CN102264396A - Hpma-多西他赛或吉西他滨缀合物及其用途 - Google Patents
Hpma-多西他赛或吉西他滨缀合物及其用途 Download PDFInfo
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- CN102264396A CN102264396A CN2009801488749A CN200980148874A CN102264396A CN 102264396 A CN102264396 A CN 102264396A CN 2009801488749 A CN2009801488749 A CN 2009801488749A CN 200980148874 A CN200980148874 A CN 200980148874A CN 102264396 A CN102264396 A CN 102264396A
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Abstract
本发明公开了通过将吉西他滨或多西他赛缀合到水溶性聚合物(例如N-2-羟丙基异丁烯酰胺(HPMA))上而形成的吉西他滨和多西他赛水溶性组合物。本发明还公开了使用本发明组合物治疗癌症的方法。
Description
技术领域
本发明涉及包含抗癌剂(例如吉西他滨或多西他赛)和/或靶向配体(例如RGDfK、EPPT1肽或叶酸)与N-(2-羟丙基)异丁烯酰胺(HPMA)之缀合物的组合物,以及利用所述组合物将这些缀合物递送至细胞的方法。
背景技术
多西他赛(泰索帝(Taxotere))是最重要的一类新型肿瘤药物的成员之一。然而,其差的溶解性提出了药学上的挑战,且新出现的数据表明了特定的组织暴露特性(例如延长时间的低药物浓度)可增强有益的抗肿瘤机制。由于多西他赛主要的缺点在于其高度亲脂并且几乎不溶于水,因此配制多西他赛制剂所考虑的因素已被广泛地研究。为了临床使用,在共溶剂体系中将其配制和施用。将药物在聚山梨酯-80(USPDI)中以40mg/ml包装。使用前,使用包含13%(V/V)乙醇的水溶液将其稀释到10mg/ml。施用前,将药物在250ml盐水或葡萄糖中进一步稀释,达到0.3-0.9mg/L的终浓度。所述溶液在4小时内使用。一些明显的特有副作用与多西他赛制剂相关。延缓发生的胸腔积液和水肿已在一些病例导致中止治疗。由于与施用紫杉烷(taxane)所需的共溶剂相关的毒性,已经研究了多种替代性的多西他赛组合物,其包括合成多西他赛类似物、包埋到脂质体中和制备聚合物-多西他赛缀合物。关于制备聚合物-多西他赛缀合物,已经提出了一些聚合物,包括聚氨基酸(WO2007/067417)和合成聚合物(例如聚乙二醇(PEG))。
在过去几年中,吉西他滨(Gemzar,一种新嘧啶核苷类似物)已经成为用于胰腺癌患者的标准化疗剂。胰腺腺癌是美国癌症死亡的第四大原因。全国每年新诊断28,000例病例。化学疗法和放射疗法在很大程度上无效,甚至在可能为治愈性的手术后也频繁发生肿瘤转移性疾病。该癌症的1年生存率为20%,5年生存率只有1-3%。不多于25%的胰腺癌患者将受益于吉西他滨。很明显,迫切需要对该破坏性疾病的有效治疗。为了提高吉西他滨在癌症患者中的益处,在本发明中首次公开了聚合物-吉西他滨缀合物的新制剂。
基于上述内容,现有技术中仍然需要对多西他赛和吉西他滨的修饰,所述修饰可保持或增加其肿瘤特异性活性,同时降低其毒性。
附图说明
图1为显示HPMA-GFLG-多西他赛(DOC)缀合物在皮下注射了Mia-Paca人胰腺癌细胞之裸鼠中对肿瘤生长的抑制作用的图。有效性表示为作为时间(天)之函数的肿瘤尺寸变化倍数。
图2为显示HPMA-GFLG-多西他赛(DOC)缀合物在皮下注射了HCT116人结肠癌细胞之裸鼠中对肿瘤生长的抑制作用的图。有效性表示为作为时间(天)之函数的肿瘤尺寸变化倍数。
图3为显示HPMA-GFLG-吉西他滨(GEM)缀合物在皮下注射了HCT116人结肠癌细胞之裸鼠中对肿瘤生长的抑制作用的图。效力表示为作为时间(天)之函数的肿瘤尺寸变化倍数。“GFLG”如SEQ ID NO:1所公开。
发明内容
本发明涉及抗癌剂(例如吉西他滨或多西他赛)和/或靶向配体(例如RGDfK、EPPT1肽或叶酸)与水溶性聚合物聚N-(2-羟丙基)异丁烯酰胺(HPMA)的缀合物,以及这些缀合物作为多西他赛或吉西他滨的特异性细胞内载体进入肿瘤血管内的用途。本发明还涉及这些缀合物降低多西他赛或吉西他滨的毒性的用途以及治疗癌症的方法。
在一个实施方案中,所述抗癌剂是多西他赛或吉西他滨。
在另一个实施方案中,组合物还包含溶酶体可降解的氨基酸序列和寡肽,其包括但不限于Gly-Phe-Leu-Gly(SEQ ID NO:1)、Gly-Ileu-Phe、Gly-Val-Phe、Gly-Gly-Phe、Gly-Gly-Phe-Phe(SEQ ID NO:2)、Gly-Ileu-Tyr、Phe、Gly、Gly-Gly、Ala、Ser、Gly-Phe、Gly-Leu-Phe、Gly-Phe-Phe、Gly-D-Phe-Phe、Ala-Gly-Val-Phe(SEQ ID NO:3)、Gly-Gly-Val-Phe(SEQ ID NO:4)、Gly-Phe-Tyr、Gly-B-Ala-Tyr、Gly-Lue、Gly-Phe-Gly、His-Ser-Ser-Lys-Leu-Gln(SEQ ID NO:5)以及戊二酰-4-羟脯氨酰-Ala-Ser-环六甘氨酰-Gln-Ser-Leu(SEQ ID NO:6)。
在另一个实施方案中,所述组合物包含HPMA共聚物-多西他赛或HPMA共聚物-吉西他滨的靶向肽,例如RGDfK、EPPT1肽或叶酸。在此情况下,所述靶向系统包括将靶向配体(例如RGDfK、EPPT1肽或叶酸)共价连接于所述聚合物。
在本发明的又一个实施方案中,包含重均分子量(MW)范围在从约10kDa到约250kDa、从约20kDa到约170kDa、从约50kDa到约250kDa、或从约100kDa到约170kDa的HPMA共聚物-药物缀合物。本发明的另一些实施方案包含重均分子量(MW)至少约20kDa、至少约50kDa、至少约100kDa、至少约125kDa或至少约150kDa的HPMA共聚物-药物缀合物。
因此,在某些实施方案中,本发明的特征在于具有或不具有靶向配体的高分子量HPMA共聚物-药物缀合物。高分子量HPMA共聚物-药物缀合物提供了未被当前药物聚合物缀合物所启示的优势。例如,高分子量HPMA共聚物-药物缀合物具有更长的血浆半衰期(t1/2),致使在血流中循环时间更长。因为聚合物的链更长,所以即使药物掺入具有相似的程度,也有更多的药物连于每一条聚合物链上。因此,使用高分子量HPMA共聚物-药物缀合物可提供将更大量药物递送到肿瘤部位。
