CN109475637A - 可切割的聚合物药物偶联物 - Google Patents
可切割的聚合物药物偶联物 Download PDFInfo
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- CN109475637A CN109475637A CN201780045704.2A CN201780045704A CN109475637A CN 109475637 A CN109475637 A CN 109475637A CN 201780045704 A CN201780045704 A CN 201780045704A CN 109475637 A CN109475637 A CN 109475637A
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Abstract
本发明涉及包含基于(甲基)丙烯酸酯的聚合物主链和至少两种侧链的聚合物药物偶联物,其中所述侧链中的一种是PEG链,另一种侧链包含与可切割接头共价键合的至少一种治疗剂,本发明还涉及制备所述聚合物‑药物偶联物的方法及其用于治疗诸如癌症的疾病的用途。
Description
本发明涉及式I的聚合物药物偶联物,制备所述聚合物-药物偶联物的方法及其用于治疗诸如癌症等疾病的用途。
背景技术
用于治疗癌症的化疗剂大多是细胞毒性的。除了目标区域之外,这些药剂可能积聚在身体组织中,这反过来导致治疗益处降低和药物在整个健康身体组织中的不希望的分布。这些药剂在整个身体中的不受控制的分布对患者造成严重的副作用。
由于化疗剂分布到包括健康组织在内的整个身体,尽管由给定剂量引起的高总体毒性,到达肿瘤组织的化疗剂的量非常低。这种情况导致患者的治疗益处低。此外,化疗剂具有低溶解度,这使得它们难以配制和给予患者。
为了解决上述问题,开发了可以将药物递送到身体的目标区域的药物递送系统。例如,在一些癌症治疗方法中,这些系统利用增强的渗透性和保留效应(EPR),这意味着具有高分子量和大流体动力学体积的药物载体在实体瘤中累积,这又使得药物分子被动靶向到肿瘤组织,并尽量减少化疗药物对健康组织的损害。
发明技术领域
存在许多可用于制备聚合物药物偶联物的聚合物。
US 6310039公开了转铁蛋白,白蛋白和聚乙二醇与细胞抑制性化合物,例如阿霉素,柔红霉素,表柔比星等的偶联物。在该文献中,药物分子附着于聚乙二醇聚合物的端基。这些系统的一个缺点是它们具有有限的药物偶联官能团,因此它们在最终的药物聚合物偶联物上具有低的药物百分比。此外,聚集是这种类型的聚合物药物偶联物难以处理的另一种现象。
例如,WO 1998/056424公开了一种聚合物药物偶联物,其中糊精形成聚合物的主链,药物分子直接或间接地与聚合物主链结合。
另一个实例是WO 2007/028347,其公开了制备阿霉素的聚合物偶联物的方法,所述阿霉素是抗癌药物分子。该文献教导了使用N-(2-羟基丙基)甲基丙烯酰胺(HPMA)单体来形成聚合物。
US 2003/0215395公开了与具有接头的药物偶联的阳离子聚合物,例如聚(L-赖氨酸),聚乙烯亚胺和壳聚糖。
上述系统使用通过接头连接到聚合物主链上的药物分子,该接头的目的是在聚合物-药物偶联物到达其靶组织后切割接头,从而在靶位点释放药物分子。然而,这些系统的缺点是药物和聚合物之间的可切割接头在血流中裂解并在药物分子到达其靶组织之前释放药物分子。
鉴于上述现有技术,需要一种新的聚合物-药物偶联物,其毒性较低并具有所需的药代动力学特征。
本发明的另一个目的是提供一种聚合物-药物偶联物,其解决了在聚合物药物偶联物到达靶组织之前药物裂解的问题。
