CN116655690A - 磷脂醚类似物作为靶向癌症的药物载体 - Google Patents
磷脂醚类似物作为靶向癌症的药物载体 Download PDFInfo
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- CN116655690A CN116655690A CN202310088164.3A CN202310088164A CN116655690A CN 116655690 A CN116655690 A CN 116655690A CN 202310088164 A CN202310088164 A CN 202310088164A CN 116655690 A CN116655690 A CN 116655690A
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Abstract
本发明涉及能够靶向癌细胞和癌干细胞的治疗化合物。本发明还涉及包括这些治疗化合物的组合物和治疗癌症的方法,包括施用这些治疗化合物。
Description
背景技术
2012年,全球共有1410万人被诊断出患有癌症,820万人死于癌症。在美国,大约有40%的人在一生中将被诊断出患有癌症。尽管接受了最好的治疗,但44%的美国人将死于癌症。
癌症是细胞无限分裂的结果。健康细胞具有防止无限细胞分裂的检查点。这些检查点的几个例子是营养物质的可用性、DNA损伤和接触抑制(即,细胞与另一个细胞接触)。此外,大多数细胞只能复制有限次数,而且因此在经历特定次数的分裂之后细胞即程序性死亡。
癌症是细胞克服这些内置检查点,并且进行不受控增殖的结果。这种不受控的增殖导致肿瘤的形成。有两种类型的肿瘤,良性和恶性。良性肿瘤不能穿过组织类型之间的自然界限。另一方面,恶性肿瘤能够侵入附近的组织或进入血液并转移到不同的位置。认为只有恶性肿瘤是癌性的。这种渗透和转移的能力使癌症成为致命的疾病。
恶性肿瘤具有不同的细胞类型,而使对抗癌症进一步复杂化。一种特别麻烦的类型是癌干细胞(“CSC”)。CSC能够自我更新和分化成恶性肿瘤中发现的不同类型的癌细胞。因此,CSC是肿瘤转移能力的主要因素。CSC通常在辐射和化疗中存活。假设辐射和化疗后癌症复发是辐射和化学疗法无法杀死所有与产生新肿瘤的能力有关的CSC的结果。
一种特别麻烦的癌症类型是脑癌。脑癌,如高级胶质瘤,常常用手术治疗,然后进行放射治疗。脑肿瘤手术往往很复杂。外科医生必须清除肿瘤,而不能损伤任何可能导致身体或认知障碍的附近脑组织。通常,外科医生不能去除接触健康组织的肿瘤的边界。通常使用放射治疗来杀死这些剩余的癌细胞。然而,辐射剂量受到对健康脑组织的潜在损伤的限制。不幸的是,脑癌通常是耐化疗的。这种阻力主要归因于血脑屏障(“BBB”)。BBB是将脑周围的流体与血细胞和血液中的其他成分分开的物理屏障。大多数抗癌药物无法通过BBB。
一种治疗脑癌的方法是抑制肿瘤尺寸发展所必需的新血管的生长。以商标(Avastin是Genentech,Inc.的注册商标)销售的贝伐单抗(bevacizumab),用于阻止甚至逆转肿瘤血管形成。然而,Rich J.及其同事,Canc Res,2006,66,7843发现,当使用治疗神经胶质瘤干细胞衍生的脑肿瘤时,其导致缺氧和pH降低。SathornsumeteeS.,Phase II trial of bevacizumab and erlotinib in patients with recurrentmalignant glioma,Neuro-Oncol,2010,Dec,12(12),1300-1310。已知缺氧和低pH都引起CSC增殖,并可促进CSC引起的肿瘤复发。
化疗是用于描述特定类型的癌症治疗的术语,其包括使用细胞毒性抗癌药物。化疗期间使用的细胞毒性药物可以分为几个主要类别,包括烷化剂、抗代谢药、抗肿瘤抗生素、拓扑异构酶抑制剂和有丝分裂抑制剂。细胞毒性抗癌药物通常导致细胞分裂停止,从而影响健康组织以及癌组织。烷化剂通过破坏癌细胞的DNA来阻止癌细胞分裂。用于治疗癌症的一些常见的烷化剂是氮芥(例如环磷酰胺(Cytoxan是Baxter International的注册商标))、亚硝基脲、烷基磺酸盐、三嗪和乙烯亚胺。铂类药物,如顺铂(cisplatin)和卡铂(carboplatin),与烷化剂作用类似。抗代谢物通过抑制DNA和RNA合成来阻止癌细胞分裂。用于治疗癌症的一些常见的抗代谢药物是6-巯基嘌呤、吉西他滨(gemcitabine(Gemzar是Eli Lilly and Company的注册商标))、甲氨蝶呤(methotrexate)和培美曲塞(pemetrexed(/>Alimta是Eli Lilly and Company的注册商标))。拓扑异构酶抑制剂通过抑制拓扑异构酶分离DNA进行复制来阻止癌细胞分裂。一些常见的拓扑异构酶抑制剂是拓扑替康(topotecan)、伊立替康(irinotecan)、依托泊苷(etoposide)和替尼泊苷(teniposide)。有丝分裂抑制剂通过抑制关键细胞分裂酶来阻止癌细胞分裂。一些常见的有丝分裂抑制剂是紫杉烷类(例如紫杉醇(paclitaxel)(/>Taxol是Bristol-Myers Squibb Company的注册商标))和多西他奇(decetaxel(/>Taxotere是Aventis Pharma SA的注册商标))、埃坡霉素(epothilones)和长春花生物碱(vincaalkaloids)。
所有这些抗癌药物的一个缺点是它们对健康组织的损害。因为药物通过抑制正常的细胞功能来治疗癌症,所以依赖不断的细胞分裂的健康组织(如血细胞、粘膜表面和皮肤)也会受到严重的损害。这种损害导致显着的发病率,并且能限制可以安全递送的化疗的量。化疗期间发生的副作用的实例包括低血细胞计数、脱发、肌肉和关节疼痛、恶心、呕吐、腹泻、口疮、发烧和发冷。为了克服这个问题,正在开发影响仅出现在癌细胞中的蛋白质和细胞功能的药物。一些特定癌症药物是伊马替尼(imatinib(Gleevec是NovartisAG的注册商标))、吉非替尼(gefitinib(/>Iressa是AstraZeneca UK Limited的注册商标))、舒尼替尼(sunitinib(/>Sutent是C.P.Pharmaceuticals,InternationalC.V.的注册商标))和硼替佐米(bortezomib(/>Velcade是MillenniumPharmaceuticals,Inc.的注册商标))。然而,这些药物没有被批准用于治疗所有癌症类型,并且通常伴随有治疗抗性的发展。因此,在本领域中需要一种抗癌药物递送载体,其可以向包括CSC在内的癌细胞递送强力的、有效的广谱抗癌药物,同时避免健康细胞对药物的大量摄取。此外,抗癌药物递送载体应该能够穿过BBB并将抗癌药物递送到大脑的癌细胞。
目前,具有优先靶向癌细胞的少数化学化合物。一种这样的化合物是CLR1404。通常,CLR1404是用于监测几种肿瘤治疗方式的治疗反应的有前景的新型肿瘤选择性诊断显像剂。放射性碘化的CLR1404,其为具有以下结构的第二代磷脂醚(“PLE”)类似物,在55/60异种移植物,原位和转基因癌症和癌干细胞衍生动物模型中显示出显著的肿瘤选择性,使核心分子成为用于抗癌药物递送载体的理想平台。参见美国专利No.8535641;美国专利申请公开No.2014/0030187和Weichert,J.P.,et al.,Alkylphosphocholine analogs for broad-spectrum cancer imaging and therapy,SciTransl Med,2014,Jun 11,6(240),240ra75;其各自的全部内容通过引用并入本文。
目前尚不清楚的是,由癌细胞和癌干细胞选择性螯合和保留的化合物是否能将抗癌药物递送至这些细胞。此外,不知道该化合物是否也能够转运抗癌药物通过BBB来治疗脑癌。最后,尚不清楚这种或类似的化合物是否可以使癌细胞保留足够量的抗癌药物足够长的时间以消除肿瘤并防止进一步的生长和转移。本发明使CLR1404核心分子适用于能够将抗癌药物靶向癌细胞和癌干细胞(包括脑癌细胞)的抗癌药物递送载体。此外,本发明的化合物保留在癌细胞中。
发明内容
本发明涉及能够靶向癌细胞和癌干细胞(包括脑肿瘤细胞)的治疗化合物。本发明还涉及能够被癌细胞和癌干细胞(包括脑肿瘤细胞)以足够量和足够的时间螯合和保留来治疗癌症并预防转移和复发的治疗化合物。
在一个实施方式中,本发明涉及式A-B-D的治疗化合物,其中:
A是至少一种式(I)的化合物,
至少一种式(II)的化合物,
至少一种式(III)的化合物,
或其组合,
其中W选自由芳基、C1-C6烷基、烯基、任选取代的C3-C6环烷基和任选取代的C3-C6杂环烷基组成的组,其中R是H或烷基,其中m是12-24的整数;
B是连接体化合物,优选是键或式(Ⅳ)的化合物,Y-(CH2)n-Z(Ⅳ),其中:
Y与A结合;
Z与D结合;
Y选自由键、O、NH、C=O、NHSO2O和OC(=O)O组成的组;
Z选自由O、NH、C=O、C(=O)O、C(=O)NH、SO2、OC(=O)OCH2、和-S-S-组成的组;以及
n为0至6的整数;以及
D是抗癌药物,
其中A与D的比为1:2至2:1。
在另一个实施方式中,本发明涉及选自由
及其组合组成的组的式A-B-D的治疗化合物,其中:
W选自由芳基、C1-C6烷基、烯基、任选取代的C3-C6环烷基和任选取代的C3-C6杂环烷基组成的组;
R是H或烷基;
m是12-24的整数;
Y选自由键、O、NH、C=O、NHSO2O和OC(=O)O组成的组;
Z选自由O、NH、C=O、C(=O)O、C(=O)NH、SO2、OC(=O)OCH2、和-S-S-组成的组;
n为0至6的整数;以及
D是抗癌药物,
其中B任选是A和D之间的键。
在一个优选的实施方式中,本发明涉及式A-B-D的治疗化合物,其中:
其中A是式(I)的化合物,其中W选自由C1烷基、组成的组,其中m是18;