进一步,将靶向配体或部分连接到聚合物-药物缀合物上导致药物对肿瘤细胞的特异性增强。在一些实施方案中,所述靶向配体可为RGDfK、EPPT1或叶酸。此效果与高分子量HPMA共聚物-药物缀合物的被动肿瘤聚积作用一起,通过增加肿瘤特异性、提高稳定性和降低毒性而产生高治疗效果。因此,该系统在递送用于癌症治疗的治疗剂方面具有巨大的潜力。
本发明的另一实施方案提供了递送治疗剂的方法,包括向对象施用有效剂量的与HPMA共聚物缀合的多西他赛或吉西他滨。
本发明的另一实施方案提供了使用包含与多西他赛或吉西他滨缀合的HPMA共聚物的组合物来递送治疗剂到细胞的方法。
发明的详细说明
下面详细地描述本发明的实施方案。在描述实施方案时,出于清楚的目的,使用特定术语。然而,本发明不意在限于所选择的特定术语。当讨论具体的示例性实施方案时,应当理解这样做仅仅是为了说明意图。相关领域的技术人员将认识到,在不背离本发明的精神和范围的情况下,也可使用其他的组分和结构。本文中引用的所有参考文献通过引用并入本文,如同其各自均单独并入本文中一样。
A.基于聚合物的治疗法
游离的抗癌药物扩散在整个细胞中,而不能集中到特定的亚细胞部位。另外,如果这些药物通过静脉施用,则它们全身性地分布于身体的所有组织。这些药物在非目的分布部位的作用导致可观测的全身性副作用。因此,使药物定位于作用所需的身体部位是优选的。将这些药剂靶向至它们最有效的亚细胞部位,提高了它们的效力且降低了它们的毒性。
抗癌药物的肿瘤靶向可通过“被动靶向”和“主动靶向”来实现。被动靶向通过将抗癌药物掺入或连接于大分子载体(例如水溶性聚合物)上来实现。主动靶向通过掺入对癌细胞表面的识别分子(受体)具有特异性的细胞靶向部分来实现。
当与正常组织比较时,聚合物优先定位于实体瘤。这是由于被称为增强的渗透和驻留(Enhanced Permeability and Retention,“EPR”)效应而发生,该效应归因于肿瘤组织的形态学改变,其中由于新血管发生产生的有漏隙的血管系统导致血管内容物泄漏到细胞外组织中。另外,淋巴系统可被阻滞,其导致大分子药剂在肿瘤细胞周围的细胞外组织中聚积。可利用该现象将药物与聚合物连接而靶向肿瘤细胞。由于聚合物定位于肿瘤细胞周围,因此连接于聚合物的药物也可以更高的浓度围绕肿瘤周围。与聚合物连接的药物以内吞作用摄取到细胞内。然而,由于药物保持共价连接于聚合物骨架,因此它们可能不像游离药物一样有效。这可以通过使用可生物降解或可水解的肽序列将药物连接到聚合物骨架上来克服。选择序列使得它们能够在特定环境下在细胞内降解。
基于聚合物的治疗具有大的流体力学体积,其转化为更长的血管内半衰期。基于聚合物的治疗法还增大了难溶性药物的溶解度和生物利用度。由基于聚合物的治疗法所带来的其他优势包括最大耐受剂量增加、非特异性毒性降低、凋亡诱导作用增强和替代性信号途径的活化(Kopecek等,Advances in Polymer Science,122(Biopolymers II):55-123(1995))。
另外,肿瘤细胞常具有表面分子,所述表明分子或者在正常组织不具有,或者与正常组织相比过表达。这些可包括生长因子受体和/或某些抗原。将结合这些分子的识别分子与聚合物相连产生在肿瘤局部环境中的高浓度聚合物。这些靶向部分包括抗体和细胞表面受体的肽配体。由这些识别分子中的一些与其受体的结合所引发的受体介导的内吞作用可导致增加的细胞内浓度和相应的增强的治疗效果。
处于临床试验中的几种聚合物-药物缀合物包括基于HPMA-共聚物或基于PGA的缀合物。HPMA共聚物是生物相容的、非免疫原性且无毒的载体,其能够特异性递送入肿瘤细胞,克服药物相关毒性的限制(Duncan等,Hum.Exp.Toxicol.,17:93-104(1998))。此外,它们的体内分布得到了良好表征,且已知它们由于增强的渗透和驻留(EPR)而选择性地聚积在肿瘤部位。该缀合物也包括针对内皮细胞增殖部位或癌细胞或与增殖细胞相关的特异性受体或标记物的靶向配体。目前有两种聚谷氨酸-药物缀合物和六种HPMA共聚物-药物缀合物处在临床试验的不同阶段,且进一步地包括葡聚糖-药物缀合物和PEG-药物缀合物的聚合物-药物缀合物也报道处于临床或临床前开发中。
本发明的化合物具有这些属性,其增加抗癌剂的递送,此外,与其他抗癌药的策略相比,所公开的组合物增强对特定细胞类型的靶向和被靶向癌细胞的摄取。
B.化合物
本文中使用的术语“HPMA”表示化合物N-(2-羟丙基)异丁烯酰胺,为下述结构代表的亲水聚合物:
本发明的“抗癌剂”在特定的实施方案中是多西他赛或吉西他滨。
相比于其它HPMA-药物缀合物,本发明的优势在几个方面:
首先,本发明缀合物的分子量大于临床上评价的HPMA药物缀合物。已知的处于临床前或临床试验中的HPMA共聚物-药物缀合物的分子量为~25-50kDa,而本发明的某些实施方案涉及分子量为~100-170kDa的HPMA。分子量增加的HPMA缀合物具有更长的血浆驻留时间和通过增强的EPR而增加的被动肿瘤靶向。本发明的另一些实施方案的HPMA共聚物-药物缀合物的重均分子量(Mw)范围为约10kDa至约250kDa、约20kDa至约170kDa、约50kDa至约250kDa、或约100kDa至约170kDa。本发明的另一些实施方案包含至少约20kDa、至少约50kDa、至少约100kDa、至少约125kDa、或至少约150kDa的重均分子量(Mw)的HPMA共聚物-药物缀合物。高分子量药物-聚合物缀合物可利用本文中公开的合成方法获得。
除增加的循环时间外,使用高分子量缀合物还可提供对特定部位提高的药物递送。尤其是在药物掺入的程度(基于百分比或摩尔百分比)对低分子量和高分子量类型是相似的情况下,单个聚合物链将比更低分子量的链具有更高数量的药物分子。因此,当本应使用低分子量时使用高分子量链,更多药物将递送至特定部位或肿瘤。这使得显著更高局部浓度的药物出现在肿瘤周围。
第二,本发明的另一个新颖性在于制备包含肿瘤特异性靶向配体(例如RGDfK、EPPT1肽或叶酸)的第二代HPMA-多西他赛或吉西他滨缀合物。通常,被动靶向的HPMA缀合物在临床试验中成功的是少数,主要是由于药物仅通过被动扩散在实体瘤中聚积有限和临床上癌症的异质性。考虑到肿瘤生理学的变化,主动靶向策略允许靶向到多种细胞类型,在最大限度地分布于实体瘤的微环境中,同时使它们在其它器官中的非特异性摄取最小化。主动靶向策略还可以通过(1)增加肿瘤特异性;(2)改善药代动力学;和(3)降低毒性而显著提高治疗效率。近些年来已经出现了几个此类的策略,可利用此策略来显著改善抗肿瘤药的肿瘤定位。通过连接分子标记物(例如肽或抗体)实现的聚合物药物递送系统的主动靶向已经表现出显著改善肿瘤定位。