本发明人惊奇地发现,根据本发明的聚合物-药物偶联物具有相当高的循环时间,提供活性剂向靶组织的选择性分布,具有较低的分布体积,较低的清除率和较高的最大浓度(C最大)且曲线下的总面积(总AUC)值更高。
发明概述
本发明涉及用于递送治疗剂的聚合物-药物偶联物,其包含基于(甲基)丙烯酸酯的聚合物主链,其特征在于所述聚合物包含至少两种类型的侧链,其中一种侧链是PEG链,例如–COOCH2CH2(OCH2CH2)nOR3,其中n是1-200之间的自然数,R3选自H或-CH3,另一种侧链是包含至少一种与可切割接头共价键合的治疗剂,如式I所示:
换句话说,本发明涉及式I的聚合物-药物偶联物,其中:
R1和R2独立地选自:H或–CH3,
R3选自:–H或–CH3,
x是1-140之间的自然数,
y是1-40之间的自然数,
n是1-200之间的自然数,
L是可切割接头,和
D是至少一种治疗剂,
Z选自:-O或-NH,
A是任选为聚合引发剂或其片段的端基或者A可以为空,
B是任选为聚合引发剂或其片段的端基或者B可以为空。
本发明人惊奇地发现,除了克服包含聚合物-药物偶联物的现有技术药物递送系统的缺点之外;由于存在可生物降解的PEG侧链,本发明的聚合物在其他器官中的积累减少。这反过来又提供了具有较低毒性的聚合物-药物偶联物。
发明详述
术语“聚合物-药物偶联物”是指具有共价连接到聚合物上的治疗剂的聚合物结构。
术语“聚合物主链”和“聚合物骨架”可互换使用,是指具有侧链或侧基的聚合物链。例如,侧链可以具有低聚乙二醇单元和可以带有一种治疗剂的侧基或可以用于连接治疗剂和/或诊断剂或靶向基团的任何其他基团。
术语“丙烯酸酯”是指丙烯酸的衍生物。这些衍生物包括母体酸(CH2CHCO2H)和酯,因此术语“基于丙烯酸酯”定义具有任何上述丙烯酸酯衍生物的官能团。
术语“甲基丙烯酸酯”是指甲基丙烯酸的衍生物。这些衍生物包括母体酸(CH2C(CH3)CO2H)和酯。因此,术语“基于甲基丙烯酸酯”定义具有任何上述甲基丙烯酸酯衍生物的官能团。
术语“(甲基)丙烯酸酯”是指术语“丙烯酸酯”和“甲基丙烯酸酯”。因此,术语“(甲基)丙烯酸酯”可与“丙烯酸酯”和“甲基丙烯酸酯”互换使用,并包括如上所述的这些术语的所有特征。术语“(甲基)丙烯酸酯”应理解为表示“甲基丙烯酸酯和/或丙烯酸酯”。
在整个文本中,术语“本发明的聚合物-药物偶联物”应理解为表示“根据式I的聚合物-药物偶联物”或“式I的聚合物-药物偶联物”或“式I”,并且这些术语可以互换使用。
术语“PEG”是指具有H-(O-CH2-CH2)n-OR3结构的聚醚化合物,n是1-200的自然数,R3选自H或-CH3。PEG定义为环氧乙烷的低聚物或聚合物。术语“PEG”,“聚乙二醇”,“聚环氧乙烷”,“PEO”,“聚氧乙烯”和“POE”是指相同的结构,并且可以在本文中互换使用。
如式I所示,本发明的聚合物-药物偶联物包含PEG侧链。侧链为本发明的聚合物-药物偶联物提供重要的物理化学性质,并导致与不具有所述侧链的偶联物相比具有更好的物理化学性质的聚合物-药物偶联物。
如上所述,式I中的“L”表示可切割的接头。术语“可切割接头”是指在空间上将药物或靶向基团与载体分子分开的基团。术语“接头”,“L”和“可切割接头”是指相同的实体并且可以互换使用。
本文中,术语“短肽”应理解为意指包含1-50个氨基酸,优选2-40个氨基酸,最优选2-30个氨基酸的肽链。
在一个实施方式中,R1=H,R2=H,R3=H;在另一个实施方式中,R1=H,R2=H,R3=-CH3;在另一个实施方式中,R1=H,R2=-CH3,R3=H;在另一个实施方式中,R1=H,R2=-CH3,R3=-CH3;在另一个实施方式中,R1=-CH3,R2=H,R3=H;在另一个实施方式中,R1=-CH3,R2=H,R3=-CH3;在另一个实施方式中,R1=-CH3,R2=-CH3,R3=H;在另一个实施方式中,R1=-CH3,R2=-CH3,R3=-CH3。