B是连接键选自键和式(IV)的化合物的连接体化合物,Y-(CH2)n-Z(IV),其中n为0至6的整数,Y与A结合,Z与D结合,Y选自由键和C=O组成的组,Z选自由NH、C=O、C(=O)NH和C(=O)O组成的组;以及
D选自由紫杉醇、伊立替康、托泊替康、吉西他滨、顺铂、格尔德霉素和美登素组成的组。
在一个更优选的实施方式中,本发明涉及式A-B-D的治疗化合物,其中:
A是式(I)的化合物,其中W是m是18;
B是式(IV)的化合物,其中Y是C=O,Z是C=O、C(=O)NH或C(=O)O,n是3或4;以及
D是紫杉醇,
其中A与D的比为1:1。
在另一个更优选的实施方式中,本发明涉及式A-B-D的治疗化合物,其中:
A是式(I)的化合物,其中W是m是18;
B是键或式(IV)的化合物,其中Y是C=O,Z是NH,n是1或3;以及
D是格尔德霉素,
其中A与D的比为1:1。
在另一个更优选的实施方式中,本发明涉及式A-B-D的治疗化合物,其中:
A是式(I)的化合物,其中W是m是18;
B是键;以及
D是美登素,
其中A与D的比为1:1。
另一方面,本发明提供含有本发明化合物与一种或多种药学上可接受的载体的药物组合物。
另一方面,本发明提供了一种治疗癌症的方法,其包括将有效量的本发明治疗化合物给予癌症受试者。
在一个实施方式中,本发明提供了一种治疗癌症的方法,其包括将有效量的本发明治疗化合物给予癌症受试者,其中癌症包括癌干细胞。
在另一个实施方式中,本发明提供了一种治疗癌症的方法,其包括将有效量的本发明治疗化合物给予癌症受试者,其中癌症是复发性的。
附图说明
图1示出磷脂醚(“PLE”)类似物通过脂筏螯合。
图2示出癌细胞优先摄取CLR1501。(A)和(C)至(F)中的癌细胞系与(B)中的正常细胞对CLR1501的摄取的比较。(A)肾(Caki-2)。(B)正常人皮肤成纤维细胞。(C)卵巢癌(OVcar-3)。(D)胰腺(Panc-1)。(E)黑色素瘤(A-375)。(F)前列腺(PC-3)。
图3示出在SCID小鼠中的人RL-251肿瘤异种移植物对131I-CLR1404的延长的保留。
图4示出使用125I-NM404检测大鼠脑中的C6-神经胶质瘤。(A)假手术对照大鼠脑的生物扫描图。(B)来自(A)的大鼠脑的生物扫描图像与显示正常脑组织中125I-NM404的背景水平的数字照片的叠加。(Α')注射125I-NM404后4天荷C6-脑胶质瘤的大鼠脑的数码照片。(Β')来自(Α')的大鼠脑的生物扫描图像。(C')(Α')和(Β')的位置和大小匹配的叠加图像,表明NM404在肿瘤中的高度集中。(D')H&E染色的样品,确认了肿瘤的存在。
图5示出124I-CLR1404在大量恶性肿瘤中的摄取。(A)至(I)是具有人癌症异种移植物的啮齿动物模型。(J)至(M)是啮齿动物癌症模型。(A)原位胶质瘤U87(大鼠)。(B)结肠HCT-116。(C)结肠HT-29,箭头表示肿瘤的位置。(D)乳腺MDA-MB-231,箭头表示肿瘤的位置。(E)前列腺PC-3。(F)转移性PC-3。(G)PC-3胫骨异种移植物。(H)胰腺BxPC3,下箭头表示肿瘤的位置,上箭头表示肝转移。(I)尤文氏肉瘤,箭头表示肿瘤的位置。(J)小鼠SV40膀胱。(K)小鼠乳腺4T1。(L)小鼠胰腺c-myc。
(M)大鼠脑CNS-1。
图6示出使用131I-CLR1404检测人类患者的非小细胞肺癌(“NSCLC”)肿瘤。(A)示出患者1在注射131I-CLR1404后4和11天的γ相机图像,注意CLR1404在NSCLC肿瘤中的强烈和延长的保留(箭头)。(B和C)示出左肺(A)中3cm灶的位置和大小,右肺(B)中大浸润性肿块(箭头)。(D和E)示出患者2在131I-CLR1404 IV给药后1、2天和4天的全身平面核医学图像。(F和G)示出轴向(F)和冠状(G)CT扫描图,表明大6cm NSCLC肿瘤(箭头)的位置。
图7示出使用124I-CLR1404检测NSCLC患者中3种以前未知的脑肿瘤转移。箭头表明在癌细胞摄取124I-CLR1404后,使用PET/CT成像肿瘤的位置。
图8示出使用124I-CLR1404检测右前额肿瘤转移的肿瘤复发。(A)放射外科手术后的脑MRI,箭头表示被解释为放射性坏死的病变。(B)使用124I-CLR1404的PET图像示出病变对124I-CLR1404的摄取。(C)立体定向放射外科术后8个月的脑MRI示出病变尺寸增加,表明可能的复发。
图9示出PLE-紫杉醇结合物对MDA-MB-468的IC50。(A)游离紫杉醇,(B)CLR1601和(C)CLR1603。
图10示出PLE-紫杉醇结合物对NCI-H1299的IC50。(A)游离紫杉醇,(B)CLR1601和(C)CLR1603。
图11示出PLE-紫杉醇结合物对NCI-H460的IC50。(A)游离紫杉醇,(B)CLR1601和(C)CLR1603。
图12示出PLE-紫杉醇结合物对Capan-2的IC50。(A)游离紫杉醇,(B)CLR1601和(C)CLR1603。
图13示出PLE-紫杉醇结合物对MiaPaCa-1的IC50。(A)游离紫杉醇,(B)CLR1601和(C)CLR1603。
图14示出PLE-紫杉醇结合物对HT29的IC50。(A)游离紫杉醇,(B)CLR1601和(C)CLR1603。
图15示出PLE-紫杉醇结合物对HCT116的IC50。(A)游离紫杉醇,(B)CLR1601和(C)CLR1603。
图16示出PLE-紫杉醇结合物对PC-3的IC50。(A)游离紫杉醇,(B)CLR1601和(C)CLR1603。
图17示出用5μM CLR1601处理72小时的MDA-MB-468细胞的代表性散点图。
具体实施方式
定义
如本文所用,术语“治疗”包括预防和病症的间歇治疗,包括减少、阻止和抑制癌症进展或复发。如本文所用,术语“减少”、“阻止”和“抑制”具有减轻或减少的通常理解的含义。如本文所用,术语“发展”是指范围或严重性增加、发展、增长或变得更糟。如本文所用,术语“复发”和“复发的”是指疾病缓解后的复发。
如本文所用,术语“给药”是指将患者、组织、器官或细胞与本发明的抗癌化合物接触。如本文所用,给药可以在体外(即在试管中)或体内(即在活生物体,例如人的细胞或组织中)实施。在某些实施方式中,本发明包括将可用于本发明的化合物给予患者或受试者。在本文中等同地使用的“患者”或“受试者”是指哺乳动物,优选人,其可以是:(1)具有通过给予使用PLE化合物的抗癌物质可治愈或可治疗的病症,或(2)易于患有通过给予本发明的抗癌化合物可预防的病症。
如本文所用,术语“有效量”是指足以影响期望生物效应的量,例如有益结果,包括但不限于预防、减少、改善或消除疾病或病症的体征或症状。因此,药物组合物或方法的每种活性成分的总量足以显示有意义的受试者益处。因此,“有效量”将取决于给药的背景。有效量可以通过一个或多个预防或治疗给药中施用。
如本文所用,术语“治疗化合物”是指能够提供癌症治疗的任何化合物。
如本文所用,术语“癌症”是指由能够转移的细胞的不受控的分裂导致的任何疾病。
在整个说明书中,术语“化疗药物”“抗癌药物”和“抗肿瘤药物”可互换使用。
在整个说明书中,术语“恶性肿瘤细胞”和“癌细胞”可互换使用。在整个说明书中,术语“恶性肿瘤干细胞”和“癌干细胞”可互换使用。
如本文所用,术语“组合物”旨在涵盖包括特定量的特定成分的产品,以及直接或间接由特定量的特定成分的组合产生的任何产品。
如本文所用,术语“A”是指式 的磷脂醚。
如本文所用,术语“W”是指芳基、C1-C6烷基、烯基、任选取代的C3-C6环烷基和任选取代的C3-C6杂环烷基。
如本文所用,术语“芳基”是指包含苯基的芳环。
如本文所用,除非另有说明,术语“烷基”是指由1至24个碳原子(C1-C24)的饱和烃基组成的支链或直链烷基。烷基可以是环的或非环的。
如本文所用,术语“烯基”是指碳-碳双键。
如本文所用,术语“环烷基”是指3至24个碳原子(C3-C24)的环烷基。
本文所用的术语“杂环烷基”是指选自碳、氮、硫、磷和氧的3至24个原子(C3-C24)的环状基团,其中至少一个原子是碳。
一般而言,术语“取代的”无论是否术语“任选地”在其之前,是指被指定部分的一个或多个氢被合适的取代基取代。除非另有说明,“任选取代的”基团可以在该基团的每个可取代的位置上具有合适的取代基,并且当任何给定结构中的多于一个位置可被多于一个选自特定基团的取代基取代时,在每个位置上的取代基可以是相同或不同的。本发明设想的取代基的组合优选是形成稳定或化学上可行的化合物的取代基。
如本文所用,术语“R”是指氢(H)或烷基。
如本文所用,术语“m”是指12至24的整数。
如本文所用,术语“n”是指0至6的整数。
如本文所用,术语“B”是指连接体化合物。如本文所用,术语“连接体化合物”是指能够与两种或更多种其它不同化学化合物形成化学键,使得所有化合物形成单一更大的化合物的任何一个化合物或多个化合物。在一个实施方式中,连接体化合物是键。可以使用多个连接体化合物来形成较大的化合物。在具体实施方式中,术语连接体化合物是键或式Y-(CH2)n-Z的化合物。
如本文所用,术语“Y”是指键、O、NH、C=O、NHSO2O或OC(=O)O。
如本文所用,术语“Z”是指O、NH、C=O、C(=O)O、C(=O)NH、SO2、OC(=O)OCH2、和-S-S-。
如本文所用,术语“D”是指目前已知或正在开发的任何抗癌药物。
如本文所定义,术语“异构体”包括但不限于光学异构体和类似物、结构异构体和类似物、构象异构体和类似物等。在一个实施方式中,本发明包括使用本发明的不同光学异构体。本领域技术人员应当理解,本发明中可用的抗癌化合物可含有至少一个手性中心。因此,本发明方法中使用的化合物能够以光学活性或外消旋形式存在并分离。一些化合物也可能表现出多态性。