粘蛋白-1是一种在多数腺上皮细胞中表达的跨膜分子。几个重要的特性使得粘蛋白-1成为具有吸引力的肿瘤靶向递送的受体。
首先,粘蛋白-1在几乎所有的人类上皮细胞腺癌上过表达,包括90%的人乳腺癌、卵巢癌、胰腺癌、结肠直肠癌、肺癌、前列腺癌、结肠癌和胃癌。此外,粘蛋白-1的表达已在非上皮细胞癌细胞系(星形细胞瘤、黑色素瘤和神经细胞瘤)中得到证实,以及在恶性血液病例如多发性骨髓瘤和一些B细胞非何杰金氏淋巴瘤中得到证实,总共占人类中所有肿瘤的50%。
其次,在腺癌组织中,由于腺体结构的遗失,粘蛋白-1在整个细胞表面上普遍表达。由于其杆状结构,该分子在表面上伸出100-200nm,其为多数膜分子长度的5-10倍。该性质使得粘蛋白-1成为治疗探针可接近的靶点。
第三,尽管在正常组织中粘蛋白-1被严重糖基化(其分子量的50-90%是糖类),但粘蛋白-1在癌组织中被低糖基化。减少的糖基化作用允许免疫系统进入肿瘤相关的低糖基化粘蛋白-1抗原的肽核心,并显露出在正常细胞中被掩蔽的表位。该特性使设计区分正常细胞和腺癌细胞的探针成为可能。
第四,粘蛋白-1的胞外结构域(通过存在PDTRP(SEQ ID NO:7)序列而定义)伸出细胞表面,因此干涉肿瘤细胞表面上的粘附分子与其淋巴细胞上配体间的相互作用,使得肿瘤表位更难以被免疫识别。因此,肿瘤抗原没有应答于免疫治疗的下调趋势,且在肿瘤和肿瘤转移期间粘蛋白-1表达同样保持上调。这些特性在设计用于肿瘤进程不同阶段的靶向药物递送中是重要的。
许多研究已经关注于使用粘蛋白-1作为免疫治疗靶标的可能性。已生产了多种单克隆抗体来识别串联重复的免疫原性APDTRP(SEQ ID NO:8)序列。然而,当抗体用作靶向分子时,这些蛋白质的免疫原性和长血浆半衰期是有害的。因此,使用小肽可减少这些弊端,因为肽配体是非免疫原性的且对受体具有高亲和力和选择性。名为EPPT1(YCAREPPTRTFAYWG(SEQ ID NO:9)的合成肽已被开发作为特异性配体并且已表现出显著的亲和力(Kd=20μM)。用(99mTc)标记的EPPT1已被用于体内乳腺癌成像。以上列出的粘蛋白-1蛋白的所有特性使EPPT1成为用作肿瘤靶向配体的理想候选物。
还已鉴定出许多肿瘤细胞以及相关的血管特异性受体将肿瘤细胞与正常细胞区分开来。αVβ3整联蛋白是其中研究最多的一种且选择性地在与新生血管相关的肿瘤中和在一些转移性癌症中过表达(Felding-Habermann等,Clin.Exp.Metastasis,19:427-436(2002))。包含三肽序列Arg-Gly-Asp(RGD)的高亲和力αVβ3选择性配体已经通过噬菌体展示研究而被鉴定出来。构象受限的RGD序列(即环状RGD)包含二硫键且比线性RGD肽结合αVβ3的程度高20-40倍(Koivunen,E.,Wang,B.和Ruoslahti,E.,Biotechnology(N.Y.),13:265-270(1995))。已将RGD肽与阿霉素缀合(Arap,W.,Pasqualini,R.和Ruoslahti,E.,Science,279:377-380(1998))用于靶向化疗和靶向放疗(Capello,A.等,J.Nucl.Med.,45:1716-1720(2004))。它们已被缀合到人源化抗体、脂质体、聚乙二醇和HPMA共聚物上,来改善生物分布和增加肿瘤聚积和抗肿瘤效力。这些研究使得RGD成为研究抗肿瘤药物靶向的理想靶向配体。
叶酸,其盐,和/或其相应还原物(统称为“叶酸”)由于用于核苷酸碱基生物合成的一碳转移反应而被真核细胞所需要。叶酸的细胞摄取被身体许多细胞中存在的低亲和力的还原叶酸载体(Km~1μM)或者被表现出高度有限分布的高亲和力连接糖基磷酯酰肌醇的叶酸受体(FR)(KD=~100pM)所促进。FR在健康细胞上表现出有限的表达,但常大量存在于癌细胞上。例如,FR在卵巢、乳腺、结肠、肺、前列腺、鼻、咽喉和脑的上皮癌上过表达。FR还在骨髓源性造血系统恶性肿瘤(包括慢性和急性骨髓性粒细胞性白血病)上过表达。已经观察到在FR表达与肿瘤的分级和组织学阶段之间的强相关性。已经设计了多种叶酸连接的分子和复合物,其能够将药物选择递送到癌细胞的FR上并活化巨噬细胞。其他特性包括低分子量(MW 441),水溶性,对多种溶剂、pH和热的稳定性、化学上易于缀合,无免疫原性以及对其受体的高亲和力等使得叶酸成为有吸引力的用于药物靶向的配体。
本文中公开了可用于例如抗癌治疗的化合物。这些化合物通常增加或改变抗癌化合物或其它治疗化合物的靶向递送。这些化合物可包含抗癌剂、载体分子、任选的连接分子和任选的靶向配体。在某些实施方案中,所述连接剂可以是寡肽,例如Gly-Phe-Leu-Gly(SEQ ID NO:1)。在某些实施方案中,所述靶向配体可以是例如RGDfK、EPPT1或叶酸。
本文还公开了包含抗癌剂、载体分子、以及任选的连接分子和任选的靶向配体的化合物,其中所述抗癌剂、所述载体分子、所述连接分子和所述靶向配体通过一个或多个共价键相互连接。
所述抗癌剂、载体分子、任选的连接分子和任选的靶向配体可以有多种方式相互连接。在一些实施方案中,所述抗癌剂、载体分子、任选的连接分子和任选的靶向配体可直接相互连接。在另一些实施方案中,所述抗癌剂通过共价键或者通过连接分子连接到载体分子上。
在另一些实施方案中,连接分子通过共价键与载体分子直接连接,且所述抗癌剂与所述连接分子直接连接。
在另一些实施方案中,抗癌剂通过共价键与所述载体分子直接连接,且靶向配体通过共价键与所述载体分子直接连接。
在另一些实施方案中,连接分子通过共价键与所述载体分子直接连接,所述抗癌剂与所述连接分子直接连接,并且靶向配体通过共价键与所述载体分子直接连接。
在另一些实施方案中,连接分子通过共价键与所述载体分子直接连接,靶向配体与所述连接分子直接连接,并且抗癌剂通过共价键与所述载体分子直接连接。
在另一些实施方案中,连接分子通过共价键与所述载体分子直接连接,抗癌剂与所述连接分子直接连接,且靶向配体与不同的连接分子直接连接,所述不同的连接分子通过共价键与所述载体分子直接连接。
以下详述用于制备化合物的所述抗癌剂、载体分子、连接分子和靶向配体。
1.抗癌剂
