沙尼(TakedaPharmaceutical Company Limited);伐他拉尼(PTK787/ZK222584;Bayer Schering andNovartis)和西地尼布(RECENTINTM,AZD 2171;AstraZeneca)。
在一些方面,700DX标记的探针还与放射性核素缀合。有用的放射性核素包括、但不限于γ-放射体例如111In、99mTc和177Lu、β-放射体例如90Y、188Re和177Lu和111In的俄歇电子。
在一些方面,700DX标记的探针还与荧光团缀合。适合的荧光团包括、但不限于4-乙酰氨基-4’-异硫氰酸根合均二苯代乙烯-2,2’二磺酸;吖啶和衍生物:吖啶、异硫氰酸吖啶;5-(2’-氨基乙基)氨基萘-1-磺酸(EDANS);4-氨基-N-[3-乙烯基磺酰基]苯基]萘酰亚胺(naphthalimide)-3,5二磺酸酯;N-(4-苯胺基-1-萘基)马来酰亚胺;邻氨基苯甲酰胺(anthranilamide);BODIPY;灿烂黄;香豆素和衍生物:香豆素、7-氨基-4-甲基香豆素(AMC,香豆素120)、7-氨基-4-三氟甲基香豆素(couluarin)(香豆满151);酞菁染料;焰红染料;4’,6-二脒基-2-苯基吲哚(DAPI);5’,5”-二溴焦没食子酚-磺基萘(sulfonaphthalein)(溴邻苯三酚红);7-二乙基氨基-3-(4’-异硫氰酸根合苯基)-4-甲基香豆素;五乙酸二亚乙基三胺酯;4,4’-二异硫氰酸根合二氢-均二苯代乙烯-2,2’-二磺酸;4,4’-二异硫氰酸根合均二苯代乙烯-2,2’-二磺酸;5-[二甲基氨基]萘-1-磺酰氯(DNS,丹酰氯);4-二甲基氨基苯基偶氮苯基-4’-异硫氰酸酯(DABITC);曙红和衍生物:曙红、异硫氰酸曙红、赤藓红和衍生物:藻红B、异硫氰酸赤藓红(erythrosin,isothiocyanate);胡米胺;荧光素和衍生物:5-羧基荧光素(FAM)、5-(4,6-二氯三嗪-2-基)氨基荧光素(DTAF)、2’,7’-二甲氧基-4’5’-二氯-6-羧基荧光素(JOE)、荧光素、异硫氰酸荧光素(FITC)、QFITC(XRITC);荧光胺;IR144;IR1446;异硫氰酸孔雀绿;4-甲基伞形酮邻甲酚酞;硝基酪氨酸;副玫瑰苯胺;酚红;B-藻红蛋白;o-酞醛;芘和衍生物:芘、丁酸芘酯、琥伯酰亚胺1-芘;丁酸量子点;活性红4(Cibacron.TM.亮红3B-A)罗丹明和衍生物:6-羧基-X-罗丹明(ROX)、6-羧基罗丹明(R6G)、丽丝胺罗丹明B磺酰氯罗丹明(Rhod)、罗丹明B、罗丹明123、异硫氰酸罗丹明X、磺基罗丹明B、磺基罗丹明101、磺基罗丹明101的磺酰氯衍生物(德克萨斯红)、N,N,N’,N’-四甲基-6-羧基罗丹明(TAMRA)、四甲基玫瑰红、异硫氰酸四甲基玫瑰红(TRITC);核黄素;玫红酸;铽螯合物衍生物;俄勒冈绿(Oregon Green);Cy 3;Cy 5;Cy 5.5;Cy 7;700;800CW;La Jolla Blue;酞菁;酞菁(naphthalo cyanine)ATT0647;和680LT。
所述探针(例如肽)可以与酞菁染料缀合,例如700DX(LI-COR,Lincoln,NE)。在一些方面,用700DX、根据制造商的方案和药盒标记探针。用于生产700DX-缀合物的方法的详细描述可以在如下文献中找到:例如Kovar等人,Biochemistry-Faculty Publications,2007,第9页;Mitsunaga等人,Nature Medicine,2011,17:1685-1691;Peng等人,Proceedingsof SPIE,2006,6097;美国专利号7,005,518和8,524,239;和美国专利申请公开号2013/0336995,为所有目的将每篇文献的公开内容以其完整的形式并入本文。
连接染料至不同类型的探针的方法是本领域众所周知的。有关例如寡核苷酸标记方法的全面综述,参见R.Haugland:Excited States of Biopolymers,Steiner ed.,Plenum Press(1983),Fluorogenic Probe Designand Synthesis:A Technical Guide,PEApplied Biosystems(1996)和G.T.Herman,Bioconjugate Techniques,Academic Press(1996)。
在一些方面,Q包含用于连接至探针的反应基团。优选地,Q包含与所述探针上的羧基、胺或硫氢基反应的反应基团。适合的反应基团包括、但不限于活化的酯、酰卤、烷基卤、任选取代的胺、酸酐、羧酸、碳二亚胺、羟基、碘乙酰胺、异氰酸酯、异硫氰酸酯、马来酰亚胺、NHS酯、亚磷酰胺、磺酸酯、硫醇或硫氰酸酯(参见下表1)。
式I中的L选自直接键或共价键,其中共价键是直链或支链的、环状或杂环、饱和或不饱和的,其具有1-60个选自C、N、P、O的原子,其中L可以具有额外的氢原子以满足化合价(除1-60个原子外),其中所述键包含醚、硫醚、胺、酯、氨基甲酸酯、脲、硫脲、氧基或酰胺键的任何组合;或单键、双键、三键或芳族碳-碳键;或磷-氧、磷-硫、氮-氮、氮-氧或氮-铂键;或芳族或杂芳族键。在一些实例中,L包含末端氨基、羧酸或硫氢基基团且表示为-L-NH2或-L-C(O)OH或-L-SH。
连接基“L-Q”可以包括亚磷酰胺基团、NHS酯、活化的羧酸、硫氰酸酯、异硫氰酸酯、马来酰亚胺和碘乙酰胺。
在一些方面,连接基L包含-(CH2)n-基团,其中r是1-10的整数,优选n是1-5的整数,例如1-4或1、2、3、4或5,且L-Q包含-O-(CH2)n-NH2或O-(CH2)n-C(O)OH或O-(CH2)n-SH。
在一个方面,式I中的L-Q是如下所示的-O-(CH2)3-OC(O)-NH-(CH2)5-C(O)O-N-琥珀酰亚胺基:
在一些实例中,所述染料与具有伯胺的探针反应形成稳定的酰胺键。在另外的方面,马来酰亚胺和硫醇可以彼此反应并且形成硫醚。烷基卤与胺类和硫醇类反应,分别形成烷基胺类和硫醚类。提供可以与探针缀合的反应部分的任意衍生物可以在本文中使用。正如本领域知晓的,包含游离氨基基团、游离羧基基团或游离硫氢基基团的部分提供用于蛋白质缀合的有用反应基团。例如,游离氨基基团可以通过与蛋白质上可利用的羧基部分的戊二醛交联或通过碳二亚胺交联与蛋白质缀合。此外,例如使用磺基琥珀酰亚胺基-4-(N-马来酰亚氨基甲基)环己烷-1-羧酸盐(磺基-SMCC),具有游离硫氢基基团的连接基可以通过蛋白质的马来酰亚胺活化与蛋白质缀合,然后与硫氢基基团键合。
当使具有用于连接的羧酸基团的染料连接至包含胺的探针分子时,可以使用活化试剂将羧酸首先转化成更具有反应性的形式,以形成例如N-羟基琥珀酰亚胺(NHS)酯或混合酸酐。用得到的活化的酸处理包含胺的探针,形成酰胺键。本领域技术人员知晓可替代地NHS酯可以位于所述探针上且所述胺可以位于染料上。