应当理解,本发明可以包括使用任何外消旋、光学活性、多晶型或立体异构体形式或其混合物,其形式具有可用于治疗本文所述和要求保护的癌症相关病症的性质。在一个实施方式中,抗癌化合物可以包括纯(R)-异构体。在另一个实施方式中,抗癌化合物可以包括纯(S)-异构体。在另一个实施方式中,化合物可以包括(R)和(S)异构体的混合物。在另一个实施方式中,化合物可以包括(R)和(S)异构体的的外消旋混合物。本领域众所周知如何制备光学活性形式(例如,通过重结晶技术拆分外消旋形式,通过由光学活性起始原料合成,通过手性合成或通过使用手性固定相的色谱分离)。
本发明包括使用氨基取代的化合物与有机和无机酸,例如柠檬酸和盐酸,形成的药学上可接受的盐。本发明还包括本文所述化合物的氨基取代基的N-氧化物。也可以通过用无机碱例如氢氧化钠处理酚类化合物制备药学上可接受的盐。而且,酚类化合物的酯也可以由脂族和芳族羧酸制成,例如乙酸和苯甲酸酯。如本文所用,术语“药学上可接受的盐”是指从碱性化合物配制的化合物,其能实现与碱性化合物基本相同的药效。
本发明还包括抗癌化合物的衍生物。术语“衍生物”包括但不限于醚衍生物、酸衍生物、酰胺衍生物、酯衍生物等。此外,本发明还包括利用抗肿瘤化合物的水合物的方法。术语“水合物”包括但不限于半水合物、一水合物、二水合物、三水合物等。
本发明还包括抗癌化合物的代谢物。术语“代谢物”是指通过代谢或代谢过程从另一物质产生的任何物质。
可用本发明化合物治疗的癌症包括但不限于:乳腺癌,包括男性乳腺癌;消化道/胃肠癌,包括肛门癌、阑尾癌、肝外胆管癌、胃肠类癌、结肠癌、食管癌、胆囊癌、胃癌、胃肠道间质瘤(“gist”)、胰岛细胞肿瘤、成人原发性肝癌、儿童肝癌、胰腺癌、直肠癌、小肠癌和胃癌;内分泌和神经内分泌癌,包括胰腺癌、肾上腺皮质癌、胰腺神经内分泌肿瘤、默克尔细胞癌、非小细胞肺神经内分泌肿瘤、小细胞肺神经内分泌肿瘤、甲状旁腺癌、嗜铬细胞瘤、垂体瘤和甲状腺癌;眼癌,包括眼内黑素瘤和视网膜母细胞瘤;泌尿生殖肿瘤,包括膀胱癌、肾脏(肾细胞)癌、阴茎癌、前列腺癌、移行细胞肾盂和输尿管癌、睾丸癌、尿道癌和肾母细胞瘤;生殖细胞癌,包括儿童中枢神经系统癌、儿童颅外生殖细胞肿瘤、外生殖细胞瘤、卵巢生殖细胞肿瘤和睾丸癌;妇科癌,包括子宫颈癌、子宫内膜癌、妊娠滋养细胞瘤、卵巢上皮癌、卵巢生殖细胞瘤、子宫肉瘤、阴道癌和外阴癌;头颈部癌,包括下咽癌、喉癌、唇和口腔癌、隐匿性原发性转移性鳞状颈癌、口癌、鼻咽癌、口咽癌、鼻旁窦和鼻腔癌、甲状旁腺癌、咽癌、唾液腺癌和咽喉癌;白血病包括成人急性淋巴细胞白血病、儿童急性淋巴细胞白血病、成人急性骨髓性白血病、儿童急性骨髓性白血病、慢性淋巴细胞白血病、慢性骨髓性白血病和毛细胞白血病;淋巴瘤,包括AIDS相关淋巴瘤、皮肤T细胞淋巴瘤、成人霍奇金淋巴瘤、儿童霍奇金淋巴瘤、孕期霍奇金淋巴瘤、蕈样真菌病、成人非霍奇金淋巴瘤、儿童非霍奇金淋巴瘤、孕期非霍奇金淋巴瘤、原发性中枢神经系统淋巴瘤、Sezary综合征和Waldenstrom巨球蛋白血症;肌肉骨骼癌,包括尤文肉瘤、骨肉瘤和骨的恶性纤维组织细胞瘤、儿童横纹肌肉瘤和软组织肉瘤;神经肿瘤,包括成人脑肿瘤、儿童脑肿瘤、星形细胞瘤、脑干神经胶质瘤、中枢神经系统非典型畸形/横纹肌瘤、中枢神经系统胚胎性肿瘤、颅咽管瘤、室管膜瘤、神经母细胞瘤、原发性中枢神经系统(CNS)淋巴瘤;呼吸/胸癌,包括非小细胞肺癌、小细胞肺癌、恶性间皮瘤、乳腺瘤和乳腺癌;和皮肤癌,包括卡波西肉瘤、黑素瘤和鳞状细胞癌。
已经证明本发明的式(I)化合物被癌干细胞螯合。参见Weichert J.P.,等人.(2014)第2页,图2(表明CLR-1501(CLR1404荧光类似物)与正常人星形胶质细胞和胎儿人神经干细胞相比,更多地被人成胶质细胞瘤干样细胞和血清培养的人成胶质细胞瘤细胞摄取)。癌干细胞与大多数(如果不是全部)主要的癌症类型相关。肿瘤缺氧可刺激癌细胞的增殖,导致抗性和转移潜能的增加。因此,化疗和放射治疗后,癌干细胞伴随有化疗抗性、肿瘤再生长和转移。因此,本发明的化合物具有治疗已被证明对传统治疗方案具有抗性的各种形式的癌症的潜力。
本发明的化合物
可用于本发明的药物递送载体包括但不限于式(I)
或式(II),
或式(III),
或其组合的化合物,
其中W选自由芳基、C1-C6烷基、烯基、任选取代的C3-C6环烷基和任选取代的C3-C6杂环烷基组成的组,其中R是H或烷基,其中m是12-24的整数;
本发明化合物的选择性肿瘤靶向的基础在于癌细胞的质膜与大多数正常细胞的差异。具体来说,癌细胞膜含有丰富的“脂筏”。癌细胞比健康细胞多出五至十倍的脂筏。脂筏是含有高浓度胆固醇和鞘脂的膜磷脂双层的特定区域,用于组织细胞表面和细胞内信号分子(例如生长因子和细胞因子受体,磷脂酰肌醇3-激酶(PI3)/Akt存活通路)。数据表明,脂筏是PLE的侵入门户。这些化合物对癌细胞与非癌细胞的显著选择性归因于PLEs对胆固醇的高亲和力以及癌细胞中富含胆固醇的脂筏的丰度。由脂筏结构的破坏抑制PLE在癌细胞的摄取的事实,强调了脂筏所起的关键作用。已经表明,当阻止脂筏形成时,PLE的摄取降低了60%。(参见实施例2和图1)
在超过55种异种移植物和自发性肿瘤模型中获得的初步结果普遍表明CLR1404经历了肿瘤内的选择性摄取和延长的保留。由于该药物在肝脏中有一定程度的代谢,并且肝脏背景放射性水平较高,本发明人没有进行早期肝肿瘤模型中的化合物评估。
CLR1404是一个PLE。在各种肿瘤模型中获得的结果表明CLR1404被癌细胞和癌干细胞螯合并选择性保留。事实上,已经表明CLR1404在癌细胞中保留长达20天。见图3。无论解剖位置如何,CLR1404均集中于原发性和转移性病变中,包括在淋巴结中发现的病变。参见实施例3-8。高的肿瘤对背景亲合力和CLR1404的肿瘤选择性表明核心分子非常适合用作抗癌药物递送载体。
可用于本发明的连接体化合物包括能够将本发明的药物递送载体与本发明的抗癌药物结合的任何化学连接体。可用于本发明的连接体化合物包括可裂解和不可裂解的连接体。在一个实施方式中,可用于本发明的连接体化合物包括但不限于氨基丁酰胺、氨基酸、戊酰胺酸、二羧酸、氨基甲酸、羰基、9,10-蒽二羧酸、联苯-3,3',5,5'-四羧酸、联苯-3,4',5-三羧酸、5-溴间苯二甲酸、5-氰基-1,3-苯二甲酸、2,2'-二氨基-4,4'-二苯乙烯二羧酸、2,5-二氨基对苯二甲酸、2,5-二羟基对苯二甲酸、5-乙炔基-1,3-苯二甲酸、2-羟基对苯二甲酸、咪唑、2-甲基咪唑、2,6-萘二甲酸、草酸二水合物(oxalic acid dehydrate)、对苯二甲酸、[1,1':4',1”]三联苯-3,3”,5,5”-四羧酸、3,3',5,5'-四羰基二苯基甲烷、1,2,4,5-四(4-羧基苯基)苯、4,4',4”-s-三嗪-2,4,6-三基-三苯甲酸、均苯三酸、1,3,5-三(4'-羧基[1,1'-联苯]-4-基)苯、1,3,5-三(4-羧基苯基)苯和1,3,5-三羧基苯基乙炔基苯。
在另一个实施方式中,可用于本发明的连接体化合物还包括但不限于具有或不具有基于苯胺的自牺牲片段的溶酶体蛋白酶敏感连接体。溶酶体蛋白酶敏感连接体的非限制性实例是其包含缬氨酸-瓜氨酸二肽连接体,旨在显示血浆稳定性和细胞内蛋白酶裂解之间的最佳平衡。参见Tranoy-Opalinski I.,Designof selfimmolative linker for tumor-activated precursors therapy,AnticancerAgents Med Chem,2008Aug,8(6):618-637,其全部内容通过引用并入本文。
在另一个实施方式中,可用于本发明的连接体化合物还包括但不限于被β-葡糖醛酸糖苷酶裂解的自牺牲连接体。β-葡糖苷酸酶在癌细胞周围的坏死区域以高浓度存在。参见Tranoy-Opalinski I.,β-glucuronidase-responsive prodrugs for selectivecancer chemotherapy:An update,Eur J Med Chem,2014Mar 3,74,302-313,其全部内容通过引用并入本文。β-葡糖苷酸酶可裂解的自牺牲连接体的非限制性实例是 其中X是NH2或NO2,其中Y是O或NCH3。
本发明优选的连接体化合物是键或式(Ⅳ)的化合物,Y-(CH2)n-Z(Ⅳ),其中:
Y与A结合;
Z与D结合;
Y选自由键、O、NH、C=O、NHSO2O和OC(=O)O组成的组;以及
Z选自由O、NH、C=O、C(=O)O、C(=O)NH、SO2、OC(=O)OCH2、和-S-S-组成的组;以及
n为0至6的整数。
本发明更优选的连接体化合物为键或式(IV)的化合物,其中n为0至6的整数,Y与A结合,Z与D结合,Y选自由键和C=O组成的组,Z选自由NH、C=O、C(=O)NH和C(=O)O组成的组。