抗癌剂意为可用于抗击癌症的任何药剂。可使用任何可与载体分子和/或连接分子直接或间接连接的抗癌剂。可与所公开的组合物一起使用的抗癌剂的部分清单可在例如美国专利5,037883中找到,其在此通过引用并入本文,并且其中所引用的包括抗癌剂的任何公开物和专利或专利申请也并入本文。美国专利6,348,209、6,346,349和6,342,221也描述了与抗癌化合物相关的试剂。抗癌剂的类别包括但不限于化疗剂、细胞毒素、抗代谢物、烷化剂、蛋白激酶抑制剂、蒽环类、抗生素、抗有丝分裂剂(例如抗微管蛋白剂)、皮质激素、放射性药物、和蛋白类(例如细胞因子、酶或干扰素)。具体的实例包括但不限于多西他赛、吉西他滨、伊马替尼(Gleevec)、5-氟尿嘧啶、9-氨基喜树碱、氨基修饰的格尔德霉素(geldanamycin)、阿霉素、紫杉醇(Taxol)、丙卡巴肼、羟基脲、内消旋-e-二氢卟酚、顺铂、Gd(+3)化合物、天冬酰胺酶和放射性核素(例如I-131、Y-90、In-111和Tc-99m)。有许多抗癌剂是本领域所知的且许多在继续开发。
基于以下说明,本领域技术人员能够对抗癌剂进行必要的化学修饰,以将抗癌剂连接到载体分子或连接分子上。
2.载体分子
可使用任何载体分子。典型的载体分子是聚合物分子。典型的载体聚合物分子为至少约5,000道尔顿的大分子。在另一些实施方案中,所述载体分子为至少约25,000道尔顿、至少约50,000道尔顿、至少约100,000道尔顿、至少约125,000道尔顿或至少约150,000道尔顿。载体分子可从约5,000道尔顿到约25,000道尔顿,或从约25,000道尔顿到约100,000道尔顿,或从约50,000道尔顿到约130,000道尔顿,或从约100,000道尔顿到约170,000道尔顿,或从约120,000道尔顿到约200,000道尔顿,或从约120,000道尔顿到约1,000,000道尔顿的范围内变化。载体分子协助抗癌剂跨细胞膜的运输。因此,当抗癌剂与载体分子直接或间接地相连时,其通常比单独使用抗癌剂更好地跨越细胞膜。存在本领域中已知的多种载体和大分子载体,其作为载体分子发挥作用。载体分子的实例还描述于名称为″Drug delivery system for the simultaneous delivery of drugs activatableby enzymes and light″的美国专利5,258,453;名称为″Synthetic polymericdrugs″的美国专利5,037,883;名称为″Hydrophilic N,N-diethyl acrylamidecopolymers″的美国专利4,074,039;名称为″Copolymers based onN-substituted acrylamides,N-substituted methacrylamides andN,N-disubstituted acrylamides and the method of their manufacturing″的美国专利4,062,831;名称为″Soluble hydrophilic polymers and process forproducing the same″的美国专利3,997,660;名称为″Hydrophilic nitritecopolymers″的美国专利3,931,123和名称为″Soluble hydrophilic polymersand process for processing the same″的美国专利3,931,111中。每一篇专利均单独且特别地通过引用全文并入本文。
在一个实施方案中,所述载体分子包括通过不饱和单体聚合反应而生产的聚合物。单体的实例包括但不限于丙烯酸酯和甲基丙烯酸酯。在一个实施方案中,所述载体分子是由N-(2-羟丙基)异丁烯酰胺(HPMA共聚单体)与包含共聚单体的药物或靶向部分或显像剂之聚合反应生产的共聚物。所得到的聚合物-药物缀合物在本文中称为HPMA共聚物。
根据本发明制备的聚合物可具有从约1.0至约2.0的多分散性。在示例性实施方案中,所述多分散性从约1.3至约1.8,从约1.3至约1.5或从约1.5至约1.7。一些实施方案具有约1.4的多分散性,而另一些实施方案可具有约1.7的多分散性。
3.连接分子
“接头”(“linker”)指将药物或靶向配体与载体分子在空间分隔开的基团。所述接头可以是任何种类的实体,例如但不限于聚乙二醇、氨基酸、聚氨基酸(例如肽或寡肽)、或多肽(例如蛋白质),其任一端能够与载体分子形成共价键,其另一端能够与药物或靶向配体形成共价键。接头还可包含易于被溶酶体降解的特定序列的短肽,例如Gly-Phe-Leu-Gly(SEQ IDNO:1)。对前列腺癌而言,其他实例包括靶向到前列腺细胞且和前列腺特异性抗原(PSA)的具有序列特异性蛋白水解能力的连接。例如,PSA水解His-Ser-Ser-Lys-Leu-Gln(SEQ ID NO:5)和戊二酰-4-羟基脯氨酰-Ala-Ser-环六甘氨酰-Gln-Ser-Leu(SEQ ID NO:6)。
所述连接子通常可断裂,从而可释放出抗癌剂,例如,在还原条件下、氧化条件下,或者通过水解酯、酰胺、酰肼或形成连接子和抗癌剂间共价键的类似连接而进行。此外,连接子的类型可通过允许在细胞附近或在细胞内选择性释放抗癌剂来增强选择性细胞毒性(并因此提高治疗指数)。
4.靶向配体
术语“靶向配体”指可将本发明化合物递送至特定部位以发挥所期望活性的分子,即,其提供化合物的定位。定位是由分子决定子的特异性识别、靶向剂或缀合物的分子大小、离子相互作用、疏水相互作用等所介导的。将药剂靶向至特定组织或部位的其它机制是本领域技术人员已知的。靶向配体包括例如与靶细胞表面上的分子相结合的分子。示例性的靶向配体包括抗体、抗体片段、有机小分子、肽、类肽、蛋白质、多肽、寡糖、转铁蛋白、HS-糖蛋白、凝血因子、血清蛋白、β糖蛋白、G-CSF、GM-CSF、M-CSF、EPO等。在本发明的示例性实施方案中,所述靶向系统包括将诸如RGDfK、EPPT1肽或叶酸的靶向配体共价连接到载体分子、连接子或抗癌剂上。
5.细胞摄取的效力和特异性
本文中所描述的化合物可以以其允许抗癌剂利用与单独使用抗癌剂时不同的机制被细胞摄取来表征。有多种方法来确定载体分子是否增加了摄取的效力和/或特异性。效力和/或特异性的典型提高可以大于或等于至少2倍、5倍、10倍、25倍、50倍、100倍、500倍、1000倍、5,000倍或10,000倍。
C.制备化合物的方法