在另外的方面,所述连接基是选自PEG、PEG-聚氨基甲酸酯的嵌段共聚物和PEG-聚丙烯的成员。在另外的方面中,所述连接基是选自多糖、多肽、寡糖、聚合物、共聚物和寡核苷酸的成员。
所述连接基L可以具有下式:
-X1-Y1-X2-
其中:X1是选自二价残基、直接键、氧、任选取代的氮和硫的成员;Y1是选自直接键和任选地被杂原子打断的C1-C10亚烷基的成员;且X2是选自二价残基、直接键、氧、任选取代的氮和硫的成员。
优选地,X1和X2的二价残基各自独立地选自直接键、任选取代的亚烷基、任选取代的亚烷基氧基羰基、任选取代的亚烷基氨基甲酰基、任选取代的亚烷基磺酰基、任选取代的亚烷基磺酰基氨基甲酰基、任选取代的亚芳基、任选取代的亚芳基磺酰基、任选取代的亚芳基氧基羰基、任选取代的亚芳基氨基甲酰基、任选取代的亚芳基磺酰基氨基甲酰基、任选取代的羧基烷基、任选取代的氨基甲酰基、任选取代的羰基、任选取代的杂亚芳基、任选取代的杂亚芳基氧基羰基、任选取代的杂亚芳基氨基甲酰基、任选取代的杂亚芳基磺酰基氨基甲酰基、任选取代的磺酰基氨基甲酰基、任选取代的硫代羰基、任选取代的磺酰基和任选取代的亚磺酰基。
或者,所述连接基是-(CH2)r-,其中r是1-50的整数。
式I的反应Q基团与所述探针上的互补基团反应,形成式Ia的化合物:
在式Ia中,式I的反应Q基团与所述探针上的互补基团反应并且形成共价键Q1。所述探针然后与所述连接基共价结合。
用于使所述染料连接至所述探针的反应官能团的选择的实例如表I中所示,其中价键因所述染料(例如检测剂或光增敏剂)与所述探针反应产生。本领域技术人员知晓适用于本发明的其它价键。
表1
*正如本领域中可以理解的,活化的酯类通常具有式-COM,其中M是良好的离去基(例如琥珀酰亚胺基氧基(-OC4H4O2)、磺基琥珀酰亚胺基氧基(-OC4H3O2SO3H)、-1-氧基苯并三唑基(-OC6H4N3);4-磺基-2,3,5,6-四氟苯基;或芳氧基基团或被吸电子取代基例如硝基、氟、氯、氰基或三氟甲基或其组合取代一次或多次的芳氧基,其用于形成活化的芳基酯类;或被碳二亚胺活化的羧酸,形成酸酐或混合酸酐-OCORa或OCNRaNHRb,其中Ra和Rb相同或不同,为C1-C6烷基、C1-C6全氟烷基或C1-C6烷氧基;或环己基、3-二甲基氨基丙基或N-吗啉代乙基)。**酰基叠氮化物还可以重排成异氰酸酯类。
在一些方面,所述连接基与探针(“C”栏)之间的共价键Q1选自直接键、酰胺键、酯键、醚键、肟键、磷酸酯键、磺酰胺键、硫醚键、硫脲键和脲键。在一个可选的实施方案中,“A”反应官能团在所述探针上且互补官能团“B”在染料上。
在另外的方面,700DX染料通过点击化学连接至探针或生物分子。点击化学使用简单的、稳定的反应,例如叠氮化物和炔类的铜-催化的环加成,生成分子间键。有关点击化学的综述,参见,例如Kolb,H.C.;Finn,M.G.;Sharpless,K.B.Angew.Chem.2001,40,2004。
2个片段结合(或连接)形成较大分子或结构通常使用所谓的Sharpless等人,Angew.Chem.,Int.Ed.40:2004(2001)所述的点击化学实现。该术语用于描述两种不同反应剂例如叠氮化物和乙炔类之间的一组生物分子反应。叠氮化物与三键的1,3-双极环加成中形成1,2,3-三唑类是已知的,但因为乙炔-叠氮化物环加成的活化能相对较高,所以该反应在环境条件下是缓慢的。
叠氮化物与炔类反应的用途因Cu(I)催化的发现而被扩展。在催化量的亚铜盐的存在下叠氮化物的1,3-环加成至末端乙炔类在室温下在有机或水溶液中是温和的。
Bertozzi等人在美国专利号7,807,619教导修饰的环炔化合物和这类化合物在修饰生物分子中的使用方法。Bertozzi等人教导可以在生理学条件下进行的环加成反应。如本文所公开的,修饰的环炔与靶生物分子上的叠氮化物部分反应,生成共价修饰的生物分子。
在另外的方面中,本发明提供用于受试者的靶细胞、组织和器官的光动力疗法(PDT)的方法和化合物。在一些实例中,所述靶细胞是实体瘤细胞。在另外的实例中,所述靶细胞位于受试者的血管系统中。PDT是两步治疗方法,其可以用于广泛的癌症和患病的组织和器官。该疗法中的第一步通过经摄入或注射全身施用光增敏剂或局部应用所述化合物至受试者特定治疗部位来进行,随后的第二步用具有相当于所述光增敏剂的特征吸收波段的波长或波段的光照射治疗部位。所述光激活光增敏剂,导致单态氧自由基和其它活性种类生成,从而产生大量生物效应,其可以破坏已经吸收所述光增敏剂的异常或患病组织。对异常组织例如癌性肿瘤或渗漏血管的细胞毒性作用(例如细胞凋亡作用)的深度和体积部分地依赖于光透入组织的深度、光增敏剂的浓度及其细胞分布和分子氧的利用度,这些取决于供应肿瘤、组织或器官的血管系统。
在一些实例中,本发明提供治疗方法,其中,例如,使用治疗剂治疗肿瘤,此后,使其成像,以便确定治疗程度。治疗可以是反复的,直到破坏肿瘤或治疗部位完全令人满意。在一些实例中,所述方法包括注射所述探针或组合物、使用光动力疗法治疗肿瘤和此后成像以确定治疗程度。
本发明的方法提供对受试者施用治疗有效量的靶向光增敏剂,例如治疗探针。所述探针可以通过摄入或注射经全身施用或局部施用于靶组织部位或手术部位。所述活性剂可以结合一种或多种类型的靶细胞或组织,例如循环的肿瘤细胞或实体瘤细胞。当暴露于适合波段的光敏化光时,所述活性剂吸收该光,导致产生通过细胞凋亡损伤或破坏靶细胞或组织的物质。优选地,所述化合物对于施用它的受试者无毒性或能够配制在可以施用于受试者的无毒性组合物中。此外,在暴露于光后,任何得到的光降解形式的化合物也优选是无毒性的。
可以通过本领域中已知用于PDT的任意方式施用所述活性剂和活化光,包括、但不限于摄入、注射、经皮施用、透皮施用和透视。优选地,将光经皮施用于受试者。例如,本文所用的“经皮”是指光通过未破坏组织的通道。如果组织层是皮肤或真皮,则经皮包括“透皮”且应当理解,光源在表皮层的外部。然而,本文所用的术语“透视”是指光通过组织层的通道,例如器官表层,例如肝,且显而易见,光源在器官的外部,但是在患者或受试者体内或植入受试者或患者。
在一些方面,用于施用PDT的能量形式包括、但不限于光(即辐射)、热、声、超声、化学、光、微波、电离(例如x-射线和γ射线)、机械和电。本文所用的术语“辐射”包括所有的波长和波段。优选地,选择放射波长或波段以便相当于或至少覆盖激发光增敏剂的波长或波段。光增敏剂典型地具有一个或多个吸收波段,可激发它们产生损伤或破坏靶细胞、组织、器官或肿瘤的物质。优选地,辐射波长或波段匹配光增敏剂的激发波长或波段,并且具有较低的被受试者的非靶细胞和其余物质包括血蛋白质吸收。
在另外的方面,用PDT治疗的靶细胞、组织、器官或肿瘤选自血管上皮组织、皮肤组织、肿瘤的异常血管壁、实体瘤、头肿瘤、颈肿瘤、胃肠道肿瘤、肝肿瘤、乳腺肿瘤、前列腺肿瘤、卵巢肿瘤、子宫肿瘤、睾丸肿瘤、肺肿瘤、非实体瘤、造血组织和淋巴组织之一的恶性细胞、血管系统中的损害、患病的骨髓和患病的细胞,其中所述疾病是自身免疫疾病和炎性疾病之一。在另一个实施方案中,所述靶组织是选自动脉硬化损害、动静脉畸形、动脉瘤和静脉损害的类型的血管系统中的损害。