可用于本发明的抗癌药物包括但不限于紫杉醇、伊立替康、托泊替康、吉西他滨、顺铂、格尔德霉素、美登素、阿比特龙(abiraterone)、阿法替尼(afatinib)、氨基乙酰丙酸(aminolevulinic acid)、阿瑞吡坦(aprepitant)、阿西替尼(axitinib)、阿扎胞苷(azacitidine)、贝利司他(belinostat)、苯达莫司汀(bendamustine)、贝沙罗汀(bexarotene)、博莱霉素(bleomycin)、硼替佐米(bortezomib)、伯舒替尼(bosutinib)、白消安(busulfan)、卡巴他赛(cabazitaxel)、卡博替尼(cabozantinib)、卡培他滨(capecitabine)、卡铂、卡非佐米(carfilzomib)、卡莫司汀(carmustine)、色瑞替尼(ceritinib)、西妥昔单抗(cetuximab)、苯丁酸氮芥(chlorambucil)、克罗拉滨(clofarabine)、克唑替尼(crizotinib)、环磷酰胺、阿糖胞苷(cytarabine)、达拉菲尼(dabrafenib)、达卡巴嗪(dacarbazine)、更生霉素(dactinomycin)、达沙替尼(dasatinib)、柔红霉素(daunorubicin)、地西他滨(decitabine)、地诺单抗(denosumab)、右丙亚胺(dexrazoxane)、多西他奇(docetaxel)、多拉司他汀(dolastatins)(如一甲基澳瑞他汀E(monomethyl auristatin E))、多柔比星(doxorubicin)、恩杂鲁胺(enzalutamide)、表柔比星(epirubicin)、甲磺酸艾日布林(eribulin mesylate)、埃罗替尼(erlotinib)、依托泊苷(etoposide)、依维莫司(everolimus)、氟尿苷(floxuridine)、磷酸氟达拉滨(fludarabine phosphate)、氟尿嘧啶(fluorouracil)、ganetespib、吉非替尼(gefitinib)、吉妥单抗(gemtuzumab ozogamicin)、六甲三聚氰胺、羟基脲、替伊莫单抗(ibritumomab tiuxetan)、依鲁替尼(ibrutinib)、艾代拉利司(idelalisib)、异环磷酰胺、伊马替尼(imatinib)、普利姆玛(ipilimumab)、伊沙匹隆(ixabepilone)、拉帕替尼(lapatinib)、甲酰四氢叶酸钙(leucovorin calcium)、洛莫司汀(lomustine)、美登素类化合物(maytansinoids)、氮芥(mechlorethamine)、美法仑(melphalan)、巯(基)嘌呤(mercaptopurine)、巯乙磺酸钠(mesna)、甲氨蝶呤、丝裂霉素C(mitomycin C)、米托坦(mitotane)、米托蒽醌(mitoxantrone)、奈拉滨(nelarabine)、奈非那韦(nelfinavir)、尼罗替尼(nilotinib)、阿托珠单抗(obinutuzumab)、奥法木单抗(ofatumumab)、高三尖杉酯碱(omacetaxine mepesuccinate)、奥沙利铂(oxaliplatin)、帕尼单抗(panitumumab)、帕唑帕尼(pazopanib)、培加帕酶(pegaspargase)、派姆单抗(pembrolizumab)、培美曲塞(pemetrexed)、喷司他丁(pentostatin)、帕妥珠单抗(pertuzumab)、plicanycin、泊马度胺(pomalidomide)、盐酸帕纳替尼(ponatinib hydrochloride)、普拉曲沙(pralatrexate)、丙卡巴肼(procarbazine)、二氯化镭223、雷莫芦单抗(ramucirumab)、瑞戈非尼(regorafenib)、瑞他霉素(retaspimycin)、鲁索替尼(ruxolitinib)、司莫司丁(semustine)、司妥昔单抗(siltuximab)、索拉非尼(sorafenib)、链脲霉素(streptozocin)、苹果酸舒尼替尼(sunitinib malate)、坦螺旋霉素(tanespimycin)、替莫唑胺(temozolomide)、西罗莫司脂化物(temsirolimus)、替尼泊苷(teniposide)、沙利度胺(thalidomide)、硫鸟嘌呤(thioguanine)、噻替派(thiotepa)、托瑞米芬(toremifene)、曲美替尼(trametinib)、曲妥珠单抗(trastuzumab)、凡德他尼(vandetanib)、维罗非尼(vemurafenib)、长春碱(vinblastine)、长春新碱(vincristine)、长春瑞滨(vinorelbine)、维莫德吉(vismodegib)、伏立诺他(vorinostat)和阿柏西普(ziv-aflibercept)。目前已知或能够作为抗癌药物的任何化合物也可用于本发明。
本发明的PLE药物递送载体可以通过连接体化合物或直接在任意数量可能稳定的附着位点单独或多个地连接到抗癌药物上。
本发明的组合物
另一方面,本发明提供含有本发明化合物与一种或多种药学上可接受的载体的药物组合物。在优选的方面,药物组合物不含EL(Kolliphor是BASF SE的注册商标)。/>EL以前称为/>EL(Cremophor是BASF SE的注册商标)。
本发明治疗组合物中活性成分的实际剂量水平是可以改变的,以获得有效实现特定患者、组合物和给药方式所需治疗反应的活性化合物的量。所选择的剂量水平将取决于特定化合物的活性、给药途径、待治疗病症的严重程度以及所治疗患者的状况和先前病史。然而,以低于达到期望的治疗效果的水平所需化合物的剂量开始化合物的剂量,并且逐渐增加剂量直到达到所需效果,属于本领域的常规技术。
本发明化合物的用语“治疗有效量”是指足以治疗病症的化合物的量,以适用于任何医学治疗的合理的效益/风险比。然而,应当理解,本发明的化合物和组合物的总日用量将由主治医师在合理的医学判断范围内决定。任何特定患者的特定治疗有效剂量水平将取决于多种因素,包括所治疗的病症和病症的严重程度;所用具体化合物的活性;所用的具体组合物;患者的年龄、体重、一般健康状况,性别和饮食习惯;给药时间、给药途径和使用的具体化合物的排泄速率;治疗的时间;与所使用的具体化合物组合或巧合使用的药物;以及医学领域众所周知的因素。例如,以低于达到期望的治疗效果的水平所需化合物的剂量开始化合物的剂量,并且逐渐增加剂量直到达到所需效果,属于本领域的常规技术。
给予人或者低等动物的本发明化合物的总日剂量可以在约0.0001至约1000mg/kg/天的范围内。为了口服给药,更优选的剂量可以在约0.001至约5mg/kg/天的范围内。如果需要,为了给药目的,有效日剂量可以分为多个剂量;因此,单剂量组合物可以含有该量或构成日剂量的分量。
本发明也提供包括本发明化合物与一种或多种药学上可接受的载体配方的药物组合物。药物组合物可以专门配制用于固体或液体形式的口服给药、肠胃外给药或直肠给药。
本发明的药物组合物能够以口服、直肠、胃肠外、脑池内、阴道内、经皮(例如使用贴片)、经粘膜下、舌下、肺、腹膜内、局部(如通过粉末、软膏或滴剂)、经颊方式或作为口或鼻喷雾剂施用于人和其它哺乳动物。如本文所用,术语“肠胃外”或“肠胃外地”是指包括静脉内、肌肉内、腹膜内、胸骨内、皮下和关节内注射和输注的给药方式。
另一方面,本发明提供包括本发明组分和生理上可耐受的稀释剂的药物组合物。本发明包括一种或多种如上所述的化合物,其与一种或多种生理上可耐受或可接受的稀释剂、介质、佐剂或载体(在本文中统称为稀释剂)配制成组合物,用于胃肠外注射、鼻内递送、固体或液体形式的口服给药、用于直肠或局部给药等。
适用于胃肠外注射的组合物可包括生理上可接受的无菌水性或非水性溶液、分散液、悬浮液或乳液以及用于重构成无菌可注射溶液或分散液的无菌粉末。合适的水性和非水性介质、稀释剂、溶剂或载体的实例包括水、乙醇、多元醇(丙二醇、聚乙二醇、甘油等)、植物油(例如橄榄油)、可注射的有机酯如油酸乙酯、及其合适的混合物。
这些组合物还可以包含佐剂,如防腐剂、润湿剂、乳化剂和分散剂。可以通过各种抗菌和抗真菌剂,例如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸等来防止微生物的作用。还可以包含等渗剂,例如糖、氯化钠等。可以通过使用延迟吸收的试剂,例如单硬脂酸铝和明胶,来延长可注射药物形式的吸收。
除了活性化合物之外,悬浮液可以含有悬浮剂,例如乙氧基化异硬脂醇、聚氧乙烯山梨糖醇和脱水山梨醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂和黄蓍胶、或这些物质的混合物等。
通过在可生物降解的聚合物例如聚丙交酯-聚乙交酯中形成药物的微胶囊基质来制备可注射的积存形式。依据药物与聚合物的比例和所用特定聚合物的性质,可以控制药物释放速率。其它生物可降解聚合物的实例包括聚(原酸酯)和聚(酸酐)。积存注射制剂也可以通过将药物包埋在与身体组织相容的脂质体或微乳液中来制备。
可注射制剂可以,例如,通过细菌保留过滤器过滤或加入无菌固体组合物形式的灭菌剂而进行灭菌,该无菌固体组合物在即将使用之前溶解或分散在无菌水或其他无菌可注射介质中。
用于口服给药的固体剂型包括胶囊、片剂、丸剂、粉剂和颗粒剂。在这样的固体剂型中,活性化合物可以与至少一种惰性的药学上可接受的赋形剂或载体混合,例如柠檬酸钠或磷酸二钙和/或a)填充剂或增量剂,如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;b)粘合剂,如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶;c)保湿剂,如甘油;d)崩解剂,如琼脂、碳酸钙、马铃薯或木薯淀粉、藻酸、某些硅酸盐和碳酸钠;e)溶液阻滞剂,如石蜡;f)吸收促进剂,如季铵化合物;g)润湿剂,如鲸蜡醇和甘油单硬脂酸酯;h)吸收剂,如高岭土和膨润土,以及i)润滑剂,如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠及其混合物。在胶囊、片剂和丸剂的情况下,剂型还可以包括缓冲剂。
类似类型的固体组合物也可用作软和硬填充明胶胶囊中的填充剂,该胶囊使用诸如乳糖以及高分子量聚乙二醇等作为赋形剂。
片剂、糖衣丸、胶囊、丸剂和颗粒剂的固体剂型可以用包衣和壳如肠溶衣和制药领域众所周知的其它包衣制备。它们可以任选地含有遮光剂,并且还可以是组合物,使得它们仅在或优选在肠道的某一部分中有选择地以延迟的方式释放活性成分。可以使用的包埋组合物的实例包括聚合物质和蜡。
如果合适,活性化合物也可以是具有一种或多种上述赋形剂的微胶囊化形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆剂和酏剂。除了活性化合物之外,液体剂型可以含有本领域通常使用的惰性稀释剂,例如水或其它溶剂、增溶剂和乳化剂如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇和脱水山梨醇的脂肪酸酯及其混合物。
除了惰性稀释剂之外,口服组合物还可以包括佐剂,例如润湿剂、乳化剂和悬浮剂、甜味剂、调味剂和芳香剂。