可使用本领域已知的技术来制备本发明的化合物。正如所述的,使用多达4种组分来制备化合物:抗癌剂、载体分子、任选的靶向配体和任选的连接分子。在特别的实施方案中,本发明的化合物包括载体分子、抗癌剂、靶向配体和至少一个连接分子。前述任何组分均可以任何可能的组合或顺序彼此反应来制备本发明的化合物。有时优选将两种组分偶联(即反应)在一起以制备新的反应产物或中间体,之后将所述中间体与下一组分化学连接。例如,抗癌剂可与载体分子反应生成抗癌/载体分子。类似地,抗癌剂可与连接分子反应生成抗癌/连接分子,或连接分子可与载体分子反应生成连接/载体分子。这些中间体中的每一种然后可与个体组分反应(例如,抗癌剂/连接子与载体分子反应以制备载体/连接子/抗癌剂),或者每一种中间体可彼此反应来制备化合物(例如,抗癌/连接分子与抗癌/载体分子的反应)。
在一个实施方案中,所述化合物可通过下述方法来制备:(1)使连接子与用于制备载体分子的单体反应以制备单体/连接子分子,(2)使所述单体/连接子分子与抗癌剂反应来制备单体/连接子/抗癌剂,和(3)使所述单体/连接子/抗癌剂与至少一种共聚单体进行聚合反应。在某些实施方案中,所述至少一种共聚单体是HPMA共聚单体。
在另一些实施方案中,所述化合物可通过下述方法来制备:(1)使连接子与用于制备载体分子的单体反应以制备单体/连接子分子,(2)使所述单体/连接子分子与抗癌剂反应来制备单体/连接子/抗癌剂,(3)使所述单体/连接子/抗癌剂与至少一种共聚单体进行聚合反应,和(4)使靶向配体与共聚物反应。在这些实施方案中,所述至少一种共聚单体包含可与靶向配体反应的反应位点。在某些实施方案中,所述至少一种共聚单体是HPMA共聚单体。在另一些实施方案中,所述至少一种共聚单体包含HPMA共聚单体和具有可被靶向配体替换的离去基团的第二共聚单体。
在一个示例性实施方案中,所述化合物可通过下述方法来制备:(1)使异丁烯酰氯(MACl)与Gly-Phe(GF)反应并将产物与Leu-Gly(LG)偶联来得到MA-GFLG-OH分子;(2)使MA-GFLG-OH分子与吉西他滨或多西他赛反应来得到MA-GFLG-抗癌分子;(3)使MA-GFLG-抗癌分子与HPMA共聚单体反应来制备HPMA共聚物-药物缀合物。该方法详细描述于以下的实施例1-2至1-8中。“GFLG”如SEQ ID NO:1所公开。
在另一个示例性实施方案中,使MA-GFLG-OH与多西他赛(DCT)反应以产生MA-GFLG-DCT,或与吉西他滨(GEM)反应以产生MA-GFLG-GEM。然后,使HPMA共聚单体与MA-GFLG-DCT或MA-GFLG-GEM以及另一种包含离去基团的共聚单体(例如异丁烯酰基-甘氨酰-甘氨酸-对硝基苯酯(MA-GG-ONp,如图6所示))发生共聚以制备HPMA-GFLG-药物-GGONp。然后使HPMA-GFLG-药物-GGONp与靶向配体反应以得到HPMA-GFLG-药物-靶向配体。在某些实施方案中,所述靶向配体可以是例如RGDfK、EPPT1肽或叶酸。该方法详细描述于以下的实施例1-9至1-12中。“GFLG”如SEQ ID NO:1所公开。
如上所述,所述抗癌剂、载体分子和连接子可彼此直接或间接连接。此外,各组分彼此间的连接可根据所选择组分的类型和所允许的组分间相互反应顺序而不同。
D.化合物的使用方法
所公开的化合物可用于将抗癌剂靶向递送至细胞。本文中公开的化合物可以以药学可接受的形式以有效量施用给需要递送抗癌剂或类似化合物的对象。所述对象可以是例如哺乳动物,诸如小鼠、大鼠、兔、仓鼠、狗、猫、猪、牛、绵羊、山羊、马,或者灵长类如猴、大猩猩、猩猩、黑猩猩或人。
本文中所公开的缀合抗癌剂可用于抑制癌细胞增殖。抑制癌细胞增殖意指减少或防止癌细胞增长。抑制剂可通过利用癌细胞测定来确定。例如,可将任一癌细胞系在存在或不存在缀合抗癌剂或单独抗癌剂或另外制备的不同于所述公开组合物的抗癌剂(例如,只是抗癌剂和载体)的情况下在96孔板上培养设定的任何时间段。然后可测定细胞。在某些实施方案中,所述缀合抗癌化合物是当通过所述测定法测定时相对于任何对照组将抑制10%或15%或20%或25%或30%或35%或40%或45%或50%或55%或60%或65%或70%或75%或80%或85%或90%或95%的生长的那些。其他实施方案包括抑制转移肿瘤形成的组合物。这些组合物可以减少对照化合物的至少10%或15%或20%或25%或30%或35%或40%或45%或50%或55%或60%或65%或70%或75%或80%或85%或90%或95%的肿瘤转移形成。
在某些实施方案中,所公开的化合物可用于治疗多种需要递送抗癌剂或相似药剂的病症。在某些实施方案中,所公开的组合物可用于治疗发生细胞增殖失控的疾病,例如癌症。本文中使用的“治疗”是指在被该状况威胁或受该状况折磨的对象中抑制、减少、调节、改善或阻断至少一种症状,所述症状为病理学状况的特征。不同类型癌症的非限定性清单如下:癌、实体组织癌、鳞状细胞癌、腺癌、肉瘤、胶质瘤、高级别胶质瘤、母细胞瘤、神经母细胞瘤、浆细胞瘤、组织细胞瘤、黑色素瘤、腺瘤、含氧量低的肿瘤、骨髓瘤、转移癌、或一般性癌症。可用所公开的组合物来治疗的具体实例包括B细胞淋巴瘤、T细胞淋巴瘤、蕈样肉芽肿病、霍奇金病、髓细胞性白血病、膀胱癌、脑癌、神经系统癌、头颈癌、头颈鳞状细胞癌、肾癌、肺癌如小细胞肺癌和非小细胞肺癌、神经母细胞瘤/胶质母细胞瘤、卵巢癌、胰腺癌、前列腺癌、皮肤癌、肝癌、黑色素瘤,口、咽、喉和肺的鳞状细胞癌,结肠癌,宫颈癌症,宫颈癌,乳腺癌和上皮癌,肾癌症,生殖泌尿器癌症,肺癌症,食管癌,头颈癌,大肠癌,造血系统癌症;睾丸癌;结直肠癌,前列腺癌或胰腺癌。
本文中公开的化合物也可用于治疗癌前病症,例如子宫颈和肛门发育异常、其它发育异常、严重发育异常、增生、非典型增生和瘤形成。
E.剂量
化合物施用的剂量范围为足以在递送处产生所期望效果的量。剂量不应大到引起不良副作用,例如不想要的交叉反应、过敏性反应等。通常,剂量随年龄、病况、性别和患者疾病的程度而不同,且可由本领域技术人员来确定。在存在任何禁忌症的情况下,所述剂量可由各医师调节。剂量可以每天一剂或多剂施用,可从约1mg/kg至30mg/kg变化,给予一天或数天。
F.可药用载体
任何化合物可以与一种或多种可药用载体相组合而治疗性地用于药物组合物中。
药学载体是本领域技术人员所熟知的。它们大多通常为用于将组合物施用给人的标准载体,包括溶液例如无菌水、盐水和生理pH下的缓冲溶液。其他化合物可根据本领域技术人员使用的标准程序来施用。
可将旨在用于药物递送的分子配制为药物组合物。除所选择的分子外,药物组合物还可包含载体、增稠剂、稀释剂、缓冲剂、防腐剂、表面活性剂等。药物组合物还可以包含一种或多种有效成分,例如抗菌剂、抗炎剂、麻醉剂等。