IV.实施例
提供下列实施例用于示例、但不限定要求保护的发明。
评价pH对染料的羧酸盐形式的稳定性的作用在室温和在37℃下进行。为了比较的目的,包括在37℃下的稳定性试验,同时溶于1X PBS。使用具有恒定离子强度的McIlaine缓冲溶液。PBS中的试验显示在1μM下几乎没有信号强度缺失(图2)。当将染料溶于具有递增pH(2.1-8.2)的不同缓冲液中时,最初在pH 4-5出现的信号强度缺失在室温下随着逐步降至pH 2.1而缺失(图3A)。在37℃下,这种缺失最初发生在pH 5-6的稍高的pH下,逐步与在室温下进行的试验类似(图3B)。
在SDS-PAGE中和非还原条件下,卵白蛋白具有约40kDa、45kDa、63kDa和72kDa的分子量。人血清白蛋白(HSA)在非还原条件下具有约66.6kDa-约66.4kDa或以下的分子量。HAS在还原条件下可以作为在SDS-PAGE中的约58-67kDa带移动。
将人血清白蛋白、牛血清白蛋白、5%FBS和700DX羧酸盐在1X PBS中在室温下温育2.5h。亚甲蓝还用作已知结合白蛋白和另外的血清蛋白的染料。使样品在4-12%Bis-Tris凝胶上运行。卵白蛋白用作阴性对照。与700DX羧酸盐一起温育的蛋白质位于凝胶的左侧,而亚甲蓝样品位于右侧(图4A-B)。
1h温育后,未检测到可测定的700DX结合至血清蛋白,包括白蛋白(图4A)。游离染料在凝胶的底部可见,这表明染料过量且可利用于结合反应。图4B显示2.5h温育后,700DX结合至血清蛋白、包括白蛋白是显而易见的。存在亚甲蓝样品的信号。在人血清白蛋白、BSA和FBS样品中检测到白蛋白。
本实施例示例基于700DX染料缀合物的光动力疗法对细胞形态的作用。用于评价PDT过程中形态改变的其它方法使用额外的关键细胞凋亡标记的试验,包括半胱氨酸天冬氨酸蛋白酶3/7、膜联蛋白-V、存活%、线粒体潜能、定位(胞内/膜、内体、溶酶体)、单态氧发生、其它自由基等。关键在于鉴定用于生成可再现作用的重要参数,包括照射水平、温育时间、探针类型和/或启动细胞毒性的所需剂量。通过测定这些关键指标,确定700DX在诱导细胞毒性能力中的作用。
形态是用于确定照射后细胞改变的常用指标。图5A-5C显示常见于细胞凋亡和坏死的非常早期的起泡特征(用箭头突出显示)。
实验清楚地证明,700DX是PDT中的活性成分。图6A-6B提供为无照射(NI)或有照射(I)的A431细胞的对照图像。用于相应治疗的所述探针剂量为0.25μM,且照射水平为16J/cm2。结果显示,细胞形态对于未处理的细胞而言未改变,这说明单独的照射水平无有害作用(图6B)。另外的对照组包括与700DX-EGF和NI一起温育(图6C),也显示对细胞形态无有害作用,表明PDT中需要照射。最终,当用700DX-EGF处理细胞并且照射时,其形态明显改变,其中核缩合且细胞脱水(图6D)。这些是细胞发生细胞凋亡和/或坏死的关键特征。当照射后24h测定细胞存活率时,结果证实仅用照射处理的所述探针诱导细胞毒性(图6A-6D)。
本实施例示例700DX-抗体探针和700DX-小蛋白配体探针的PDT作用。700DX-EGF探针在结合至其关连受体之后被摄入并且在数分钟内快速地被处理。所述小分子探针诱导细胞凋亡,而700DX-抗体探针诱导坏死。
已经启示,使用700DX在光免疫疗法(PIT)中的作用机制与PDT相比不同。为了测试这种推断,评价用700DX-帕木单抗(约0.1μM;抗体)和EGF(0.5μM;小蛋白配体)标记的两种探针。两种探针均可以结合EGFR并且每个缀合物分子具有约2个染料分子。推断与小蛋白(nM)相比,对该受体的亲和力不同于对所述抗体(通常为pM)。尽管所述探针剂量不同,但是温育时间相同,仅为10min。温育后,从细胞中冲洗掉所述探针。图7A和7B示例分别与IRDye 700DX-帕木单抗或IRDye 700DX-EGF一起温育且此后照射的A431细胞。所述探针显示对细胞形态的类似作用,正如照射后24小时检查的。细胞毒性水平对于两种探针而言是不同的,表明两种探针通过两种不同途径启动细胞毒性,例如细胞凋亡和坏死途径。用700DX-帕木单抗处理的照射的细胞62%死亡,而用700DX-EGF处理的照射的细胞36%死亡。
700DX-帕木单抗探针位于细胞表面并且结合细胞膜。因此,在照射时,在细胞表面上产生单态氧。典型地,EGF配体在结合EGF受体后被摄入。照此,700DX-EGF探针被细胞胞吞并且在细胞内产生细胞毒性活性氧。
进行实验以便评价700DX羧酸盐在接受2或4nmoles所述化合物的裸鼠中的清除。这是所述染料的非反应性形式,且体内消除动力学可以用于测定所述染料和随后染料-标记的缀合物的生物分布。两种剂量的结果极为类似(仅呈现4nmole动物的图像)。清除显示是在肾,正如背侧(图8A)和腹侧全身视图(图9A)中注意到的。肾在背侧系列的自始至终可见(图8A)且肝在腹侧系列中可忽略不计(图9A)。肾信号超过肝,这启示在肝中无明显保留,且肾排泄是主要的消除途径(图10A-10C)。切下后器官的接近检查示例在图10B中(2nmole剂量)。通过肾的纵向切片(4nmole剂量)显示所述染料的主要位置在肾皮质的近端小管中。这一结果在所有动物中观察到,与染料的浓度无关。分析全部成像的器官(肌肉、心脏、肺、肝、脑、脾、肠和肾)对区域校正的信号。图解表示法提供在图10C中。有意义地,剂量并不显著地影响保留在肾中的染料的量。这可以启示所述染料持续地和极为快速地被身体清除。
尽管推断用于本文所述试验中的剂量过低以至于难以成为使用700DX-标记的帕木单抗观察到的细胞死亡中的促成因素,但是进行少量研究以证实不存在因试验系统导致的治疗作用。本试验包括如下4种治疗:未标记的帕木单抗和无照射的处理1(图11A)、700DX-标记的帕木单抗和无照射的处理2(图11B)、未标记的帕木单抗和照射的处理3(图11C)和700DX-标记的帕木单抗和照射的处理4(图11D)。照射剂量为24J/cm2,其中所述探针的温育时间为10分钟,且浓度为0.1μM。图11E显示治疗后和在37℃温育24小时后的坏死细胞的百分比。形态数据显示仅标记的帕木单抗和照射的处理4(图11D)诱导细胞死亡。对于未标记的或标记的-抗体与无照射未观察到可测定的作用(图11A-11C)。数据显示该抗体在所用试验系统中未提供任何显著的作用。
测试不同的LED源并且评价,以确定LED的第二个来源是否可以产生与所用标准LED类似的作用。设定4种治疗的直接评价(处理A-D)。一式三份进行本试验,以便检查再现性。本试验包括如下4种治疗:无探针和照射的处理A、700DX-标记的EGF和无照射的处理B、700DX-标记的EGF和照射的处理C、和700DX-标记的帕木单抗和照射的处理D。所述探针剂量约为0.1μM标记的帕木单抗和0.5μM 700DX-标记的EGF。照射在32J/cm2照射剂量下进行10分钟。
图12A-12D显示来自每种相应探针的有代表性的治疗的细胞形态与相应的700nm图像,以便示例在照射前如何有效地标记。
