CN109310681A - 包含对肿瘤酸度有选择性的抗肿瘤剂、抗氧化剂和p-糖蛋白抑制剂的抗肿瘤混合物 - Google Patents
包含对肿瘤酸度有选择性的抗肿瘤剂、抗氧化剂和p-糖蛋白抑制剂的抗肿瘤混合物 Download PDFInfo
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Abstract
本发明涉及以选择性地破坏实体肿瘤细胞而不影响快速复制的健康细胞为目的抗肿瘤混合物，其包含商业抗肿瘤药物(1)例如9‑吖啶羧酸联合抗氧化剂(2)例如辅酶Q10以及P‑糖蛋白抑制剂(3)例如二甲双胍、酮康唑、奎尼丁、维拉帕米、环孢菌素、红霉素、螺内酯、伊曲康唑、他立喹达、唑喹达、依克立达、拉尼喹达、个体发育剂、咪唑、邻氨基苯甲酰胺、右维拉帕米和/或右尼古地平的组合。
Description
本发明涉及一种对抗所有类型的实体癌症的混合物，此处称为“抗肿瘤混合物”，所述抗肿瘤混合物包含对肿瘤酸度有选择性的抗肿瘤剂、抗氧化剂和P-糖蛋白抑制剂。这种混合物能够有效地选择性地破坏实体肿瘤的细胞，而不影响快速复制的健康细胞。
针对癌症的第一化疗剂是吖啶。吖啶(二苯[b,e]吡啶或10-氮杂蒽)由Graebe于1871年分离；由Wirth于1926年从高沸点油中分离(专利DE440771)；由Perkin于1923年从N-苯基邻氨基苯甲酸制备(专利GB214756)；由Koller于1928年从邻氨基苯甲酸钙制备(Monatsh.50,51)；由Myer于1916年(Monatsh.,37,698)以及由Ullmann于1907年(Ber.40,2521)通过热铂丝传递苄基苯胺的蒸气而制备。Lhome等人(1994年11月14日的专利申请WO94/25439)制备了衍生自吖啶的具有抗肿瘤性质的物质，例如(3,6-双-二甲基氨基-吖啶-4-基)-甲醇。Ferlin等人(Eur.J.Med.Chem.35:827-837,2000)制备了具有抗肿瘤活性(包括对DNA-拓扑异构酶II的抑制作用)的9-吖啶和氮杂吖啶(m-AMSA类似物)的被取代的衍生物。尽管这些吖啶类物质对DNA拓扑异构酶呈现了选择性活性，但是已知它们表现出高毒性，同时破坏肿瘤细胞和健康细胞。上文引用的文献均未提出对肿瘤具有高选择性的化合物。目前，更大活性的且毒性更小的化疗剂可用于在临床实践中使用。化疗剂通过中断或减缓快速生长和分裂的癌细胞的生长而工作。然而，除了能够经常导致肾和心脏并发症之外，化疗剂还可以损害快速分裂的健康细胞，例如口腔和肠的内衬(lining)中的那些细胞、负责防御的白细胞以及使毛发生长的细胞。开发抗肿瘤化疗剂的主要目的是提高选择性，并且因此减少不期望的副作用。为了减少由于这些抗肿瘤药物的非选择性引起的其副作用，将这些抗肿瘤药物与糖分子化学结合，因为恶性肿瘤需要比健康细胞多约十倍的葡萄糖。通过葡萄糖携带的抗肿瘤药物的实例是D-19575，也被称为葡磷酰胺，其被公布在美国专利第5 622936号中，以及葡萄糖-苯丁酸氮芥的衍生物(Halmos,T.,Santarromana,M.,Antonakis,K.,Sherman,D.European Journal of Pharmacology:318:477-484,1996)。然而，这些药物最终影响健康细胞，因为健康细胞也需要葡萄糖来生存。