用于直肠或阴道给药的组合物优选是栓剂,其可以通过将本发明的化合物与合适的无刺激性赋形剂或载体例如可可脂、聚乙二醇或栓剂蜡混合而制成,他们在室温下是固体,但在体温下是液体,因此在直肠或阴道腔中熔化并释放活性化合物。
本发明的化合物也能够以脂质体的形式给药。如本领域已知的,脂质体通常衍生自磷脂或其它脂质物质。脂质体由分散在水性介质中的单层或多层水合液晶形成。可以使用任何能够形成脂质体的生理上可接受和可代谢的脂质。除了本发明的化合物之外,脂质体形式的本发明组合物还可含有稳定剂、防腐剂、赋形剂等。优选的脂质是分别或一起使用的天然和合成的磷脂和磷脂酰胆碱(卵磷脂)。形成脂质体的方法是本领域已知的。参见,例如,Prescott,Ed.,Methods in Cell Biology,Volume XIV,Academic Press,New York,N.Y.(1976),p.33 et seq。这些组合物将影响物理状态、溶解度、稳定性、体内释放速率和体内清除率。
在本发明的一种方法中,药物组合物可以在控释系统中递送。例如,可以使用静脉内输注、可植入渗透泵、透皮贴剂、脂质体或其他施用方式来施用药剂。在一个实施方式中,可以使用泵(参见Langer,supra;Sefton,CRC Crit.Ref.Biomed.Eng.14:201(1987);Buchwald et al.,Surgery 88:507(1980);Saudek et al.,N.Engl.J.Med.321:574(1989)。在另一个实施方式中,可以使用聚合物材料。在又一个实施方式中,控释系统可以放置在接近治疗靶标(例如肝脏)处,因此仅需要全身剂量的一部分(参见例如,Goodson,inMedical Applications of Controlled Release,supra,vol.2,pp.115-138(1984)。Langer(Science 249:1527-1533(1990))综述讨论了其他控释系统。
在另一方面,本发明涉及一种治疗受试者的疾病或病症的方法,包括向所述受试者施用有效量的本发明化合物。
通常,本发明不限于治疗任何特定的疾病或病症,而是包括治疗其机制可能受本发明化合物影响的任何疾病或病症。
代表性实施方式
紫杉醇-CLR1 404结合物
在本发明的一个实施方式中,治疗化合物是通过二羧酸连接体与CLR1404核心化合物连接的紫杉醇,其中二羧酸连接体通过酰胺键连接到CLR1404核心化合物上,并通过酯键连接到紫杉醇的2’-OH上。
在本发明的一个优选实施方式中,治疗化合物是通过谷氨酸连接体与CLR1404核心化合物连接的紫杉醇,其中谷氨酸连接体通过酰胺键连接到CLR1404核心化合物上,并通过酯键连接到紫杉醇的2’-OH上。
在本发明的另一个实施方式中,治疗化合物是通过二羧酸连接体与CLR1404核心化合物连接的紫杉醇,其中二羧酸连接体通过酰胺键连接到CLR1404核心化合物上,并通过酯键连接到紫杉醇的7-OH上。
在本发明的另一个实施方式中,治疗化合物是通过氨基甲酸连接体与CLR1404核心化合物连接的紫杉醇,其中氨基甲酸连接体通过酰胺键连接到CLR1404核心化合物上,并通过酯键连接到紫杉醇的7-OH上。
在本发明的另一个实施方式中,治疗化合物是通过碳-羧酸连接体与CLR1404核心化合物连接的紫杉醇,其中碳-羧酸连接体通过酰胺键连接到CLR1404核心化合物上,并通过酯键连接到紫杉醇的7-OH上。
在本发明的另一个实施方式中,治疗化合物是通过二羧酸连接体与两个CLR1404核心化合物连接的紫杉醇,其中二羧酸连接体通过酰胺键连接到CLR1404核心化合物上,并通过酯键连接到紫杉醇的2’-OH和7-OH上。
在本发明的另一个实施方式中,治疗化合物是通过二羧酸连接体与CLR1404核心化合物连接的紫杉醇,其中二羧酸连接体通过酰胺键连接到CLR1404核心化合物上,并通过碳酸酯或氨基甲酸酯键连接到紫杉醇的2’-OH上。
在本发明的另一个实施方式中,治疗化合物是通过二羧酸连接体与CLR1404核心化合物连接的紫杉醇,其中二羧酸连接体通过酰胺键连接到CLR1404核心化合物上,通过碳酸酯或氨基甲酸酯键连接到紫杉醇的7-OH上。
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在本发明的另一个实施方式中,治疗化合物是通过二羧酸连接体与两个CLR1404核心化合物连接的紫杉醇,其中二羧酸连接体通过酰胺键连接到两个CLR1404核心化合物上,通过碳酸酯或氨基甲酸酯键连接到紫杉醇的2’-OH和7-OH上。
在本发明的一个实施方式中,治疗化合物是通过羧酸连接体与C18烷基磷酸胆碱化合物连接的紫杉醇,其中羧酸连接体通过酰胺或碳酸酯键与C18烷基磷酸胆碱化合物连接,通过碳酸酯或氨基甲酸酯键连接到紫杉醇的2’-OH上。
伊立替康-CLR1404结合物
在本发明的一个实施方式中,治疗化合物是通过二羧酸连接体与CLR1404核心化合物连接的伊立替康,其中二羧酸连接体通过碳酸酯或氨基甲酸酯键连接到CLR1404核心化合物上,并通过酯键连接到伊立替康上。
伊立替康-C18烷基磷酸胆碱结合物
在本发明的一个实施方式中,治疗化合物是通过羰基连接体与C18烷基磷酸胆碱化合物连接的伊立替康,其中羰基连接体通过碳-碳键与C18烷基磷酸胆碱化合物连接,通过酯键连接到伊立替康上。
拓扑替康-CLR1404结合物
在本发明的一个实施方式中,治疗化合物是通过不可水解的苯基醚与CLR1404核心化合物连接的拓扑替康。
在本发明的另一个实施方式中,治疗化合物是通过二羧酸连接体与CLR1404核心化合物连接的拓扑替康,其中二羧酸连接体通过碳酸酯或氨基甲酸酯键连接到CLR1404核心化合物上,通过酯键连接到拓扑替康上。
吉西他滨-C18烷基磷酸胆碱结合物
在本发明的一个实施方式中,治疗化合物是通过羰基连接体与两个C18烷基磷酸胆碱化合物连接的吉西他滨,其中羰基连接体通过碳-碳键与C18烷基磷酸胆碱化合物连接,通过酯键连接到吉西他滨上。
在本发明的另一个实施方式中,治疗化合物是通过羰基连接体与C18烷基磷酸胆碱化合物连接的吉西他滨,其中羰基连接体通过碳-碳键与C18烷基磷酸胆碱化合物连接,通过酯键与西他滨连接。
顺铂-CLR1404核心结合物
在本发明的一个实施方式中,治疗化合物是直接连接到CLR1404核心化合物的顺铂。
格尔德霉素-CLR1404结合物
在本发明的一个实施方式中,治疗化合物是直接连接到CLR1404核心化合物的格尔德霉素。
在本发明的另一个实施方式中,治疗化合物是通过短氨基酸连接体与CLR1404核心化合物连接的格尔德霉素,其中短氨基酸连接体通过碳酸酯或氨基甲酸酯键连接到CLR1404核心化合物上,通过酯键连接到格尔德霉素上。
在本发明的一个优选实施方式中,治疗化合物是通过氨基丁酰胺连接体与CLR1404核心化合物连接的格尔德霉素,其中氨基丁酰胺连接体通过氨基甲酸酯键连接到CLR1404核心化合物上,通过酰胺键连接到格尔德霉素上。
美登素-CLR1404结合物
在本发明的另一个实施方式中,治疗化合物是通过马来酰亚胺连接体与CLR1404核心化合物连接的美登素,其中马来酰亚胺连接体通过酰胺键连接到CLR1404核心化合物上,通过碳-硫键连接到美登素上。
对于所有代表性实施方式,n是2至6的整数,X是O或NH。
实施例
实施例1-结合物的合成
I.CLR1601的合成
A.CLR1401叠氮化物的合成
在反应器内,将18-(对碘苯基)十八烷基磷酸胆碱(4.01g,6.3mmol)、叠氮化钠(818mg,12.6mmol)和抗坏血酸钠(140mg,0.71mmol)溶于脱气乙醇(28ml)和水(12ml)的混合物中。向反应混合物中加入碘化亚铜(I)(120mg,0.63mmol)和N,N'-二甲基-乙二胺(0.1ml,0.94mmol)。将反应器密封并将混合物在80℃下搅拌45分钟。将反应混合物冷却至室温,加入水(60ml),在空气中将混合物搅拌30分钟。将混合物转移到分液漏斗中,加入氯仿(80ml)和甲醇(52ml),振荡萃取。除去氯仿层,重复萃取(2×80ml氯仿)。合并的氯仿萃取液用0.01N HCl洗涤,用Na2SO4干燥,过滤并蒸发至干。将残余物溶于氯仿(4ml)中,并在搅拌下缓慢加入丙酮(170ml)。将混合物搅拌30分钟并过滤。将产物用丙酮在过滤器上漂洗,并在高真空下干燥,得到3.31g(95%)的18-(对-叠氮苯基)十八烷基磷酸胆碱。
B.CLR1401胺的合成
将18-(对-叠氮苯基)十八烷基磷酸胆碱(3.116g)加入Parr压力瓶中,加入甲醇(30ml)和10%Pd/C催化剂(100mg)。在氢气压力(55psi)和振荡下进行加氢反应24小时。将瓶减压,加入氯仿和甲醇以溶解一些沉淀的反应产物,并将混合物过滤除去催化剂。将滤液蒸发至干,将残余物溶于温热的氯仿-甲醇(1:1)混合物(10ml)中。在搅拌下缓慢加入热丙酮(150ml),将混合物在搅拌下冷却至环境温度并过滤。将产物用丙酮在过滤器上漂洗并在高真空下干燥。18-(对-氨基苯基)十八烷基磷酸胆碱的产量:2.597g(87%)。
C.紫杉醇-2'-半戊二酸酯的合成
将紫杉醇(404mg,0.437mmol)和戊二酸酐(67mg,0.588mmol)溶于氯仿(8ml)中,加入吡啶(0.5ml)。将反应混合物在室温下搅拌24小时并蒸发至干。将残余物保持在高真空下1.5小时以除去残留的吡啶。用氯仿-甲醇(梯度为98:2至95:5)通过硅胶色谱法纯化粗产物,得到452mg(99%)紫杉醇-2'-半戊二酸酯。
D.CLR1601的合成
将紫杉醇-2'-半戊二酸酯(947mg,0.978mmol)和18-(对-氨基苯基)十八烷基磷酸胆碱(492mg,0.934mmol)悬浮于氯仿(40ml)和异丙醇(1.2ml)混合物中。向该悬浮液中加入三甲胺(0.27ml,1.957mmol)和COMU(419mg,0.978mmol)。将反应混合物在室温下搅拌20小时,此时变得澄清和均匀。将反应混合物转移到分液漏斗中并与氯仿(40ml)、甲醇(80ml)和冷水(72ml)混合。除去氯仿层,重复萃取(2×80ml氯仿)。合并的氯仿萃取液用Na2SO4干燥,过滤并蒸发至干。剩余的残余物用氯仿-甲醇(梯度为9:1至5:5)通过硅胶色谱法纯化,最后用氯仿-甲醇-水(65:25:4)洗脱。蒸发溶剂后,将产物在高真空下干燥,得到1.167g(85%)CLR1601。