用700DX-EGF或700DX-帕木单抗处理的细胞分析受到照射能的显著影响并且濒临死亡(分别为图12C和12D)。两种探针一起和一式三份进行的提供清楚证据的显著和类似的作用,即700DX-标记的小蛋白可以与IRDye 700DX-标记的抗体类似地杀伤细胞。下表2中提供了%坏死和%存活。用于任一探针的条件可能对于各探针而言是唯一的。数据还显示单独地照射细胞难以产生任何作用,由此启示照射剂量不会导致对细胞的过度伤害。700nm图像的荧光等级对于处理的细胞组而言是相同的(图12C-12D)。尽管抗体探针的确切浓度未知,但是来自不同探针的信号在水平和强度上显然是类似的。
本实施例显示细胞的不同靶向剂和IRDye 700DX NHS酯标记的评价。测试小分子RGD标记的探针。应当注意,A431细胞表达极低水平的整合蛋白受体且并非用于这种探针的理想细胞类型。
简言之,用相应的探针标记A431细胞用于特定处理(如下所列);冲洗细胞并且评价标记。本试验包括如下处理:700DX 1μM和照射的处理1-2;700DX 0.5μM和照射的处理3-4;700DX NHSe 5μM和照射的处理5-6;700DX约0.1μM和照射的处理7-8;使用无探针和无照射的处理9;和700DX和无照射的处理10。将所述探针温育约10分钟且对于RGD探针温育约20分钟的较长时间期限。使用显微镜监测细胞并且在处理后24小时检查形态。
图13A-13G显示接受处理1、3、5或7的细胞形态与相应的700nm图像,以便示例如何在照射前进行有效的标记。对于RGD探针预期低结合率,这归因于A431细胞上整合蛋白受体的低水平。处理3、5和7均显示细胞毒性,其中最有效的是NHSe和帕木单抗探针。图14A-14D显示照射后2小时接受处理1(图14A)、3(图14B)、5(图14C)或7(图14D)的细胞DIC图像。截止到,照射后3小时,全部处理除外RGD(治疗1)均显示显著的细胞毒性。进行活力、存活和坏死试验,例如VB-48试验和JC-1试验。数据如表3中所示。
表3.处理1-10的%活力、存活率和坏死
简言之,将150,000个细胞铺板并且在37℃、5%CO2温育过夜。将约1ml所述探针加入到适合的处理中。温育期后冲洗细胞并且成像。用小LED仪器照射细胞。将细胞在37℃、5%CO2进一步温育,然后在照射后2-3小时成像。然后收获细胞并且重新混悬于250μl PBS。用NC-100TM (ChemoMetec A/S;Allerod,Denmark)计数细胞。根据制造商的方案分析细胞,以便进行半胱氨酸天冬氨酸蛋白酶3/7试验(ImmunoChemistryTechnologies,LCC,Bloomington,MN)。数据如表4中所示。NC表示阴性对照,例如无探针。
表4.处理1-6后细胞凋亡和坏死细胞的%
对于所述处理,测定半胱氨酸天冬氨酸蛋白酶3/7活性显示当使用700DXEGF时探针剂量的作用。当测试处理1和3(不接受照射)时,它们显示最高的%健康细胞和最低的半胱氨酸天冬氨酸蛋白酶活性(图15A和15C)。当健康细胞百分比随递增的探针剂量下降时,检测到浓度的作用(图15B、15D-15G)。晚期细胞凋亡百分比随剂量的增加而增加。两种最高测试剂量(1μM和0.5μM)之间几乎没有差异。在该系统中已经达到施用剂量的上限最大值,约为未观察到另外的作用。总之,用700DX-标记的EGF配体处理的细胞在暴露于约32J/cm2下的照射光时发生细胞凋亡。
实施例8.生产IRDye 700DX缀合的氯代毒素(chlorotoxin)(CLTX-700DX)
用PBS缓冲液pH 8.5以1mg/mL重构氯代毒素(AnaSpec,AS-60770)。用PBS缓冲液pH8.5将IRDye 700DX NHSE(LI-COR,P/N 929-70010)重构至1mg/mL。即刻以等效于氯代毒素的2-3摩尔加入所述染料并且使其在黑暗中在室温下温育2小时。使用Slide-A-Lyzer透析盒(Pierce)纯化IRDye 700DX-氯代毒素以除去未缀合的游离染料。
氯代毒素(CLTX)是在Leiurusquinquestriatu的毒液中发现的36个氨基酸肽。它可以阻断小-电导氯化物通道。还证实该分子结合膜联蛋白A2受体并且对MMP-2酶活性具有双重作用。
(Affibody,Solna Sweden)亲和配体被描述为具有优良特征的抗体模拟物。它们约为6kDa大小且无Fc功能。Affibodies还并入了AlbumodTM技术,该技术可以通过强力结合白蛋白而延长其循环半衰期。商购的分子包括抗-EGFR抗-ErbB2抗-纤维蛋白原抗-胰岛素抗-TNFα抗-转铁蛋白等。
用700Dx标记CLTX的方法与用800CW标记CLTX的方法类似(Kovar等人,Anal i,2013,440(2):212-9)。这种基础结构未改变且发生与暴露的赖氨酸残基结合。D/P比为~2。进行稀释并且在双-Tris甘氨酸凝胶上运行以便显影。据估计标记的分子的总大小约为5950MW。
为了处理研究,准备HTB-186细胞(促结缔织增生性小脑髓母细胞瘤细胞系)并且在平皿上铺板。将细胞在37℃、5%CO2温育过夜。用相应的探针和照射水平的处理呈现在表5中。处理剂量为10μl/500μl板。将所述探针在37℃、5%CO2下在细胞上温育约5小时。
表5.处理条件
# | 探针 | 照射 |
1 | 对照:无探针 | 无照射 |
2 | 对照:无探针 | 32J/cm<sup>2</sup> |
3 | CLTX-700DX(0.2μg/m1) | 无照射 |
4 | CLTX-700DX(0.2μg/ml) | 16J/em<sup>2</sup> |
5 | CLTX-700DX(0.2μg/ml) | 32J/cm<sup>2</sup> |
在照射后几个时间点,使用落射荧光显微镜评估细胞的形态改变。在与探针一起处理后和照射前使处理成像以便记录形态。此外,细胞是在如下时间点的图像:照射后即刻、1h、2h和24h。
温育和照射前即刻来自处理(处理1-5)的细胞在外观上是健康的。在任意处理中均未检测到细胞形态改变。接受探针的那些处理(处理3-5)显示所述探针并入细胞的类似斑点。700nm图像显示所述探针通过细胞吞噬被摄入细胞。
对于所有处理,包括接受照射(处理2、4和5)的那些,照射后即刻,细胞形态仍然保持健康。在700nm通道中捕捉到的信号显示所述探针强度在接受探针的细胞中类似(处理3、4和5)。
在照射后2h,所述探针的斑点模式保持与接受无照射的处理(处理3)的起始图像相比无改变。然而,对于接受最高水平照射的处理5检测到改变。斑点模式显示更明亮且多数在胞内定位。处理5的细胞形态与其它处理相比保持正常。
照射后24小时,在2h时注意到的在700nm信号中的可辨别的改变显然更为显著。来自所述探针的明亮信号目前定位于细胞内部并且是在一些情况中,特别是在细胞区域中。此外,还检测到预示发生细胞凋亡的细胞的特征性起泡和圆形外观。