无一例外，实体肿瘤在其细胞组织中呈现高酸度，其特征在于氢离子(H+)的存在。众所周知的是，当实体肿瘤达到一定尺寸时，氧气在实体肿瘤中的渗透变得受限。在这样的条件下，因为氧气不足，氧化磷酸化作用不能正常地进行，导致高乳酸产生量，这导致恶性肿瘤组织的酸化，甚至允许其增殖(Gatenby,R.A.,Gillies,R.J.Nat.Rev.Cancer 4:891-899,2004；Warburg,O.,Review.Science 123:309-315,1956)。关于实体肿瘤的酸度参见下表1(a：pHi，通过NMR-P31测量；B：pHe:通过玻璃微电极或电位计测量)。Br.J.Cancer(1991)64,425-427。
表1
本发明涉及一种由三种分子组成的混合物，此处称为“抗肿瘤混合物”，所述抗肿瘤混合物包含对肿瘤酸度有选择性的抗肿瘤剂、抗氧化剂和P-糖蛋白抑制剂，能够通过对肿瘤细胞的酸度的选择性使用混合物的抗肿瘤剂中的羧基型载体(该载体对所有类型的恶性实体肿瘤中存在的酸度敏感)选择性地破坏实体肿瘤的细胞，而不影响快速复制的健康细胞。由于实体肿瘤的特征性酸度，包含具有负电荷的羧酸基团的这种抗肿瘤化合物(衍生自吖啶)，通过静电力被吸引至肿瘤的内部，所述实体肿瘤具有过量的带正电荷的氢离子(H+离子)，当吖啶的羧酸基团与肿瘤的氢离子H+结合时，带正电荷的氢离子吸引并然后中和吖啶的羧酸基团的负电荷，由于肿瘤酸度，实体肿瘤具有过量的带正电荷氢离子，以将吖啶药物携带至肿瘤细胞的DNA，因为仅中性分子可以非常容易地穿过细胞膜，导致肿瘤细胞凋亡或细胞自我破坏，而快速繁殖的健康细胞不在它们周围呈现酸度，即它们不具有吸引带负电荷的抗肿瘤化合物的能力，因此免受化疗剂的破坏作用。
此外，本发明还使用抗氧化剂例如辅酶Q10，其功能是降低由抗肿瘤剂天然产生的自由基的毒性，因此在治疗期间保护健康细胞免受这些自由基的作用的影响。此外，根据本发明的混合物还包含P-糖蛋白抑制剂，例如二甲双胍、酮康唑、奎尼丁、维拉帕米、环孢菌素、红霉素、螺内酯、伊曲康唑，P-糖蛋白抑制剂的功能是抵消肿瘤细胞中大量存在的P-糖蛋白的耐受效应，P-糖蛋白负责将化疗剂从肿瘤细胞的内部泵送至外部，使这些化疗剂在肿瘤细胞内的浓度非常低，这通常导致抗肿瘤化疗剂无效。
根据本发明的详细描述和所附的权利要求，将更好地理解和认识本发明的这些目的和其他目的，其中：
图1表示混合物包含的组分，该混合物通过由9-吖啶羧酸代表的抗肿瘤剂(1)、由辅酶Q10代表的抗氧化剂(2)和由酮康唑(参见图1中的式3)、或维拉帕米、或他立喹达(tariquidar)、唑喹达(Zozuquidar)、依克立达、拉尼喹达(Laniquidar)、个体发育剂(ontogen)、咪唑、邻氨基苯甲酰胺、右维拉帕米或右尼古地平代表的P-糖蛋白抑制剂形成。最有效的P-糖蛋白抑制剂是被认为是“最近的一代”的他立喹达、唑喹达、依克立达或拉尼喹达。
根据附图，根据本发明的抗肿瘤混合物包含抗肿瘤药物(1)联合抗氧化剂(2)例如辅酶-Q10以及P-糖蛋白抑制剂(3)的组合，所述抗肿瘤药物(1)可以是商业化的，例如9-吖啶羧酸(由附图中的式(1)图示)，所述P-糖蛋白抑制剂(3)例如他立喹达和酮康唑，以便完全对抗实体肿瘤而不影响身体的健康细胞。图中图示的式(3)是酮康唑。所述他立喹达抑制剂具有下式：
9-吖啶羧酸是优选的抗肿瘤剂，因为它容易在市场上获得。然而，当然，还可以使用其他抗肿瘤剂及其生理学上可接受的盐或生理学上可接受的衍生物。因此，抗肿瘤剂可以是根据以下通式的化合物：