II.CLR1602的合成
A.18-[对-(4-N-BOC-氨基丁酰氨基)苯基]十八烷基磷酸胆碱的合成
将18-(对-氨基苯基)十八烷基磷酸胆碱(76mg,0.144mmol)和4-N-BOC-氨基丁酸(38mg,0.188mmol)悬浮于氯仿(5ml)和异丙醇(0.15ml)中,然后加入三乙胺(0.05ml,0.38mmol),然后加入COMU(80mg,0.188mmol)。将反应混合物在室温下搅拌24小时,并用2ml饱和NaHCO3水溶液淬灭。将淬灭的反应混合物转移到分液漏斗中并与氯仿(35ml)、甲醇(40ml)和冷水(36ml)混合。除去氯仿层,重复萃取(2×40ml氯仿)。合并的氯仿萃取液用Na2SO4干燥,过滤并蒸发至干。残余物用氯仿-甲醇(梯度为9:1至5:5)通过硅胶色谱法纯化,最后用氯仿-甲醇-水(65:25:4)洗脱。溶剂蒸发后,将产物溶于温热的氯仿-甲醇混合物(1.5ml)中,用丙酮沉淀。通过过滤收集产物,并在高真空下干燥,得到白色粉末(100mg,97%)。
B.18-[对-(4-氨基丁酰氨基)苯基]十八烷基磷酸胆碱的合成
将18-[(4-N-BOC-氨基丁酰氨基)苯基]十八烷基磷酸胆碱(98mg,0.138mmol)溶于氯仿(4ml)、甲醇(2ml)和浓HCl(0.2ml)的混合物中。将反应混合物在环境温度下搅拌过夜,然后通过缓慢加入饱和NaHCO3溶液(3ml)淬灭。将淬灭的反应混合物转移到分液漏斗中并与氯仿(40ml)、甲醇(40ml)和冷水(36ml)混合。除去氯仿层,重复萃取(2×40ml氯仿)。合并的氯仿萃取液用Na2SO4干燥,过滤并蒸发至干。产物用氯仿-甲醇(100:65)通过硅胶色谱法纯化,最后用氯仿-甲醇-浓NH4OH(aq)(100:65:15)洗脱。蒸发溶剂后,将产物在高真空下干燥,得到50mg(60%)18-[对-(4-氨基丁酰氨基)苯基]十八烷基磷酸胆碱。
C.7-(对硝基苯基碳酸酯)紫杉醇的合成
将紫杉醇(100mg,0.117mmol)溶于氯仿(4.5ml)中,加入8滴吡啶,将溶液在冰浴中冷却。一份加入固体对-硝基苯基氯甲酸酯(200mg,1mmol)。将反应混合物温热至室温并搅拌24小时,然后用水(1ml)淬灭并搅拌15分钟。混合物用氯仿萃取,萃取液用水洗涤,用Na2SO4干燥,过滤并蒸发至干。粗二-2',7-(对硝基苯基碳酸酯)紫杉醇溶解在氯仿中并上样到硅胶柱上。使粗产物在柱中停留72小时以完成对-硝基苯基碳酸酯2'-位上的水解。用二氯甲烷-乙酸乙酯(梯度为98:2至90:10)洗脱柱子。蒸发溶剂后,产物用己烷沉淀并在高真空下干燥,得到63mg(53%)7-(对-硝基苯基碳酸酯)紫杉醇。参见Arpicco S.,et al.,IntJ Pharm,2013,454,653-659。
D.CLR1602的合成
7-(对-硝基苯基碳酸酯)紫杉醇(53mg,0.052mmol)和18-[对(4-氨基丁酰氨基)苯基]十八烷基磷酸胆碱(47mg,0.077mmol)悬浮于氯仿(2ml)和吡啶(0.5ml)中,并在40℃下搅拌5小时。将反应混合物蒸发至干,残余物用氯仿-甲醇(梯度为9:1至5:5)在硅胶上进行色谱纯化,最后用氯仿-甲醇-水(65:25:4)洗脱。蒸发溶剂后,将化合物在高真空下干燥,得到67mg(86%)固体CLR1602。
III.CLR1603的合成
A.18-[对-(5-苄氧基-戊酰氨基)苯基]十八烷基磷酸胆碱的合成
将18-(对-氨基苯基)十八烷基磷酸胆碱(760mg,1.443mmol)和5-苄氧基戊酸(361mg,1.732mmol;根据Can J Chem,1992,70,1472-1445和Org Lett,2014,16,516-519合成)悬浮于氯仿(25ml)中,加入三乙胺(0.3ml,2.164mmol),然后加入固体COMU(741mg,1.732mmol)。将反应混合物在室温下搅拌24小时,完成后转移到分液漏斗中,与氯仿(55ml)、甲醇(80ml)和冷水(72ml)混合。除去氯仿层,重复萃取(2×80ml氯仿)。合并的氯仿萃取液用Na2SO4干燥,过滤并蒸发至干。残余物用氯仿-甲醇(梯度为9:1至5:5)通过硅胶色谱法纯化,最后用氯仿-甲醇-水(65:25:3)洗脱。溶剂蒸发后,在高真空下干燥,将产物溶于温热的氯仿-甲醇混合物(3ml)中,搅拌下缓慢加入热丙酮(75ml)。将混合物在搅拌下冷却至环境温度并过滤。收集的产物在高真空下干燥,得到18-[对-(5-苄氧基-戊酰氨基)苯基]十八烷基磷酸胆碱(887mg,86%),为白色粉末。
B.18-[对-(羟基-戊酰氨基)苯基]十八烷基磷酸胆碱的合成
将18-[对(5-苄氧基-戊酰氨基)苯基]十八烷基磷酸胆碱(868g)溶解在甲醇(15ml)中,转移到Parr压力瓶中,并加入10%Pd/C催化剂(75mg)。在氢气压力(55psi)和振荡下进行加氢反应24小时。将瓶减压,混合物过滤除去催化剂。将滤液蒸发至干,将残余物溶于温热的氯仿-甲醇混合物(3-4ml)中。在搅拌下缓慢加入热丙酮(75ml)。将混合物在搅拌下冷却至环境温度并过滤。收集的产物在高真空下干燥,得到18-[对-(5-羟基)-戊酰氨基)苯基]十八烷基磷酸胆碱(718mg,95%),为白色粉末。
C.18-[对-(5-硝基-苯氧基羰基氧基)戊酰氨基)苯基]十八烷基磷酸胆碱的合成
将18-[对-(5-羟基-戊酰氨基)苯基]十八烷基磷酸胆碱(40mg,0.064mmol)和氯甲酸对-硝基苯酯(25mg,0.124mmol)悬浮于氯仿(3ml)中,加入吡啶(0.2ml)。将反应混合物在室温下搅拌24小时。加入额外的氯甲酸对-硝基苯酯(15mg),继续搅拌1.5小时。通过TLC分析反应完成。将反应混合物用1ml 1N HCl淬灭并用氯仿(20ml)、甲醇(20ml)和冷水(15ml)转移到分液漏斗中。重复萃取(3×20ml氯仿)。合并的氯仿萃取液用Na2SO4干燥,过滤并蒸发至干。残余物用氯仿-甲醇(梯度为9:1至5:5)通过硅胶色谱法纯化,最后用氯仿-甲醇-水(65:25:4)洗脱。蒸发溶剂后,用丙酮沉淀,残余物在高真空下干燥,得到48mg(95%)固体物质。
D.CLR1603的合成
在反应瓶中,将紫杉醇(46mg,0.054mmol)和18-[对(5-(对-硝基-苯氧基羰氧基)戊酰氨基)苯基]十八烷基磷酸胆碱(43mg,0.054mmol)悬浮于氯仿(2ml)和吡啶(0.5ml)中。加入DMAP(8mg,0.065mmol),将反应瓶密封并将内容物在60℃下搅拌48小时。加入额外量的紫杉醇(20mg),并在60℃下继续反应48小时。浓缩反应混合物,残余物用氯仿-甲醇(梯度为9:1至5:5)通过硅胶色谱纯化,最后用氯仿-甲醇-水(65:25:2)和(65:25:4)洗脱。蒸发溶剂并在高真空下干燥,得到CLR1603(50mg,62%)。
IV.CLR1607的合成
将格尔德霉素(111mg,0.198mmol)和18-[对-(4-氨基丁酰氨基)苯基]十八烷基磷酸胆碱(110mg,0.18mmol)溶于氯仿(3.5ml)和甲醇(1ml)中。加入一滴三乙胺,将反应混合物在室温下搅拌24小时。TLC显示反应完成约80%。加入额外的格尔德霉素(10mg),继续搅拌24h。将反应混合物浓缩,残余物用氯仿-甲醇(梯度为9:1至5:5)通过硅胶色谱纯化,最后用氯仿-甲醇-水(65:25:2),(65:25:3)和(65:25:4)洗脱。溶剂蒸发后,在高真空下干燥,加入丙酮,蒸发混合物。获得紫色固体的CLR1607(174mg,85%)。
通过1H-nmr和质谱分析证实了每种分离产物。
实施例2至8显示CLR1404和相关分子被各种癌症类型耦合和保留,同时从健康组织中消除的能力。
V.CLR1608的合成
A.CLR1401马来酰胺酸的合成
将CLR1401胺(300mg,0.57mmol)在90℃下溶于N,N-二甲基乙酰胺(12ml)中,一份中加入马来酸酐(61mg,0.627mmol)。将反应混合物在90℃下搅拌1小时,冷却至室温并搅拌24小时。在搅拌下缓慢加入丙酮(25ml),将混合物在室温下搅拌1小时。将沉淀的产物过滤并用丙酮在过滤器上漂洗,然后在高真空下干燥。产量:327mg(92%)。
B.CLR1401马来酰亚胺的合成
将CLR1401马来酰胺酸(100mg,0.16mmol)悬浮于不含乙醇的氯仿(5ml)中,然后加入三乙胺(0.05ml,0.352mmol)和COMU(75mg,0.176mmol)。将反应混合物搅拌24小时,然后转移到分液漏斗中,与氯仿(40ml)、甲醇(40ml)和冷水(36ml)混合。除去氯仿层,重复萃取(2×40ml氯仿)。合并的氯仿萃取液用Na2SO4干燥,过滤并蒸发至干。剩余的残余物用氯仿-甲醇(梯度为9:1至5:5)通过硅胶色谱法纯化,最后用氯仿-甲醇-水(65:25:4)洗脱。蒸发溶剂后,产物用丙酮沉淀,收集,在高真空下干燥,得到87mg(90%)CLR1401马来酰亚胺。
C.CLR1608的合成
将CLR1401马来酰亚胺(40mg,0.066mmol)和美登素(53mg,0.072mmol)溶于氯仿(1.7ml)和甲醇(0.3ml)的混合物中。加入三乙胺(0.08ml),将混合物在37℃下搅拌24小时。将反应混合物浓缩,残余物用氯仿-甲醇(梯度为9:1至5:5)在硅胶上色谱纯化,最后用氯仿-甲醇-水(65:25:3)洗脱。蒸发溶剂后,将产物在高真空下干燥,得到62mg(70%)CLR1608。
实施例2-CLR1501被癌细胞通过脂筏优先耦合
材料和方法:
PC-3细胞用2μg/ml的菲律宾菌素III或载体预处理15分钟,然后洗涤并用2μCi的125I-CLR1404培养1小时。除去培养基,用含有0.1%牛血清白蛋白的磷酸盐缓冲盐水洗涤细胞,胰蛋白酶消化,然后分成两个样品用于通过DNA含量(与细胞系特异性标准曲线相比的A280)测定细胞数并使用伽马计数器(Perkin Elmer)测定每分钟计数。
结果:
与未处理的对照细胞相比,用菲律宾菌素III(其是螯合胆固醇并破坏脂筏的物质)预处理PC-3细胞,导致125I-CLR1404的摄取减少近40%(图1)。这支持了CLR1404使用脂筏作为癌细胞侵入门户的假设。值得注意的是,更高的菲律宾菌素III浓度是细胞毒性的,因此不能证明脂筏完全消融(并且推测完全抑制CLR1404类似物的摄取)。
实施例3-癌细胞相对于健康细胞对CLR-1501的优先摄取
材料和方法:
人癌细胞系购自美国典型培养物保藏中心(ATCC),包括:Caki-2(肾,透明细胞癌)、HCT-116(结肠直肠癌)、MES-SA/Dx5(子宫肉瘤)[全部保持在补充有10%胎牛血清(FBS)的McCoy's 5a培养基中]、Ovcar-3(卵巢腺癌)[保持在补充有20%FBS的RPMI培养基中]、U87-MG(神经胶质瘤)[保持在补充有10%FBS的最小必需培养基中]、Mia Paca-2(胰腺癌)(保持在补充有10%FBS的Dulbecco改性的Eagle's培养基中)、PC-3(前列腺癌)(保持在补充有10%FBS的F-12K培养基中)、MDA-MB-231(三阴性乳腺癌)(保持在补充有10%FBS的Leibovitz’s培养基中)和A549(非小细胞肺癌)(保持在补充有10%FBS的F-12培养基中)。正常人皮肤成纤维细胞购自ATCC,并在补充有无血清试剂盒的成纤维细胞基础培养基PCS-201-030(成纤维细胞生长试剂盒-无血清PCS-201-040)中生长。所有培养基(MDA-MB-231细胞系除外)还含有青霉素(100U/ml)和链霉素(100μg/ml),并保持在37℃、含有5%CO2的空气中。
所有细胞保持在37℃补充有10%FBS和5%CO2的合适培养基中。在成像之前,用0.25%胰蛋白酶从烧瓶中取出细胞,并在显微镜载物片VI(Ibidi)上生长过夜。第二天,用磷酸盐缓冲盐水(PBS)洗涤细胞,并在合适的无血清培养基中用5或7.5μM(如所指出的)的CLR1501培养24小时。CLR1501是荧光标记的CLR1404类似物。用0.4%的聚山梨酸酯20、2%的乙醇和盐水配制CLR1501。用PBS彻底洗涤后,使用Bio-Rad Radiance2100MP彩虹激光扫描/多光子共聚焦显微镜,以1秒曝光时间对细胞进行成像。或者使用Nikon AIR共焦显微镜(Keck Laboratory,University of Wisconsin-Madison)观察细胞。使用Alexa Fluor 488滤波器(ex/em 480/520nm)检测CLR1501的发射信号。
结果:
CLR1501体外给药于五种不同的癌细胞系(肾、卵巢、胰腺、黑素瘤和前列腺)和正常人皮肤成纤维细胞系。二十四小时后,CLR1501在这些癌细胞系中的体外优势摄取为正常成纤维细胞的五至九倍(图2)。保留的CLR1501与血浆和细胞器膜有关。
实施例4-大鼠胶质瘤模型
材料和方法:所有动物根据威斯康辛大学研究动物资源中心指南进行饲养和处理。在补充有10%热灭活FBS(BioWhittaker,Walkersville,MD)、100U/ml青霉素G、100mg/ml链霉素和0.01M HEPES(Life Technologies,Gaithersburg,MD)的DMEM培养基(LifeTechnologies,Gaithersburg,MD)中繁殖大鼠C6胶质瘤细胞。如前所述进行颅内肿瘤植入。Cohen JD,et al.,Intracranial C6 glioma model in adult Wistar-Furth rats.JNeuro Oncol 19908(1):95-6。简言之,将1×106个C6细胞重悬于5ml 1.2%甲基纤维素中,并注射到麻醉的雌性Wistar大鼠(Harlan,Indianapolis,IN)的额叶上。假手术的动物进行等体积不含肿瘤细胞的甲基纤维素的颅内注射。
成像研究:植入10天后,MRI证实存在颅内肿瘤。简言之,麻醉大鼠(6)腹膜内接受2ml钆双胺(Gd,Omniscan 287mg/ml,Nycomed,Princeton,NJ),并使用1.5特斯拉临床MR系统(GE Signa LX)和GE相控阵列末端线圈成像。检查覆盖每只大鼠全脑的Tl加权(TR=500ms,TE=16.5ms)多层序列以选择具有不同肿瘤大小的荷瘤大鼠,以及用于NM404注射的假手术大鼠。
将NM404[18-(4-碘苯基)-十八烷基磷酸胆碱](100mg)通过与新戊酸熔体中的Na125I进行同位素交换用125I进行放射性碘化。Weichert,et al.Int J Appl RadIsotopes.1986;37:907-913。NM404具有与CLR1404相同的化学结构,不同之处在于其用125I而不是124I或131I进行放射性碘化。在HPLC纯化之后,将NM404溶于2%聚山梨醇酯20水溶液中,然后在尾静脉注射(5-20μCi/200g大鼠)到四个荷瘤和三只假手术大鼠中。在NM404注射后的1天(n=1)、2天(n=1)和4(n=2)天,将动物安乐死(CO2),并将大脑切除并在改良的Bioscan AR2000放射性TLC扫描仪(1毫米增量,2分钟采集/通道和1毫米高分辨率准直器)上成像。此外,对正常脑、血液、肾脏、肝脏、脾脏、甲状腺和肿瘤组织称重,并在γ计数器中计数放射性。然后将放射性的组织分布与脑组织学相关。
结果与讨论:NM404的初始影像学检查结果显示,在直径为3-5毫米所有神经胶质瘤中具有显著的摄取和延长的保留。在假手术对照动物中,正常脑组织的放射性最小(图4A和4B)。而NM404在神经胶质瘤中高度集中(图4A’-D’)。在荷C6神经胶质瘤的大鼠中肿瘤与脑的比例(%注射剂量/g)在24、48和96h时分别为10.5、12.2和6.7。如先前的细胞培养和体内动物模型研究中已经观察到的,NM404明显地被代谢并从正常细胞中消除,但被代谢地集中在肿瘤细胞膜中。以前在其他肿瘤模型中的放射自显影实验表明,只有活的肿瘤细胞,而不是正常组织或坏死组织,才能积累NM404。有趣的是,甚至在NM404给药后也检测到直径为几毫米的小肿瘤。这些初步研究结果表明,CLR1404也可用于小型侵入性肿瘤灶的可视化。
结论:
如以前检测的所有肿瘤模型中,NM404在本研究中评估的大鼠C6-神经胶质瘤显示出选择性和延长的保留。
实施例5-各种恶性肿瘤中124I-CLR1404的摄取
材料和方法:
所有描述的动物研究均按照机构动物护理和使用委员会批准的动物方案进行。使用重16-18g(n=6)的约4至5周龄的雌性无乳腺裸小鼠(Hsd:Athymic Nude-Foxnlnu或Crl:NU-Foxnlnu,Charles River Laboratories)进行人肿瘤异种移植研究。将小鼠用异氟烷麻醉并皮下注射置于100μl Dulbecco's PBS中的活肿瘤细胞(或胶质瘤细胞,50ml PBS)到右侧腹部。接种量为1×106(对于肾、卵巢、神经胶质瘤、胰腺、前列腺和NSCLC模型)、2×106(用于结直肠和子宫模型)或3×106(乳腺)。
结果:
在60种不同的自发、转基因、人和啮齿动物恶性细胞系和肿瘤类型的皮下和原位异种移植物中测试放射性碘化的124I-CLR1404。静脉内给药后,无论解剖位置如何,124I-CLR1404集中于几乎所有原发性和转移性恶性肿瘤中。代表性的例子是人(图5A-5I)和啮齿动物(图5J-M)肿瘤。
表1.124I-CLR1404在大量癌症类型中的摄取
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*如果肿瘤与肌肉之比大于3,认为肿瘤摄取是阳性的。肿瘤与肌肉之比小于或等于2,认为肿瘤摄取是阴性的。
实施例6-使用CLR1404评价非小细胞肺癌患者(“NSCLC”)的临床试验
尽管在55/60异种移植物和自发性啮齿动物模型中CLR1404已经显示出选择性和延长的肿瘤保留,但是医师赞助IND启动了4期人NSCLC患者的药物的临床评价,以确定其在人体内是否将表现出类似的肿瘤摄取和保留的性质。到目前为止,对两名注射了<1mCi131I-CLR1404的晚期NSCLC患者进行成像。在预定时间收集血液和尿样,并在给药后的几个时间点进行γ成像。在两个患者中,证实在原发性肺肿瘤中,CLR1404具有显著的肿瘤摄取和保留,如图6所示。相对于先前使用其第一代前身NM324时观察到的高的肝摄取值,CLR1404的肝脏和腹部活性要低得多,表明在其他腹部癌症包括胰腺、结肠和前列腺中评估该药物的可行性。
材料和方法:在静脉注射碘-131标记的CLR1404(1mCi/20μg)后,在3、6、24、48、96h和7天和11天,用GE Maxxus双倍体头SPECT扫描仪对晚期NSCLC患者进行扫描。收集血液和尿样进行药代动力学分析以及临床血液学、肾脏和肝脏生物分析。
结果:初始定性成像结果表明,碘-131标记的CLR1404早在注射后24h明确集中在双侧肺肿块中,并且选择性保留在这些肿瘤中超过11天。此外,肝脏和下腹部区域(包括膀胱、肾脏和肠)的背景放射性显著小于其前身NM324先前观察到的背景放射性。在任何患者中均未观察到不良反应。
结论:这些初步研究结果表明CLR1404在人NSCLC中表现出类似的肿瘤摄取和保留性质,如之前在啮齿动物模型中所见。虽然现在只有两名患者,但似乎CLR1404确实集中于人非小细胞肺癌中并具有选择性和延长的肿瘤保留。
患者1:55岁,男性,患有双侧3厘米左叶和浸润性右叶NSCLC和脑转移和小的右肾上腺肿块。他参加了许多标准和实验治疗方案。图像示于图6A-C。
患者2:70岁,男性,最近诊断为6厘米上叶非小细胞肺癌,5厘米肝脏肿块,髂骨转移和非常少的脑转移。在开始CLR1404试验前一周,他最近完成了低剂量卡铂/紫杉酚化疗和姑息性放射治疗髂和脑转移。图像示于图6D-G。