在照射后2小时以上之后细胞起泡的外观启示该细胞发生细胞凋亡,而非在较快期限时发生的坏死。例如,对于光动量抗体探针的坏死响应发生在照射后15分钟内。
为了进一步研究700Dx小分子探针的亚细胞定位,我们使用荧光细胞器特异性染料以便寻找共区域化。我们使用对线粒体具有特异性的Green,以便测定CLTX-700DX位置上的所述探针在线粒体处的摄入。将HTB-186细胞在平皿中的玻璃盖玻片上铺板,并且使其在完全培养基中平衡24h。将细胞与CLTX-700DX一起温育4-5h,此后,以32J/cm2照射细胞。将板在37℃5%CO2再温育24h。用Green、根据制造商的说明将细胞处理45min。柔和地冲洗细胞并且与DAPI一起温育15min以便染色核。再进行冲洗并且在包含FluoromountTM培养基的载玻片上固定盖玻片。进行显微镜检查成像以便记录荧光团和探针的位置。
显微镜检查分析揭示出,CLTX-700DX探针不位于线粒体或核中。在温育后4-5小时显影的所述探针的斑点模式显示所述探针通过细胞吞噬被细胞摄入。
为了处理研究,将A431细胞(表皮样癌细胞系)接种在平皿中的盖玻片上并且温育24h。将细胞在37℃、5%CO2下温育。用相应的探针和照射水平处理呈现在表6中。处理剂量为10μl/500μl板。将所述探针在37℃、5%CO2下在细胞上温育约4-5小时。冲洗细胞并且在如上所示的水平下照射。将平皿放回到温育箱中直到24h。
表6.处理条件
在照射前且然后在照射后1h、2h和24h俘获图像,以便追踪预示细胞凋亡或坏死的任何形态改变。
对于无探针的对照(处理1和2)未检测到形态改变。在照射后1h,在处理4的细胞中可见细胞变圆和皱缩并且在处理5的细胞中达到更大的程度。处理3的细胞中所述探针的细胞表面定位与处理4和5的细胞中的定位相比是不同的。在这两种处理中,所述探针定位于细胞的更分散的位置。所述探针的定位直接或间接归因于改变的细胞形状或为细胞凋亡的结果。
在照射后2h,处理4和5的细胞保持圆形并且开始显示出作为细胞凋亡标志的起泡。处理5的细胞还显示与早期时间点和其它处理的细胞相比健康程度较低。
在照射后24h,处理1、2和3均显示正常外观。在不接受所述探针(处理2)的细胞中未检测到照射(32J/cm2)的作用。此外,在无照射的情况下未检测到探针对细胞的作用(处理3)。
处理4的细胞在外观和形态上表现出与在照射后2h的早期时间点时类似。数据启示细胞启动程序性细胞死亡途经并且未发展成晚期细胞凋亡。一些细胞显示具有正常、健康的形态,这启示处理4的处理条件是不到致死量的。
接受更高水平照射(32J/cm2)的处理5的细胞表现出完全的细胞破碎和显著的形态改变,这显然与在用700DX标记的抗体处理的细胞中观察到的结果类似。使用这些处理未观察到健康细胞。应当注意到,需要比700DX标记的抗体更长(更多时间)时间700DX标记的小分子探针才能杀伤细胞。由于细胞凋亡在更长时间期限内发生,所以显然700DX标记的小分子探针诱导细胞凋亡且700DX标记的抗体诱导坏死。
为了进一步研究700DX抗-EGFR的亚细胞定位,我们使用如上所述的Green。将A431细胞在平皿中的玻璃盖玻片上铺板,并且使其在完全培养基中平衡24h。将细胞与700DX抗-EGFR一起温育4-5h,此后,照射细胞(32J/em2)。将板在37℃5%CO2再温育24h。用Green、根据制造商的说明将细胞处理45min。柔和地冲洗细胞并且与DAPI一起温育15min以便染色核。再进行冲洗并且在包含FluoromountTM培养基的载玻片上固定盖玻片。通过落射荧光显微镜检查检测荧光团和探针。700DX抗-EGFR未定位于线粒体或核中。
本实施例示例700DX小分子缀合物诱导细胞、例如癌细胞中细胞凋亡的能力。本研究中,用700DX小分子缀合物(700DX标记的氯代毒素、RGD肽和EGF配体)处理HTB-186细胞(促结缔织增生的小脑髓母细胞瘤细胞系)。通过评价半胱氨酸天冬氨酸蛋白酶3/7活性和线粒体膜电位确定细胞凋亡。细胞凋亡的特征可以在于各种细胞形态和生物化学改变,包括膜起泡、细胞皱缩、膜不对称性和渗透性改变和/或染色质和核融合(Coleman等人,Nat Cell Biol,2001,3(4):339-45,Bortner和Cidlowski,BiochemPharmacol,1998,56(12):1549-59;van Engeland等人,ExperimentalCellResearch,1997,235:421-430)。
氯代毒素(CLTX)是全蝎来源的肽(36-氨基酸肽),其可以特异性地结合至脑的肿瘤细胞表面。可以结合至人EGFR。RGD或精氨酰基甘氨酰基天冬氨酸(arginylglycylaspartic acid)是由精氨酸-甘氨酸-天冬氨酸组成的三肽。EGF配体是54个氨基酸的具有约6.2kDa分子量的多肽。
表7.治疗条件
# | 探针 | 照射 |
1 | 对照:无探针 | 无照射 |
2* | 对照:无探针 | 32J/cm<sup>2</sup> |
3* | 对照 | 无照射 |
4 | CLTX-700DX | 16J/cm<sup>2</sup> |
5 | CLTX-700DX | 32J/cm<sup>2</sup> |
6* | 700DX-Affy探针* | 32J/cm<sup>2</sup> |
7 | 700DX-RGD(500nM) | 32J/cm<sup>2</sup> |
8 | 700DX-EGF(500nM) | 32J/cm<sup>2</sup> |
*表示因技术误差被视为阴性对照的治疗。
实验方法:
(1)在37℃、5%CO2下与指定的探针一起温育相应处理约5小时。
(2)在完全培养基中冲洗细胞以除去未结合的探针并且加入新鲜培养基。
(3)然后照射细胞至上表7中所示的特定水平。
(4)将平皿在37℃、5%CO2下温育过夜。
(5)在照射后20小时使培养物成像并且准备进一步分析:线粒体电位研究(JC-1)和使用用于NC-3000TM (ChemoMetec A/S;Allerod,Denmark)的方案的半胱氨酸天冬氨酸蛋白酶3/7试验。
在本研究中,对来自处理1-8的细胞进行线粒体膜电位试验,以便确定处理的细胞是否发生细胞凋亡。膜渗透性JC-1染料常用作细胞中线粒体膜电位的指示剂。在细胞凋亡过程中,线粒体发生改变,例如膜电位的改变,改变至细胞器的氧化-还原电位且破碎。线粒体膜电位指示剂染料例如荧光JC-1染料带正电荷且可以蓄积在线粒体的负电性内部。当JC-1染料蓄积在线粒体中时,其荧光发射从绿色(约529nm)转移至红色(约590nm)。归因于JC-1聚集物形成的红色荧光存在相当于高线粒体极化区。去极化的线粒体由JC-1单体的绿色荧光指示。在红色/绿色荧光强度比中可检测到的减小表明线粒体去极化和由此的细胞凋亡。在膜电位试验中,将细胞与JC-1染料一起温育并且通过例如流式细胞术、荧光显微镜和基于荧光的图像细胞测量术检测荧光。