根据优选的抗肿瘤剂，羧酸基团位于第9位。然而，原则上它还可以位于第1位、第2位、第3位、第4位、第5位、第6位、第7位和第8位中的一些位置。
根据本发明的混合物可以由上文提及的三种基本的成分组成，即对肿瘤酸度有选择性的抗肿瘤剂、抗氧化剂和P-糖蛋白抑制剂。然而，如本领域公知的，还可以取决于情况添加各种添加剂，例如可接受的药学上相容的载体材料或稀释剂。载体可以是适合于经肠、经皮、皮下或肠胃外施用的任何惰性的有机材料或无机材料，例如：水、明胶、阿拉伯树胶、乳糖、微晶纤维素、淀粉、淀粉甘氨酸钠(sodium glycinate starch)、磷酸氢钙、硬脂酸镁、滑石、胶体二氧化硅及类似物。这样的组合物还可以包含第四药理学上有活性的剂和常规添加剂，例如稳定剂、润湿剂、乳化剂、调味剂、缓冲剂及类似物。本发明的混合物还可以按照可接受的药学程序被转化成适当的形式，例如用于口服使用、注射、以鼻喷雾剂或类似形式施用的组合物。根据本发明的这样的药物组合物包含有效量的三种组分，这三种组分可能与各种提及的添加剂联合。根据本发明的混合物可以例如以固体或用于口服施用的液体形式获得，例如片剂、丸剂、胶囊、粉末、糖浆剂、酏剂、可分散的颗粒、栓剂及类似物，以用于肠胃外施用的无菌溶液、悬浮液或乳液的形式获得，以喷雾剂例如鼻喷雾剂，经皮制剂例如膏药及类似形式获得。
三种基本成分的含量的比例可以相当大地变化。精确的比例难以计算，因为每种化合物取决于患者的体重和健康状态。在静脉内途径中，他立喹达具有等于300mg/kg体重(小鼠内)的毒性(LD50)。因此，剂量应低于此值。为了安全性，我们建议治疗期间5mg/kg体重的剂量。在另一个方面，辅酶-Q10具有接近20g/kg体重的毒性(LD50)(口服)。我们建议口服施用20mg/kg。最后，9-吖啶羧酸具有等于240mg/kg的毒性(LD50)。在静脉内途径的治疗期间，我们建议最大使用20mg/kg。因此，近似比例是1:4:4(分别为：他立喹达；辅酶-Q10；和9-吖啶)。因此，(1)抗肿瘤剂、(2)抗氧化剂和(3)P-糖蛋白抑制剂在根据本发明的混合物中的重量之间的关系，重量比率(1):(2):(3)可以是约1:4:4。如本领域公知的，可以使用稀释剂。如果使用稀释剂、载体、其他常规添加剂例如稳定剂、润湿剂、乳化剂、调味剂、缓冲剂及类似物，则根据本发明的混合物的按重量计的至少10％应由所述三种成分组成。
实验
体内测定在伯南布哥州联邦大学(the Federal University of Pernambuco)的Bioterium of the Department of Antibiotics(巴西)在瑞士白化小鼠中进行。遵循Stock等人(1955)并且由Komiyama(1992)修改的方法将肿瘤植入小鼠内。将小鼠(每只重30g)分成两组，治疗组和对照组。治疗组通过腹膜内注射接受按重量计10mg/kg和20mg/kg的剂量的化疗剂，在6天时间段期间每天一次剂量。另一方面，对照组在相同的时间段仅接受安慰剂(2％盐水溶液)。测定中使用了总共48只动物。
目的是确定新的化合物在现有的肿瘤(肉瘤180)中是否具有抗肿瘤活性。结果是对肿瘤呈阳性，在对于小鼠10mg/kg和20mg/kg的剂量下，肿瘤抑制的百分比分别为48％和90％。在20mg/kg的剂量下，在治疗组的一半小鼠中存在完全缓解。
抗肿瘤混合物的组分的毒性