术语“无规共聚物”是指其中形成共聚物的单体遵循任意顺序的共聚物。术语“嵌段共聚物”是指其中所有一种类型的单体聚集在一起并且所有其他类型的单体聚集在一起的共聚物。本发明的聚合物-药物偶联物可以是嵌段共聚物或无规共聚物的形式。本发明的聚合物-药物偶联物是无规共聚物的形式。
接头是可切割的,使得治疗剂可以例如在还原条件,氧化条件下或通过酯、酰胺、酰肼或类似键的水解而释放,所述酯、酰胺、酰肼或类似键在接头和治疗剂之间形成共价键。另外,接头的类型可以通过允许邻近细胞或在细胞内选择性释放治疗剂来增强选择性细胞毒性(并因此改善治疗指数)。
所述可切割接头可以是任何能够在生理条件下解离的烃或取代的烃基化合物。在一个优选的实施方式中,接头可选自在肿瘤的酸性条件下发生裂解(例如任何包含缩醛或酯官能团的C1-C10取代的烃)或借助于在肿瘤细胞的细胞间或细胞内基质中存在的过表达的酶发生裂解的化合物。
接头可以是能够与聚合物主链和药物结合的任何种类的实体,例如聚(乙二醇),氨基酸,聚(氨基酸)(例如肽或寡肽)或多肽(例如蛋白质),使得其一端能够与聚合物主链形成共价键,并且其另一端能够与治疗剂形成共价键。接头还可以包括具有对组织蛋白酶B不稳定的特定肽序列的短肽,例如Gly-Phe-Leu-Gly(SEQ ID NO:1),也表示为GFLG或Val-Cit或Phe-Lys,或Val-Ala或Ala-Leu-Ala-Leu(SEQ ID NO:2)。
接头也可以是C1-C10烃或C1-C10取代或杂取代的烃,使得它包含在生理条件下解离的官能团,例如缩醛、酯、亚胺、酰胺、二硫化物、碳酸酯、氨基甲酸酯、腙。
术语“C1-C10烃”是指在主链中具有1至10个C原子的烃链。
术语“C1-C10取代的烃”是指在主链中具有1至10个C原子的烃链,其中一个或多个氢原子被其他元素的基团的原子取代,例如醇,胺,羧基,硫醇等。
术语“C1-C10杂取代的烃”是指在主链中具有1至10个C原子的烃链,其中至少一个C原子被除C以外的原子如氮,氧,磷,硫或卤素原子取代。这些取代基包括但不限于:低级烷氧基,如甲氧基,乙氧基,丁氧基;醚;缩醛;缩酮;酯;杂芳基;杂环基;羟基;保护的羟基;酰基;酰氧基;氨基;酰胺基;亚胺,二硫化物,碳酸酯,氨基甲酸酯,腙,肼。
在本发明的一个实施方式中,接头(L)是GFLG。在本发明的一个实施方式中,接头是Val-Cit。在本发明的一个实施方式中,接头是Phe-Lys。在本发明的一个实施方式中,接头是Val-Ala。在本发明的一个实施方式中,接头是Ala-Leu-Ala-Leu。
在本发明的一个实施方式中,接头是包含至少一个二硫化物官能团的C1-C10杂取代的烃。在本发明的一个实施方式中,接头是包含至少一个缩醛官能团的C1-C10杂取代的烃。在本发明的一个实施方式中,接头是包含至少一个酯官能团的C1-C10杂取代的烃。在本发明的一个实施方式中,接头是包含至少一个亚胺官能团的C1-C10杂取代的烃。在本发明的一个实施方式中,接头是包含至少一个酰胺官能团的C1-C10杂取代的烃。在本发明的一个实施方式中,接头是包含至少一个碳酸酯官能团的C1-C10杂取代的烃。在本发明的一个实施方式中,接头是包含至少一个氨基甲酸酯官能团的C1-C10杂取代的烃。在本发明的一个实施方式中,接头是包含至少一个腙官能团的C1-C10杂取代的烃。
在本发明的另一个实施方式中,接头可包含C1-C10取代或杂取代的烃,其包含两个或更多个选自缩醛、酯、亚胺、酰胺、二硫化物、碳酸酯、氨基甲酸酯、腙的官能团。