半胱氨酸天冬氨酸蛋白酶3/7试验用于测定来自上述列出的处理中的细胞中的半胱氨酸天冬氨酸蛋白酶3/7活性。在细胞凋亡过程中,半胱氨酸天冬氨酸蛋白酶、包括半胱氨酸天冬氨酸蛋白酶3和7被活化,且可以裂解特异性肽底物。用于本研究的半胱氨酸天冬氨酸蛋白酶3/7试验包括包含用于半胱氨酸天冬氨酸蛋白酶3/7的切割位点的细胞-渗透性底物。该底物保持无荧光,直到半胱氨酸天冬氨酸蛋白酶3或半胱氨酸天冬氨酸蛋白酶7在凋亡细胞中被活化。在活化时,半胱氨酸天冬氨酸蛋白酶切割底物且由此发射荧光信号。具有活化的半胱氨酸天冬氨酸蛋白酶3/7的凋亡细胞发出荧光,而不具有活化的半胱氨酸天冬氨酸蛋白酶3/7的细胞表现出最低或背景荧光。例如,可以通过流式细胞术、荧光显微镜检查和基于荧光的图像细胞测量术检测荧光。
在照射后20h俘获平皿中的细胞的显微镜检查图像。用DIC和700nm捕捉图像以使所述探针显影,且生成复合图像(DIC+700nm)以使覆盖物显影。
DIC图像提供细胞健康和用于比较的一般生长模式的良好的有代表性的示意图。在前3种处理(处理1-3)中,几乎未观察到总体细胞形态差异或无差异。细胞显然是非常健康的。对于在700nm图像中的这些处理未观察到信号。我们还检测到照射(光暴露)对未用700DX探针处理的细胞(处理2)无作用。
在处理4和5中,将CLTX-700DX探针与细胞一起温育并且使细胞暴露于16J/cm2或32J/cm2的光。接受较低水平照射(处理4)的细胞显示与接受较高水平的那些细胞(处理5)相比几乎无细胞形态改变。在较高照射水平下,观察到明显不同的形态模式。例如,处理5的细胞具有较为圆形的形状,表现出细胞皱缩,并且显然脱离板。这些细胞还表现出缩合的和交叉通过板的更为不连续的模式。
处理6-8代表3种不同的上述700DX-标记的小分子靶向剂。处理6的结果显示700DX-Affy探针可能降解,这归因于在检测700nm信号时,观察到活性剂几乎不结合。或者,这可以归因于所述探针的浓度不足以启动细胞毒性作用。这可以解释在照射时无作用,正如通过健康外观的细胞所注意到的那样。
在用700DX-RGD(处理7)、700DX-EGF(处理8)和CLTX-700DX(处理5)处理的细胞中观察到类似的细胞形态。照射后20小时,这些细胞与对照处理细胞相比显然时更为圆形和较小。此外,几乎没有细胞粘附板。此外,在处理5、7和8的细胞内部检测到所述探针。细胞的700nm图像揭示出斑点模式。结果显示700DX-标记的小分子探针被细胞摄入,且在照射时,处理的细胞发生细胞死亡。
为了确定处理的细胞是否发生细胞凋亡,进行半胱氨酸天冬氨酸蛋白酶3/7试验和线粒体电位试验。回收来自每种处理的全部细胞并且因此加工处理。下表8提供如通过半胱氨酸天冬氨酸蛋白酶3/7试验测定的细胞数量、%存活、JC-1%转移和%晚期细胞凋亡和死亡细胞。
表8.来自半胱氨酸天冬氨酸蛋白酶3/7试验和JC-1线粒体膜电位试验的结果
*表示处理因技术误差被视为阴性对照。
处理1的细胞显然是形态正常的和健康的,且细胞存活率高(90.3%)。处理2、3和6被视为对照,这归因于不存在探针(处理2和3)或无效探针浓度(处理6)。这些处理具有最高的活细胞百分比,即大于90%的存活率。
基于半胱氨酸天冬氨酸蛋白酶3/7试验,700DX-标记的小分子(CLTX-700DX、700DX-RGD和700DX-EGF)产生晚期细胞凋亡+死亡细胞的最高百分比(处理5、7和8)。数据还显示在用CLTX-700DX处理的细胞中,较高量的光暴露(32J/cm2对16J/cm2)诱导较高百分比的半胱氨酸天冬氨酸蛋白酶-3阳性细胞(59%对32%)和进行JC-1转移的细胞(44%对37%)。类似的结果还在使用700DX-RGD或700DX-EGF处理并暴露于32J/cm2的细胞中观察到。结果显示对用700DX-标记的小分子探针处理的细胞实施光动力疗法发生程序性细胞死亡,即细胞凋亡。
如上所述,JC-1信号的转移表明线粒体去极化,这表示细胞处于细胞凋亡的早期阶段。表8中提供的数据显示小于35%的细胞显示出在对照处理(处理1、2、3和6)中JC-1转移。相反,接受700DX-标记的小分子探针和以16或32J/cm2照射的至少37%的细胞显示出JC-1转移。换句话说,来自处理4、5、7和8处理的高于另外处理(处理1-3和6)的百分比的细胞发生细胞凋亡,正如根据半胱氨酸天冬氨酸蛋白酶3/7活性和线粒体膜电位所确定的。总之,本实施例示例700DX-标记的小分子探针被细胞摄入,并且在照射时,细胞发生细胞凋亡,而不是坏死。
光动力治疗(PDT)例如摄入IRDye 700DX-标记的小分子、然后照射诱导单态氧和超氧化物产生。该反应可以影响细胞的内部结构,例如线粒体膜,且由此影响线粒体膜电位。此外,光动力治疗还可以诱导蛋白酶半胱氨酸天冬氨酸蛋白酶活化。这些对于处理细胞的改变表明使用小分子探针的光动力疗法可以诱导细胞凋亡。
实施例11.单态氧的产生
评价用于使用单态氧绿色传感器(Singlet Oxygen Green Sensor(LifeTechnologies))生产单态氧的染料和缀合的探针(IRDye 700DX羧酸盐(700DX)、EGF、RGD和IgG缀合物)并且通过稳态荧光计(ex 504nm/em 525nm)测定。包括对照品(水或DMEM培养基)和亚甲蓝(MB)阳性对照。对于MB和全部700DX缀合物注意到3-至4-倍的增加。当将单态氧叠氮化钠(叠氮化物)清除剂加入到亚甲蓝或700DX中时,注意到荧光减少。这些数据证实在使用适合的光暴露(690nm)照射后,700DX和所述缀合物产生单态氧是存在的。
测定每隔1秒进行1次,持续30秒,并且取平均值。结果如图16中所示。溶液组成:SOGS(1μM)、染料或探针添加(10μM)、Tris pH 7.5(50uM)和氧化氘(50%)。光暴露=32J/cm2。
尽管为清楚理解的目的通过示例和实施例在一定程度上详细描述了上述发明,但是本领域技术人员可以理解,可以在待批权利要求范围内实施一些改变和变型。此外,将本文提供的每篇参考文献以其完整的形式并入作为参考,其程度与将每篇参考文献各自并入作为参考相同。
非正式序列表
SEQ ID NO:1
EGF
NSDSECPLSHDGYCLHDGVCMYIEALDKYACNCVVGYIGERCQYRDLKWWELR
SEQ ID NO:2
TNFR1抑制剂肽
YCWSQYLCY
SEQ ID NO:3
血管活性肠肽
HSDAVFTDNYTRLRKQMAVKKYLNSILN
SEQ ID NO:4
铃蟾肽
Pyr-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met
SEQ ID NO:5
物质P
RPKPQQFFGLM
SEQ ID NO:6
SPARC肽
CFGIKQKDIDKDLVI
SEQ ID NO:7
奥曲肽
H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr(ol)
SEQ ID NO:8
毒蜥外泌肽-4
HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2
SEQ ID NO:9
SOR-C13
KEFLHPSKVDLPR
SEQ ID NO:10
SOR-C27
EGKLSSNDTEGGLCKEFLHPSKVDLPR
SEQ ID NO:11
soricidin
DCSQDCAACSILARPAELNTETCILECEGKLSSNDTEGGLCKEFLHPSKVDLPR
SEQ ID NO:12
氯代毒素(CLTX)
MCMPCFTTDHQMARKCDDCCGGKGRGKCYGPQCLCR-NH2
SEQ ID NO:13
序列表
<110> 乐天医药生技股份有限公司
<120> 酞菁探针及其用途
<130> 85409-946834
<140> PCT/US2015/033759
<141> 2015-06-02
<150> US 62/006,790
<151> 2014-06-02
<150> US 62/017,165
<151> 2014-06-25
<150> US 62/066,807
<151> 2014-10-21
<150> US 62/082,052
<151> 2014-11-19
<160> 13
<170> PatentIn version 3.5
<210> 1
<211> 53
<212> PRT
<213> 人工序列
<220>
<223> 合成的表皮生长因子
<400> 1
Asn Ser Asp Ser Glu Cys Pro Leu Ser His Asp Gly Tyr Cys Leu His
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Asp Gly Val Cys Met Tyr Ile Glu Ala Leu Asp Lys Tyr Ala Cys Asn
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Cys Val Val Gly Tyr Ile Gly Glu Arg Cys Gln Tyr Arg Asp Leu Lys
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Trp Trp Glu Leu Arg
50
<210> 2
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成的构建体, WP9QY, TNF - α拮抗剂
<400> 2
Tyr Cys Trp Ser Gln Tyr Leu Cys Tyr
1 5
<210> 3
<211> 28
<212> PRT
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<223> 合成的血管活性肠肽(VIP)
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His Ser Asp Ala Val Phe Thr Asp Asn Tyr Thr Arg Leu Arg Lys Gln
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Met Ala Val Lys Lys Tyr Leu Asn Ser Ile Leu Asn
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<211> 14
<212> PRT
<213> 铃蟾
<220>
<221> 变体
<222> (1)..(1)
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Xaa Gln Arg Leu Gly Asn Gln Trp Ala Val Gly His Leu Met
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<210> 5
<211> 11
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<213> 智人
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Arg Pro Lys Pro Gln Gln Phe Phe Gly Leu Met
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<223> 合成的构建体, 奥曲肽
<220>
<221> 变体
<222> (1)..(1)
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<220>
<221> 变体
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<210> 13
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000
Claims (49)
2.权利要求1的方法,其中所述疾病或病症选自血管疾病、癌症、由细菌生物膜导致的感染、抗生素抗性伤口感染、光化性角化病、酒渣鼻、痤疮和银屑病。
3.权利要求2的方法,其中所述血管疾病是湿型年龄相关性黄斑变性。
4.权利要求1的方法,其中所述癌症选自乳腺癌、结直肠癌、食管癌、肺癌、前列腺癌、宫颈癌、卵巢癌、胃癌、胰腺癌、肝癌、膀胱癌、脑癌、头颈癌、神经内分泌癌、皮肤癌及其组合。
5.权利要求1的方法,其中所述受试者具有实体瘤或已经具有实体瘤。
6.权利要求5的方法,其中所述细胞在实体瘤中或在受试者血液中。
7.权利要求1的方法,其中所述激发光具有660-740nm的波长。
8.权利要求1的方法,其中所述探针选自配体、肽、小分子及其组合。
9.权利要求8的方法,其中所述探针具有小于约50kDa的分子量。
10.权利要求8的方法,其中所述探针具有小于约10kDa的分子量。
11.权利要求8的方法,其中所述配体是EGF。
12.权利要求8的方法,其中所述肽选自YC-27、cRGDfK、血管活性肠肽、胃泌素释放肽、神经降压肽、AH111585、FPPRGD2、PK11195、SPARC、铃蟾肽、神经降压肽、物质P、生长抑素、胆囊收缩素、胰高血糖素样肽-1、神经肽Y、奥曲肽、DOTA-TOC、DOTA-TATE、毒蜥外泌肽-4、其类似物、其衍生物及其组合。
13.权利要求8的方法,其中所述肽选自soricidin、SOR-13和SOR-C27。
14.权利要求8的方法,其中所述小分子选自VEGFR抑制剂、TNFR1抑制剂、生长因子受体抑制剂及其组合。
15.权利要求14的方法,其中所述小分子VEGFR抑制剂选自帕唑帕尼、司马沙尼、阿昔替尼、卡博替尼、阿柏西普、布立尼布、tivozanib、雷莫芦单抗、莫替沙尼、伐他拉尼、西地尼布及其组合。
16.权利要求1的方法,其中所述探针与放射性核素缀合。