胃肠外施用的制剂包括无菌水或非水溶液、混悬液和乳液,其也可包含缓冲剂、稀释剂和其他合适的添加剂。非水溶剂的实例为丙二醇、聚乙二醇、植物油例如橄榄油,和可注射的有机酯例如油酸乙酯。水性载体包括水、醇/水溶液、乳液或混悬液,其包括盐水和缓冲介质。胃肠外载体包括氯化钠溶液、林格氏葡萄糖、葡萄糖和氯化钠、乳酸化林格氏液或不挥发性油。静脉内载体包括液体和营养补充剂、电解质补充剂(例如那些基于林格氏葡萄糖溶液的)等。还可存在防腐剂和其他添加剂,例如抗微生物剂、抗氧化剂、螯合剂和惰性气体等。
本文中所述的组合物也可以作为通过与无机酸或有机酸或无机碱或有机碱反应而形成的酸或碱加成盐来施用,所述无机酸例如盐酸、氢溴酸、高氯酸、硝酸、硫氰酸、硫酸和磷酸,所述有机酸例如甲酸、乙酸、丙酸、乙醇酸、乳酸、丙酮酸、草酸、丙二酸、琥珀酸、马来酸和延胡索酸,所述无机碱例如氢氧化钠、氢氧化铵、氢氧化钾,所述有机碱例如单烷基胺、二烷基胺、三烷基胺和芳基胺以及取代的乙醇胺。
G.药物组合物
可以与载体材料组合以制备单剂量形式的活性成分的量可根据所治疗的对象和特定施用方式而不同。
使用本发明的化合物和/或组合物治疗疾病状况的施用方案根据多种因素来选择,所述因素包括患者的类型、年龄、体重、性别、饮食和医疗条件,疾病的严重程度,施用途径,药理学考量因素如所应用特定化合物的活性、效力、药代动力学和毒理学特性,是否利用药物递送系统以及是否所述化合物作为药物组合之一部分施用。因此,实际上使用的施用方案可广泛变化,并因此可能偏离上述的优选施用方案。
可注射的制剂(包括例如无菌可注射水性或油性混悬液)可根据现有技术使用合适的分散剂或润湿剂和助悬剂来配制。无菌可注射制剂也可以是在无毒的胃肠外可接受稀释剂或溶剂中的无菌可注射溶液或混悬液(例如在1,3-丁二醇中的溶液)。在可使用的可接受载体和溶液中包括水、林格氏溶液和等渗氯化钠溶液。此外,无菌的不挥发性油通常作为溶剂或助悬介质使用。出于该目的可使用任何温和的不挥发油,包括合成的甘油一酯或甘油二酯。此外,发现脂肪酸(例如油酸)用于可注射制剂中。
虽然本发明化合物可作为唯一的药物活性剂施用,但是它们也可以与一种或多种治疗剂(例如免疫调节剂、抗病毒剂或抗感染剂)联合使用。
上述内容仅是对本发明的举例说明,且不意在将本发明限于所公开的化合物。对本领域技术人员来说显而易见的变化和改变旨在落入所附权利要求中所定义的本发明的范围和本质内。从以上描述的内容来看,本领域技术人员可以容易地确定本发明的必要特征,而不背离本发明的精神和范围,可对本发明作出多种变化和修改以使其适用不同的应用和条件。
具体实施方案
参考以下实施例,可进一步阐明本发明,所述实施例用于举例说明一些优选的实施方案,但不以任何方式限制本发明。
实施例1:用于药物递送的HPMA-吉西他滨或多西他赛缀合物的合成
HPMA共聚单体药物缀合物通过HPMA单体与活化的MA-GFLG-药物(SEQ ID NO:1)共聚单体以不同摩尔比的聚合作用来合成。
1)HPMA共聚单体的合成
如以前所述进行HPMA单体的合成(Kopecek和Bazilova,Eur.Polym.J.,9:7-14(1973)),如图1所示。通过改良的多步反应制备了MA-GG-ONp共聚单体(Kopecek等,Ann.N Y Acad.Sci.,446:93-104(1985))。
方案1
在-5℃下于剧烈搅拌下向1-氨基-2丙醇(65.6ml,0.84mol)的250ml乙腈溶液中逐滴加入新蒸馏的异丁烯酰氯(MACl)(41ml,0.42mol,20ml乙腈中)。向溶液中加入少量抑制剂叔辛基邻苯二酚。反应混合物在室温下再搅拌30分钟。作为副产物形成的1-氨基-2-丙醇盐酸盐沉淀且被滤除。将残余物用预冷的乙腈洗涤。滤液冷却至-70℃,HPMA沉淀出来。待平衡至室温后,将产物滤出并用预冷的乙腈洗涤。从丙酮中重结晶分离出纯品(熔点:67-69℃)。MS(ESI)m/z 144(M+1).1H NMR(400MHz,CDCl3):δ1.20和1.22(d,J=6.4Hz,3H)),1.97(s,3H),3.18-3.21(m,1H),3.48-3.51(m,1H),3.95-3.96(m,1H),5.36(s,1H),5.74(s,1H).
2)MA-GF-OH的合成
如图2所述,通过异丁烯酰氯(MACl)与甘氨酰苯丙氨酸(GF)的反应制备了异丁烯酰基甘氨酰苯丙氨酸(MA-GF-OH)。
将甘氨酰苯丙氨酸(Gly-Phe,5.0g,22.5mmol)溶于5.6ml 4N NaOH(22.5mmol)中并冷却至0-5℃。逐滴加入在10ml二氯甲烷中的新蒸馏的MACl(2.3g,22.5mmol)。加入少量抑制剂叔辛基邻苯二酚以防止单体的聚合作用。同时但稍有延迟,向反应混合物中逐滴加入5.6ml(22.5mmol)4N NaOH溶液。在加入MACl和NaOH后,将反应混合物温热至室温并使其反应一小时。使pH保持在约8-9。将二氯甲烷层与水层分离,用2ml水洗涤并弃之。将合并的水层与40ml乙酸乙酯混合。在剧烈搅拌和冷却下,缓慢加入稀HCl直到pH达到2-3。分离有机层并用乙酸乙酯萃取水层三次。将合并的有机层用无水硫酸钠干燥过夜。过滤经干燥的溶液并用乙酸乙酯洗涤。通过旋转蒸发除去乙酸乙酯,得到白色粉末产品。从乙酸乙酯中重结晶(熔点:141.8-143.4℃)。1H NMR(400MHz,CDCl3):δ1.96(s,3H)),3.06-3.20(2m,2H),3.85-4.11(2m,2H),4.83-4.85(m,1H),5.41(s,1H),5.79(s,1H),7.20-7.30(m,5H).
3)LG-OMe HCl的合成
如图2所示,由亮氨酰甘氨酸(LG)与亚硫酰氯/甲醇反应制备了亮氨酰甘氨酸-OMe(LG-Ome)。
将亮氨酰甘氨酸(Leu-Gly,4.0g 21mmol)溶于35ml甲醇中并冷却至-15℃。搅拌下逐滴加入稍过量的亚硫酰氯(SOCl2)(2ml,26mmol)。待平衡至室温后将混合物回流3小时。蒸发溶剂至干,将残留物溶于甲醇中并再次蒸发除去痕量的HCl和SOCl2。将残留物溶于苯并蒸发以获得白色无定形固体。粗产物(LG-OMe.HCl)不经纯化而用于随后的步骤中。1HNMR(400MHz,DMSO-d6):δ0.89-0.93(m,6H),1.56-1.61(m,2H)),1.71-1.78(m,1H),3.65(s,3H),3.77-3.85(m,2H),3.88-4.00(m,1H),5.41(s,1H),5.79(s,1H),7.25-7.28(m,5H).