当静脉内应用时，他立喹达具有等于300mg/kg(小鼠内)的毒性(LD50)。因此，其剂量应低于此值。为了安全，我们在治疗期间使用5mg/kg的剂量。
在另一个方面，辅酶-Q10具有接近20g/kg的毒性(LD50)(口服)。我们在我们的测试中使用口服100mg/天。
最后，9-吖啶羧酸经由腹膜内应用(皮下)具有等于240mg/kg的毒性(LD50)。
Claims (9)
1.抗肿瘤混合物，其特征在于所述抗肿瘤混合物包含对肿瘤酸度有选择性的抗肿瘤剂、抗氧化剂和P-糖蛋白抑制剂，所述抗肿瘤剂包含被连接至羧酸基团的吖啶。
2.根据权利要求1所述的混合物，其特征在于，在肿瘤酸度的存在下，具有负电荷的所述抗肿瘤剂将仅被由于其酸度具有过量正电荷的肿瘤细胞吸收，而免于被具有中性电荷的健康细胞吸收。
3.根据权利要求1或2所述的混合物，其特征在于所述抗氧化剂对抗由所述抗肿瘤剂天然产生的自由基的作用，降低所述抗肿瘤剂对于重要器官例如心脏的毒性。
4.根据权利要求1、2或3所述的混合物，其特征在于所述P-糖蛋白抑制剂是二甲双胍、酮康唑、奎尼丁、维拉帕米、环孢菌素、红霉素、螺内酯、伊曲康唑、他立喹达、唑喹达(zozuquidar)、依克立达、拉尼喹达、个体发育剂、咪唑、邻氨基苯甲酰胺、右维拉帕米和/或右尼古地平。
5.根据权利要求4所述的混合物，其特征在于所述P-糖蛋白抑制剂是他立喹达、唑喹达、依克立达和/或拉尼喹达。
6.根据权利要求5所述的混合物，其特征在于所述P-糖蛋白抑制剂是他立喹达。
7.根据权利要求1至6中任一项所述的混合物，其特征在于所述抗氧化剂是辅酶Q10。
8.根据权利要求1至7中任一项所述的混合物，其特征在于，对肿瘤酸度有选择性的所述抗肿瘤剂是9-吖啶羧酸或包含9-吖啶羧酸。
9.根据权利要求1-5中任一项所述的混合物，其特征在于，所述混合物通过任何可接受的施用方式或通过具有类似用途的剂施用，例如通过口服施用、鼻内施用、肠胃外(静脉内、皮下、肌内)施用、舌下施用、直肠施用、局部施用、经皮施用和膀胱内施用。
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| SUN YL等: "Reversal of MRP7 (ABCC10)-mediated multidrug resistance by tariquidar", 《PLOS ONE》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111718296A (zh) * | 2019-03-20 | 2020-09-29 | 复旦大学 | 靶向cd133的小分子化合物ly335979在制备抗肿瘤药物中的应用 |
| CN111718296B (zh) * | 2019-03-20 | 2023-10-20 | 复旦大学 | 靶向cd133的小分子化合物ly335979在制备抗肿瘤药物中的应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2017173509A1 (pt) | 2017-10-12 |
| EP3441067A1 (en) | 2019-02-13 |
| US20190175566A1 (en) | 2019-06-13 |
| EP3441067A4 (en) | 2020-01-01 |
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