在本发明的另一个实施方式中,接头可以是C1-C10取代的烃的组合,其包含至少一个选自缩醛、酯、亚胺、酰胺、二硫化物、碳酸酯、氨基甲酸酯、腙的官能团和选自GFLG,Val-Cit或Phe-Lys或Val-Ala或Ala-Leu-Ala-Leu的肽链。
术语“治疗剂”是指适用于治疗疾病的任何化合物。术语“治疗剂”,“化学治疗剂”,“抗癌剂”和“抗肿瘤剂”均指适用于治疗疾病的化合物,这些术语可互换使用。在一个实施方式中,该疾病是癌症。
另外,“治疗剂”还指适用于治疗疾病(例如癌症)的任何药剂。可以使用任何可以直接或间接连接到本发明的聚合物-药物偶联物上的治疗剂。美国专利66,342,221也描述了与抗癌剂有关的药剂,该文献在此引入作为参考。抗癌剂可分类为但不限于: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(例如抗微管剂),皮质类固醇,放射性药物和蛋白质(例如细胞因子,酶,或干扰素)。抗癌剂的具体实例是例如多西他奇,吉西他滨,伊马替尼,5-氟尿嘧啶,9-氨基喜树碱,胺改性的格尔德霉素,阿霉素,紫杉醇,丙卡巴肼,羟基脲,内消旋-二氢卟酚,顺铂和放射性核素(例如1-131,Y-90,In-111和Tc-99m)。本领域已知有许多其他抗癌剂,并且许多抗癌剂继续被开发,这些药剂也包括在本发明的范围内。
治疗剂还可以选自亚组,包括但不限于核苷类似物,抗叶酸剂,其他代谢物,拓扑异构酶I抑制剂,蒽环类,鬼臼毒素,紫杉烷,长春花生物碱,烷化剂,铂化合物,抗激素,放射性药物,单克隆抗体,酪氨酸激酶抑制剂,哺乳动物雷帕霉素靶蛋白(mTOR)抑制剂,类维生素A,免疫调节剂,组蛋白去乙酰化酶抑制剂和其他药剂。
核苷类似物可选自包括但不限于:阿扎胞苷,克拉屈滨,氯法拉滨,阿糖胞苷,地西他滨,氟尿嘧啶,氟达拉滨,氟尿嘧啶(5-FU),吉西他滨,巯基嘌呤,尼拉滨,喷司他丁,硫鸟嘌呤(tioguanine),三氟尿嘧啶(trifluridine),替吡嘧啶。
抗叶酸剂可选自包括但不限于:甲氨蝶呤,培美曲塞,普拉曲塞(pralatrexed),雷替曲塞。其他代谢物可选自包括但不限于:羟基脲。拓扑异构酶I抑制剂可选自包括但不限于:伊立替康和拓扑替康。蒽环类抗生素可选自包括但不限于:柔红霉素,阿霉素,表柔比星,伊达比星,米托蒽醌,戊柔比星(valrubicin)。鬼臼毒素可选自包括但不限于:依托泊苷和替尼泊苷。紫杉烷可选自包括但不限于:卡巴他赛,多西他奇,紫杉醇。长春花生物碱可选自包括但不限于:长春碱,长春新碱,长春地辛,长春氟宁,长春瑞滨。烷化剂可选自包括但不限于:苯达莫司汀,苯丁酸氮芥,达卡巴嗪,美法仑,链脲佐菌素,曲贝替定(trabectedin)。抗激素化合物可选自包括但不限于:阿比特龙,比卡鲁胺,环丙孕酮,地加瑞克,依西美坦,氟维司群,戈舍瑞林,组氨瑞林,亮丙瑞林,米非司酮,曲普瑞林。酪氨酸激酶抑制剂可选自包括但不限于:阿法替尼,阿西替尼,博舒替尼,可比美替尼(cobimetinib),克唑替尼,达沙替尼,厄洛替尼,吉非替尼,伊马替尼,拉帕替尼,尼罗替尼,奥西噻尼,帕唑帕尼,鲁索替尼(ruxolitinib),舒尼替尼,凡德他尼。哺乳动物雷帕霉素靶蛋白(mTOR)抑制剂可选自包括但不限于:依维莫司,替西罗莫司。类视黄醇可选自包括但不限于:阿利维A酸,贝沙罗汀,异维甲酸,他巴罗汀,维甲酸。免疫调节剂可选自包括但不限于:来那度胺,泊马度胺,沙利度胺。组蛋白脱乙酰酶抑制剂可选自包括但不限于:贝利司他,帕比司他(panobinostat),丙戊酸盐,伏立诺他。