17.权利要求16的方法,其中所述探针是选自DTPA-奥曲肽、[Gluc-Lys]-TOCA、半乳糖-RGD、AH111585、RGD-K5、FPPRGD2、RP-527、BZH3、[DTPA-Lys40]-毒蜥外泌肽-4和Tc-NT-X1的成员。
18.权利要求1的方法,其中所述探针与荧光团缀合。
19.权利要求1的方法,其中施用步骤(a)包含将治疗有效剂注入受试者血液。
20.权利要求1的方法,其中照射步骤(b)包含使用包含近红外(NIR)光发射二极管的装置。
21.权利要求1的方法,还包含对所述受试者施用抗癌药。
23.权利要求22的方法,其中所述实体瘤选自乳腺肿瘤、结直肠肿瘤、肺肿瘤、前列腺肿瘤、卵巢肿瘤、胃肿瘤、胰腺肿瘤、肝肿瘤、膀胱肿瘤、脑瘤、神经内分泌瘤及其组合。
24.权利要求22的方法,其中所述激发光具有660-740nm的波长。
25.权利要求22的方法,其中所述探针选自配体、肽、小分子及其组合。
26.权利要求25的方法,其中所述探针具有小于约50kDa的分子量。
27.权利要求25的方法,其中所述探针具有小于约10kDa的分子量。
28.权利要求25的方法,其中所述配体是EGF。
29.权利要求25的方法,其中所述肽选自YC-27、cRGDfK、血管活性肠肽、胃泌素释放肽、神经降压肽、AH111585、FPPRGD2、PK11195、SPARC、铃蟾肽、神经降压肽、物质P、生长抑素、胆囊收缩素、胰高血糖素样肽-1、神经肽Y、奥曲肽、DOTA-TOC、DOTA-TATE、毒蜥外泌肽-4、其类似物、其衍生物及其组合。
30.权利要求25的方法,其中所述肽选自soricidin、SOR-13和SOR-C27。
31.权利要求25的方法,其中所述小分子选自VEGFR抑制剂、TNFR1抑制剂、生长因子受体抑制剂及其组合。
32.权利要求31的方法,其中所述小分子VEGFR抑制剂选自帕唑帕尼、司马沙尼、阿昔替尼、卡博替尼、阿柏西普、布立尼布、tivozanib、雷莫芦单抗、莫替沙尼、伐他拉尼、西地尼布及其组合。
33.权利要求22的方法,其中所述探针与放射性核素缀合。
34.权利要求33的方法,其中所述探针是选自DTPA-奥曲肽、[Gluc-Lys]-TOCA、半乳糖-RGD、AH111585、RGD-K5、FPPRGD2、RP-527、BZH3、[DTPA-Lys40]-毒蜥外泌肽-4和NT-X1的成员。
35.权利要求22的方法,其中所述探针与荧光团缀合。
36.权利要求22的方法,其中照射包含使用包含近红外(NIR)光发射二极管的装置。
37.权利要求22的方法,还包含对所述受试者施用抗癌药。
38.治疗有效量的组合物,其包含与特异性地结合受试者的癌细胞的与探针缀合的酞菁染料,其中所述探针具有小于约50kDa的分子量。
39.权利要求38的组合物,其中所述探针小于约10kDa。
40.权利要求38的组合物,其中所述探针选自配体、肽、小分子及其组合。
41.权利要求40的组合物,其中所述配体是EGF。
42.权利要求40的组合物,其中所述肽选自YC-27、cRGDfK、血管活性肠肽、胃泌素释放肽、神经降压肽、AH111585、FPPRGD2、PK11195、SPARC、铃蟾肽、神经降压肽、物质P、生长抑素、胆囊收缩素、胰高血糖素样肽-1、神经肽Y、奥曲肽、DOTA-TOC、DOTA-TATE、毒蜥外泌肽-4、其类似物、其衍生物及其组合。
43.权利要求40的组合物,其中所述肽选自soricidin、SOR-13和SOR-C27。
44.权利要求40的组合物,其中所述小分子选自VEGFR抑制剂、TNFR1抑制剂、生长因子受体抑制剂及其组合。
45.权利要求44的组合物,其中所述小分子VEGFR抑制剂选自帕唑帕尼、司马沙尼、阿昔替尼、卡博替尼、阿柏西普、布立尼布、tivozanib、雷莫芦单抗、莫替沙尼、伐他拉尼、西地尼布及其组合。
46.权利要求38的组合物,其中所述探针与放射性核素缀合。
47.权利要求46的组合物,其中所述探针是选自DTPA-奥曲肽、[Gluc-Lys]-TOCA、半乳糖-RGD、AH111585、RGD-K5、FPPRGD2、RP-527、BZH3、[DTPA-Lys40]-毒蜥外泌肽-4和NT-X1的成员。
48.权利要求38的组合物,其中所述探针与荧光团缀合。
49.权利要求40的组合物,其中所述肽是氯代毒素。
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Cited By (2)
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CN113512089A (zh) * | 2021-06-30 | 2021-10-19 | 兰州大学 | 一种水溶性量子点的多肽稳定剂及应用 |
CN113512089B (zh) * | 2021-06-30 | 2023-06-13 | 兰州大学 | 一种水溶性量子点的多肽稳定剂及应用 |
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US20150374819A1 (en) | 2015-12-31 |
US20150343084A1 (en) | 2015-12-03 |
CN106573054B (zh) | 2021-04-13 |
EP3148583A4 (en) | 2018-01-17 |
JP2020125343A (ja) | 2020-08-20 |
EP3148583A1 (en) | 2017-04-05 |
CN106573054A (zh) | 2017-04-19 |
JP6741599B2 (ja) | 2020-08-19 |
US20200179514A1 (en) | 2020-06-11 |
CA2950299A1 (en) | 2015-12-10 |
AU2015271830A1 (en) | 2016-12-22 |
JP2017524659A (ja) | 2017-08-31 |
WO2015187677A1 (en) | 2015-12-10 |
US10588972B2 (en) | 2020-03-17 |
US20180339048A1 (en) | 2018-11-29 |
EP3718570A1 (en) | 2020-10-07 |
US20150343060A1 (en) | 2015-12-03 |
AU2015271830B2 (en) | 2020-03-05 |
US10064943B2 (en) | 2018-09-04 |
JP2022023175A (ja) | 2022-02-07 |
WO2015187651A1 (en) | 2015-12-10 |
EP3148583B1 (en) | 2020-04-29 |
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