4)MA-GFLG-OMe(SEQ ID NO:1)的合成
如图2所示,由异丁烯酰基甘氨酰苯丙氨酸(MA-GF-OH)与亮氨酰甘氨酸-OMe(LG-OMe)反应制备了异丁烯酰基甘氨酰苯丙氨酰亮氨酰甘氨酸OMe(MA-GFLG-OMe)(SEQ ID NO:1)。
将4.0g 1-羟基苯甲腈(HOBT,25mmol)、4.0ml N,N’-二异丙基乙胺(DIEA,25mmol)和6.0g MA-Gly-Phe(20.7mmol)加入到含有5.0gLeu-Gly-OMe HCl(21mmol)的40ml二甲基甲酰胺(DMF)溶液中。搅拌反应混合物并冷却至-10℃。在5分钟内逐滴加入含5.2g N,N’-二环己基碳二亚胺(DCC,25mmol)的20ml DMF。将溶液在0℃搅拌2小时,然后在室温下搅拌24小时。在将所析出的副产物搅拌过夜后,滤出二环己基脲(DCU)。将滤液旋转蒸发以完全除去DMF。将残留物与40ml 5%NaHCO3溶液混合并用乙酸乙酯萃取三次。将萃取物用40ml 5%柠檬酸溶液、40ml 5%NaHCO3溶液和饱和盐水洗涤,并用无水硫酸钠干燥。在滤出干燥剂后,将滤液在真空下浓缩以获得产物(MA-GFLG-OMe(SEQ IDNO:1))。由乙酸乙酯重结晶(熔点:140.9-143.0℃)。
5)MA-GFLG-OH(SEQ ID NO:1)的合成
如方案2所示,由异丁烯酰基甘氨酰苯丙氨酰亮氨酰甘氨酸OMe(MA-GFLG-OMe(SEQ ID NO:1))的水解制备了异丁烯酰基甘氨酰苯丙氨酰亮氨酰甘氨酸(MA-GFLG-OH(SEQ ID NO:1))。
将过量的1N NaOH(18ml,18mmol)在搅拌下逐滴加入到含6.9gMA-GFLG-OMe(SEQ ID NO:1)(14.5mmol)的80ml甲醇冷溶液中。在加入少量抑制剂(叔辛基邻苯二酚)后将反应混合物在0℃搅拌一个半小时,然后室温下搅拌2小时。来自之前反应的额外量的DCU副产物析出并被滤出。将滤液在真空下浓缩以除去甲醇,与160ml蒸馏水混合,用浓柠檬酸酸化至pH为2.0。将游离酸用4x 200ml乙酸乙酯萃取,用饱和盐水洗涤并用无水硫酸钠干燥过夜。真空下蒸除溶剂后,将四肽产物(MA-GFLG-OH(SEQ ID NO:1))由乙酸乙酯重结晶(熔点:161.4-165.6℃)。MS(ESI)m/z 483(M+Na).
方案2“GFLG”如SEQ ID NO:1所公开。
6)异丁烯酰基甘氨酰苯丙氨酰亮氨酰甘氨酰基-吉西他滨(MA-GFLG-吉西他滨)(SEQ ID NO:1)的合成(方案3)。
持续搅拌下将1-羟基苯并三唑(1.2x)溶液加入MA-GFLG-OH(SEQID NO:1)的DMF溶液(1x)中。将温度冷却至-10℃并在搅拌下逐滴加入DCC(1.2x)的DMF溶液。然后向反应混合物中加入盐酸吉西他滨的DMF溶液和N,N’-二异丙基乙胺。使反应混合物达到室温。将析出的DCU滤出,旋转蒸发除去DMF。通过柱色谱纯化产物(硅胶,洗脱剂:乙酸乙酯/甲醇)并通过质谱(M+1=706.3)和TLC进行分析。
方案3“GFLG”如SEQ ID NO:1所公开。
7)异丁烯酰基甘氨酰苯丙氨酰亮氨酰甘氨酰基-多西他赛(MA-GFLG-多西他赛)(SEQ ID NO:1)的合成(方案4)。
将MA-GFLG-OH(SEQ ID NO:1)溶于无水DMF中,在0℃下向该溶液中加入二异丙基碳二亚胺(DIPC,1x)、多西他赛(1x)和4-二(甲氨基)吡啶(DMAP,1.5x)。将所得溶液温热至室温并放置16小时。将反应混合物用0.1N HCl洗涤,干燥,并真空干燥得白色固体产物,将其通过柱色谱纯化(硅胶,洗脱剂:乙酸乙酯/甲醇)。产物通过薄层色谱和质谱验证m/z 1272.3(M+Na)。
方案4“GFLG”如SEQ ID NO:1所公开。
8)聚合物-药物缀合物的合成
HPMA共聚物-药物(其中药物代表吉西他滨和多西他赛)缀合物由共聚单体合成,如方案5所示,通过在丙酮(0.72ml)/DMSO(0.08ml)中在50℃下使用N,N’-偶氮二异丁腈(AIBN,4.4mg)作为引发剂,由HPMA共聚单体(86.7mg,0.603mmol)与MA-GFLG-药物(SEQ ID NO:1)(其药物为多西他赛的情况为5mg,0.004mmol)24小时的自由基沉淀共聚作用而制得。改变共聚单体的原料组成,使之分别包含0、2和10mol%的MA-GFLG-药物(SEQ ID NO:1)。共聚单体∶引发剂∶溶剂的比例保持恒定的12.5∶0.6∶86.9wt%。通常,将AIBN和HPMA溶于丙酮中并与少量DMSO中的MA-GLFG-药物(SEQ ID NO:1)溶液混合。将混合物在氮气下密封于安瓿中并使之在搅拌下于50℃聚合24小时。将析出的聚合物溶于甲醇并在20倍体积的醚中再沉淀。将小分子量的未反应单体和其他杂质通过重溶于蒸馏水中并用蒸馏水透析除盐而与聚合缀合物分离,随后冻干获得纯品。
方案5“GFLG”如SEQ ID NO:1所公开。
9)HPMA共聚物-RGDfK-多西他赛缀合物的合成
如方案6所示,在两步方法中合成了聚合缀合物。在第一步中,通过HPMA、MA-GFLG-多西他赛(SEQ ID NO:1)和异丁烯酰基甘氨酰甘氨酰-对硝基苯基酯(MA-GG-ONp)共聚单体在丙酮/5%DMSO中的自由基沉淀共聚反应合成了HPMA共聚物-药物缀合物。所述共聚单体的原料组成分别为89.34%、0.66%和10%。使用N,N’-偶氮二异丁腈(AIBN)作为引发剂。简而言之,将HPMA((54.24mg,0.38mmol)、MA-GFLG-多西他赛(SEQ ID NO:1)(3.5mg,0.0028mmol)和MA-GG-ONp(13.62mg,0.0424mmol)以及AIBN(3.43mg)溶于1ml丙酮(5%DMSO)中。共聚单体∶引发剂∶溶剂的比率保持在恒定的12.5∶0.6∶86.9wt%。将混合物在氮气下密封于安瓿中并50℃搅拌下使之聚合24小时。将析出的聚合物前体溶于甲醇中并在20倍体积的醚中再沉淀。将小分子量的未反应单体和其他杂质通过重溶于蒸馏水中并用蒸馏水透析除盐而与聚合缀合物分离,随后冻干获得纯品。聚合物的ONp含量通过分光光度法于272nm测定。
在第二步中,通过氨解反应将靶向肽RGDfK与聚合物前体缀合。简而言之,将35.69mg HPMA-(GFLG-多西他赛)-GG-ONp(SEQ ID NO:1)前体(含有0.02mmol ONp基团)溶于1.6ml无水DMF中(经分子筛干燥)。以相对于聚合物前体中MA-GG-ONp的含量1.3倍摩尔过量的量加入RGDfK(16.7mg,0.03mmol)。反应在氮气下于室温下行24小时。使用1-氨基-2丙醇(0.02mmol)终止反应。将缀合物用去离子水透析并冻干。
方案6“GFLG”如SEQ ID NO:1所公开。
10)HPMA共聚物-RGDfK-吉西他滨缀合物的合成与表征。
标题的聚合物-药物缀合物可使用与HPMA-共聚物-RGDfK-多西他赛缀合物相似的方法来制备。
11)HPMA共聚物-EPPT1-多西他赛缀合物或HPMA共聚物-EPPT1-吉西他滨缀合物的合成。
标题的聚合物-药物缀合物可使用与HPMA-共聚物-RGDfK-多西他赛缀合物相似的方法来制备。
12)HPMA共聚物-叶酸-多西他赛缀合物或HPMA共聚物-叶酸-吉西他滨缀合物的合成。