实施例7-使用124I-CLR1404检测NSCLC患者中3种以前未知的脑肿瘤转移
材料和方法:
在注射大约5mCi的124I-CLR1404之后的多个时间点,使用90分钟动态采集序列(2D、每10分钟9个帧,VIP列表模式)在64层PET/CT扫描仪(Discovery VCT,GeneralElectric)上获得人PET脑扫描图,并重建[Advantage Workstation version AW4.4,General Electric,30cm DFOV(显示视野),128×128,OSEM VUE点,有两个迭代的10个子集,标准z轴,衰减校正和死时间,散射和衰减校正]。
结果:
使用124I-CLR1404 PET/CT,在无神经症状的NSCLC患者中获得初步结果。成像显示三个以前未知的脑损伤高度可疑的转移,随后用钆增强MRI证实(图7)。
实施例8-使用124I-CLR1404检测右前额肿瘤转移的肿瘤复发
60岁女性恶性黑色素瘤患者复发性脑转移。磁共振(“MR”)(图8A)和124I-CLR1404PET图像(图8B)和立体定向放射外科手术治疗肿瘤复发的右前额肿瘤转移8个月后的图像(图8C)表明CLR1404异常活动病灶(箭头)。对初始MR成像的相应增强病灶被解释为对抗可能的复发的辐射坏死。随后的MR成像表明非特异性增强病变的尺寸进一步增加,加上周围水肿增加,表明恶性肿瘤复发。这些结果表明,124I-CLR1404被耐放射外科手术的癌细胞螯合,最终建立了复发性肿瘤。
本发明的化合物包括与CLR1404核心分子连接的抗癌药物。这些化合物能够靶向包括脑癌细胞在内的癌细胞和癌干细胞,使得抗癌药物被癌细胞螯合和保留。这些化合物提供了能够适应于向癌细胞特异性施用一系列抗癌药物以治疗癌症并预防转移和复发的癌症的第一靶向治疗。
实施例9-紫杉醇结合物和在各种癌细胞系的IC50
方法
用系列浓度的紫杉醇和CLR1404-紫杉醇结合物(即CLR1601、CLR1602和CLR1603)处理癌细胞系,包括MDA-MB-468(乳腺)、NCI-H1299(肺)、NCI-H460(肺)、Capan-2(胰腺)、MiaPaCa-1(胰腺)、HT29(结直肠)、HCT116(结直肠)和PC-3(前列腺)。然后测量细胞系的细胞活力,并报告每次治疗的IC50。
结果:
CLR1601和CLR1603能够降低MDA-MB-468(乳腺)、NCI-HI299(肺)、NCIH460(肺)、Capan-2(胰腺)、MiaPaCa-1(胰腺)、HT29(结直肠)、HCT116(结直肠)和PC-3(前列腺)癌细胞系的细胞活性。分别见图9-16。每种紫杉醇-1440结合物(即CLR1601和CLR1603)和紫杉醇的IC50报告在表2中。但未显示CLR1602的IC50,因为CLR1602是不可水解的,所以CLR1602不能显着降低癌细胞系的活力。在体内,由于紫杉醇摄取的非特异性,游离紫杉醇以较低的速率被癌性肿瘤细胞摄取。因此,在体内,癌细胞死亡所必需的PLE-紫杉醇结合物的量应等于或小于紫杉醇的量,并且可能使对非癌细胞的毒性大大降低。
表2.CLR1601、CLR1603和紫杉醇的IC50
实施例10-流式细胞术测定
方法
利用Annexin V和PI(磷脂酰肌醇)染色通过流式细胞术测定活细胞、早期凋亡细胞、晚期凋亡细胞和坏死细胞的百分比。简而言之,用细胞毒性药物处理细胞并用AnnexinV PI标记试剂盒(Life Technologies)染色。在LSRII流式细胞仪(BD Biosciences)上分析细胞。如表3-9所示,细胞分为:活细胞(Annexin V阴性,PI阴性)、早期凋亡细胞(Annexin V阳性,PI阴性)、晚期凋亡细胞(Annexin V阳性,PI阳性)和坏死细胞(Annexin V阴性,PI阳性)。图17中显示了用5μM CLR1601处理72小时的MDA-MB-468细胞的代表性散点图。AnnexinV(附着于AlexaFluor 488)显示在x轴上,PI显示在y轴上。左下象限表示活细胞,左上象限表示坏死细胞,右上象限表示晚期凋亡细胞,右下象限表示早期凋亡细胞。该分析中去除了碎片。
结果:
MDA-MB-468细胞(三阴性乳腺癌细胞系),用CLR结合物(CLR1601和CLR1603)处理72小时,用紫杉醇(“PTX”)处理24小时。见表3。MDA-MB-468细胞也用CLR结合物(CLR1606和CLR1607)处理72小时,用格尔德霉素(“GEL”)处理48小时。见表4。对于PTX结合物,用1μMCLR1601、5μM CLR1601、1μM CLR1603、5μM CLR1603、100nM PTX和1μM PTX处理后,细胞活力从61.1%(无药物处理)分别降低至17.0%、17.8%、22.2%、19.7%、53.8%和48.9%。见表3。对于GEL结合物,用1μM CLR1606、10μM CLR1606、1μM CYR1607、10μM CLR1607和1μM GEL处理后,细胞存活率从61.1%分别降低至58.8%、42.7%、52.7%、56.9%和26.2%。见表4。
表3.用紫杉醇结合物处理72小时的MDA-MB-468
表4.用格尔德霉素结合物处理72小时的MDA-MB-468细胞
COLO 829细胞(黑素瘤细胞系)用GEL结合物(CLR1606和CLR1607)处理72小时和GEL处理48小时。见表5。用1μM CLR1606、10μM CLR1606、1μM CLR1607、10μMCLR1607、100nMGEL和1μM GEL处理后,细胞活力从80.8%(无药物处理)分别降低至70.4%、21.1%、67.9%、54.3%、32.4%和18.6%。见表5。
表5.用格尔德霉素结合物处理72小时的COLO 829细胞
PANC-1细胞(胰腺癌细胞系)用GEL结合物(CLR1606和CLR1607)处理72小时和GEL处理48小时。见表6。用1μM CLR1606、10μM CLR1606、1μM CLR1607、10μMCLR1607、100nM GEL和1μM GEL处理后,细胞活力从44.2%(无药物处理)分别降低至42.0%、21.5%、44.0%、33.0%、23.3%和18.9%。见表6。
表6.用格尔德霉素结合物处理72小时的PANC-1细胞
22RV1细胞(前列腺细胞系)用GEL结合物(CLR1606和CLR1607)处理72小时和GEL处理48小时。见表7。无药物处理后和用1μM CLR1606、10μM CLR1606、1μMCLR1607、10μMCLR1607、100nM GEL和1μM GEL处理后,细胞活力分别为20.3%、21.3%、16.0%、21.9%、15.7%、19.4%和28.1%。见表7。该细胞系的基底细胞死亡率高;细胞对细胞收集的方法没有很好的反应。
表7.用格尔德霉素处理72小时的22RV1细胞
CLR结合物似乎需要更长的细胞治疗期,来诱导细胞死亡。用1μM CLR1601和1μMCLR1603处理MDA-MB-468细胞48小时导致细胞活力从86.2%(无药物处理)分别降低至79.4%和81.4%。见表8。用1μM CLR1606和1μM CLR1607处理COLO 829细胞48小时导致细胞活力从91.7%(无药物处理)分别降低至90.1%和82.7%。见表9。
表8.用紫杉醇结合物处理48小时的MDA-MB-468
表9.用格尔德霉素结合物处理48小时的COLO 829细胞
总体上,表明PLE-紫杉醇和PLE-格尔德霉素结合物能够降低肿瘤细胞活力,包括诱导多种肿瘤类型的细胞死亡。
Claims (10)
1.一种包括式A-B-D的治疗化合物,其中:
A是至少一种式(I)的化合物,
(I),至少一种式(II)的化合物,
(II),至少一种式(III)的化合物,
(III),或其组合,
其中W选自由芳基、C1-C6烷基、烯基、任选取代的C3-C6环烷基、任选取代的C3-C6杂环烷基、组成的组,其中R是H或烷基,其中m是12-24的整数;
B是连接体化合物,所述连接体化合物是键或式(Ⅳ)的化合物,
Y-(CH2)n-Z(Ⅳ),其中:
Y与A结合;
Z与D结合;
Y选自由键、O、NH、C=O、NHSO2O和OC(=O)O组成的组;
Z选自由O、NH、C=O、C(=O)O、C(=O)NH、SO2和OC(=O)OCH2组成的组;以及
n为0至6的整数;以及
D是抗癌药物,所述抗癌药物选自由紫杉醇(paclitaxel)、伊立替康(irinotecan)、托泊替康(topotecan)、吉西他滨(gemcitabine)、顺铂(cisplatin)、格尔德霉素(geldanamycin)和美登素(mertansine)组成的组。
2.根据权利要求1所述的治疗化合物,其中:
A是式(I)的化合物,其中W是m是18;
B是式(Ⅳ)的化合物,其中Y是C=O,Z是C=O、C(=O)NH或C(=O)O,n是3或4;以及
D是紫杉醇。
3.根据权利要求1所述的治疗化合物,其中:
A是式(I)的化合物,其中W是m是18;
B是键或式(IV)的化合物,其中Y是C=O,Z是NH,n是1或3;以及
D是格尔德霉素。
4.根据权利要求1所述的治疗化合物,其中:
A是式(I)的化合物,其中W是m是18;
B是键;以及
D是美登素。
5.一种选自由
以及/>组成的组的治疗化合物,
其中n为0至6的整数,X是O或NH。
6.一种式(V)的治疗化合物,
7.一种药物组合物,包括权利要求1、5或6所述的治疗化合物和一种或多种药学上可接受的载体。
8.一种如权利要求1、5或6所述的治疗化合物在制备治疗癌症的药物中的应用,包括将有效量的权利要求1、5或6所述的治疗化合物给予癌症受试者。
9.根据权利要求8所述的应用,其中所述癌症包括癌干细胞。
10.根据权利要求8所述的应用,其中所述癌症是复发性的。
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