使用与HPMA-共聚物-RGDfK-多西他赛缀合物相似的方法制备了标题的聚合物-药物缀合物。
13)聚合物-药物缀合物的物理化学表征
成功地合成了一系列聚合物药物缀合物,如表1所列。通过用Superose12HR 10/30柱(Amersham Biosciences)的尺寸排阻色谱在快速蛋白液相色谱(FPLC)系统(Amersham Biosciences)上评估了所合成聚合物-药物缀合物的重均分子量(Mw)和多分散性。以0.4ml/分钟的流速用PBS作为洗脱溶剂洗脱1mg/ml的样品。使用已知分子量的聚HPMA级分由校准曲线估计了聚合物的数均分子量(Mn)、重均分子量(Mw)和多分散性(n=Mw/Mn)。利用氨基酸分析(Commonwealth Biotechnologies Inc,Richmond,VA)获得了药物含量。结果显示在表1中。聚合物的总体尺寸分布与文献中所报道的相似系统的确定值相符。
表1.聚合物-药物缀合物的物理化学特性,“GFLG”如SEQ ID NO:1所公开。
实施例2:生物学试验
1)癌细胞系的生长
用于测定HPMA-药物缀合物作用的癌细胞系从以下来源获得:人MDA-MB-231(乳腺)、HCT116(结肠)和PANC-1(胰腺)来自美国标准培养物中心(ATCC)(Manassas,VA)。UMRC2(肾)来自美国国家癌症研究所(Bethesda,MD)。细胞保存在添加有10%FBS、P/S和10mM HEPES的Dulbecco改良伊格尔培养基(“DMEM”,Invitrogen)中。所有的细胞均在37℃下于加湿的5%CO2下孵育。
2)针对人肿瘤细胞系的体外细胞增殖测定
使用磺酰罗丹明B(″SRB″)法(Skehan等,J.National Cancer Institute,82:1107-1112(1990))进行了HPMA-药物缀合物针对人癌细胞系的生长抑制测定。简而言之,将指数增长的癌细胞以2-3x103个细胞/孔的密度接种于96孔板并在第二天用HPMA共聚物-药物缀合物处理。每一处理使用一式三份的孔。使用水作为对照。将细胞与HPMA共聚物-药物缀合物在37℃下在加湿的5%CO2气氛中孵育96小时。孵育96小时后,将细胞用10%三氯乙酸(“TCA”)固定,在4℃孵育1小时,用自来水洗涤3次。之后,将细胞用在1%乙酸中的0.4%磺酰罗丹明B染色30分钟,用1%乙酸洗涤3次,再晾干。在10mM Tris溶液中搅拌5分钟后,使用Benchmark Plus酶标仪(Bio-Rad Laboratories,Hercules,CA)在530nm处测量每孔的吸光度。吸光度值提供了用HPMA共聚物-药物缀合物处理后生存细胞数量的直接度量。
为了将OD530值转换成每孔中的生存细胞数,将OD530值与那些为每个细胞系产生的标准OD530对细胞数目之曲线上的值进行比较。用下式计算生存百分率:
生存%=生存细胞数[试验]/生存细胞数[对照]x 100
通过非线性回归分析计算了IC50值。
表2归纳了测定的HPMA-共聚物-药物缀合物的细胞生长抑制(IC50,μM)。
表2.游离药物、HPMA-GFLG、HPMA-GFLG-药物缀合物和HPMA-GFLG-药物-靶向配体缀合物针对人癌细胞系的体外细胞毒性。“GFLG”如SEQ ID NO:1所公开。
实施例3:异种移植研究
为了观察动物模型中的肿瘤生长抑制,如下所述,使用HPMA缀合的多西他赛或吉西他滨在裸鼠异种移植模型上实施。
在0天时将Mia-Paca人胰腺癌细胞或HCT116细胞悬液(3x106个细胞)皮下注射于六周龄的雌性FoxN1裸鼠的下侧肋腹。当肿瘤达到适当的尺寸(例如约50-60mm3的体积)时,每4-5天给小鼠静脉内注射仅磷酸盐缓冲液(PBS)或本发明的药物缀合物。监视动物几周直到对照肿瘤达到例如约1cm直径,这时对动物实施安乐死。测定了肿瘤尺寸和肿瘤组成并报告为肿瘤尺寸变化的倍数(图1-图3)。
利用本实施例中描述的模型,显示本发明的药物缀合物(例如实施例1中所所述的药物缀合物)能够抑制或稳定体内细胞增殖,这支持了其抗癌作用和性质。
Claims (18)
1.一种化合物,包含载体分子、与所述载体分子共价连接的连接分子、以及与所述连接分子共价连接的抗癌剂,其中所述抗癌剂是吉西他滨或多西他赛。
2.一种化合物,包含载体分子、与所述载体分子共价连接且任选地通过连接分子连接的抗癌剂、和与所述载体分子共价连接且任选地通过第二连接分子连接的靶向配体,其中所述靶向配体选自RGDfK、EPPT1和叶酸。
3.根据权利要求2的化合物,其中所述抗癌剂是吉西他滨或多西他赛。
4.根据权利要求1至3中任一项的化合物,其中所述连接分子和所述第二连接分子各自包含氨基酸或寡肽。
5.根据权利要求4的化合物,其中所述氨基酸或寡肽选自
Gly-Phe-Leu-Gly(SEQ ID NO:1),Gly-Ileu-Phe,Gly-Val-Phe,Gly-Gly-Phe,Gly-Gly-Phe-Phe(SEQ ID NO:2),Gly-Ileu-Tyr,Phe,Gly,Gly-Gly,Ala,Ser,Gly-Phe,Gly-Leu Phe,Gly-Phe-Phe,Gly-D-Phe-Phe,Ala-Gly-Val-Phe(SEQ ID NO:3),Gly-Gly-Val-Phe(SEQ ID NO:4),Gly-Phe-Tyr,Gly-B-Ala-Tyr,Gly-Lue,Gly-Phe-Gly,His-Ser-Ser-Lys-Leu-Gln(SEQ ID NO:5),和
戊二酰-4-羟脯氨酰-Ala-Ser-环六甘氨酰-Gln-Ser-Leu(SEQ ID NO:6)。
6.根据权利要求1-5中任一项的化合物,其中所述载体包含聚(N-2-羟丙基异丁烯酰胺)(聚-HPMA)。
7.根据权利要求1或3的化合物,其中所述载体分子包含聚-HPMA,且所述抗癌剂通过Gly-Phe-Leu-Gly(GFLG(SEQ ID NO:1))寡肽链连接到所述载体分子上。
8.根据权利要求1至7任一项的化合物,其中所述载体分子包含分子量从约10,000道尔顿到约250,000道尔顿的大分子。
9.根据权利要求8的化合物,其中所述载体分子包括分子量从约10,000道尔顿到约170,000道尔顿的大分子。
10.根据权利要求1的化合物,还包含与所述载体分子共价连接且任选地通过第二接头连接的靶向配体。
11.根据权利要求10的化合物,其中所述靶向配体通过第二接头与所述载体分子共价连接。
12.根据权利要求2或11中任一项的化合物,其中所述第二接头是氨基酸或寡肽。
13.根据权利要求12的化合物,其中所述寡肽包含Gly-Gly(GG)。
14.根据权利要求10或11中任一项的化合物,其中所述靶向配体选自RGDfK、EPPT1和叶酸。
15.根据权利要求3或14中任一项的化合物,其中所述载体分子包含聚-HPMA,所述抗癌剂通过GFLG(SEQ ID NO:1)寡肽接头与所述载体分子相连,并且所述第二接头是GG寡肽接头。
16.根据权利要求15的化合物,其中所述载体分子的分子量从约10,000道尔顿到约250,000道尔顿。
17.根据权利要求16的化合物,其中所述载体分子的分子量从约100,000道尔顿到约170,000道尔顿。
18.一种治疗癌症的方法,包括对有此需要的人施用治疗有效量的根据权利要求1至17任一项的化合物。
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