其他药剂可选自包括但不限于:阿那格雷,色瑞替尼(ceritinib),达拉菲尼(dabrafenib),艾代拉利司(idelalisib),依鲁替尼,帕博昔尼(palbociclib),维拉菲尼(vemurafenib),博来霉素,硼替佐米,放线菌素(dactinomycin),艾日布林,雌莫司汀,伊沙匹隆,丝裂霉素,丙卡巴肼,阿拉替尼(alectinib),氟甲睾酮(fluxymesterone),碘苄胍(iobenguane),咪喹莫特(imiguimod),干扰素,伊克昔佐米(ixazomib),兰瑞肽(lanreotide),香菇菌多糖(lentinan),奥曲肽(octreotide),高三尖杉酯碱(omacetaxine),替加氟(tegafur),吉美嘧啶(gimerazil),欧塔拉昔(oteracil),尿嘧啶,考布他汀,氯喹。
在本发明的一个优选实施方式中,治疗剂选自:紫杉烷,抗叶酸剂,酪氨酸激酶抑制剂,蒽环类,核苷类似物或其他试剂。最优选地,治疗剂选自:多西他奇,培美曲塞,氯喹,考布他汀,吉西他滨,阿霉素,氟尿嘧啶(5-FU),5'-脱氧5-氟尿嘧啶(5'-DFCR),拉帕替尼和上面列出的治疗剂中的任何一种。作为这样的治疗剂。
本文中,术语“药剂”是指至少一种或多种治疗剂。
在本发明的一个实施方式中,治疗剂是多西他奇。在本发明的一个实施方式中,治疗剂是培美曲塞。在本发明的一个实施方式中,治疗剂是氯喹。在本发明的一个实施方式中,治疗剂是考布他汀。在本发明的一个实施方式中,治疗剂是吉西他滨。在本发明的一个实施方式中,治疗剂是阿霉素。在本发明的一个实施方式中,治疗剂是5-FU。在本发明的一个实施方式中,治疗剂是5'-脱氧5-氟代胞苷(5'-DFCR)。在本发明的一个实施方式中,治疗剂是拉帕替尼。
在本发明的一个实施方式中,治疗剂是两种或更多种治疗剂的组合,所述治疗剂选自:多西他奇,培美曲塞,氯喹,考布他汀,吉西他滨,阿霉素,5-FU,5'-脱氧5-氟代胞苷(5'-DFCR)和拉帕替尼以及上面列出的任何其他药剂。作为两种或更多种治疗剂的组合的这种治疗剂可以选自上面列出的主要的组或主要的组的具体成员。
治疗剂可以以聚合物-药物偶联物的1重量%至40重量%的量存在,优选地以聚合物-药物偶联物的2重量%至35重量%的量存在,最优选地以聚合物-药物偶联物的3重量%至30重量%的量存在。治疗剂可以以例如聚合物-药物偶联物的以下重量百分比的量存在:4%至25%或5%至24%或6%至23%或7%至22%或8%至20%。
术语“端基”是指位于聚合物末端的官能团或结构单元。显示为A和B的端基可以彼此相同或不同。
A和B可任选为聚合引发剂或其片段。特别是当引发剂用于聚合反应时,引发剂片段可以作为聚合物的端基保留。这里使用的引发剂可以是适合引发本领域已知的聚合反应的任何材料。
在一个实施方式中,A和/或B选自:4,4′-偶氮二(4-氰基戊酸),4,4′-偶氮二(4-氰基戊酸),1,1′-偶氮二(环己腈),2,2′-偶氮二(2-甲基丙脒)二盐酸盐,2,2′-偶氮二(2-甲基丙腈)(也称为AIBN),过硫酸铵,羟基甲烷亚磺酸单钠二水合物,过硫酸钾,过硫酸钠,叔丁基过氧化氢,过氧乙酸叔丁酯,过氧化氢异丙苯(Cumenehydroperoxide),2,5-二(叔丁基过氧)-2,5-二甲基-3-己炔,二枯基过氧化物,2,5-二(叔丁基过氧)-2,5-二甲基己烷,1,1-二(叔丁基过氧)-3,3,5-三甲基环己烷,1,1-二(叔戊基过氧)环己烷,过氧化苯甲酰,过氧化2-丁酮,叔丁基过氧化物,二叔戊基过氧化物,过氧化月桂酰,过氧化苯甲酸叔丁酯,叔丁基过氧化2-乙基己基碳酸酯,叔丁基过氧化氢,2-叠氮基乙基2-溴异丁酸酯,二[2-(2-溴异丁酰氧基)十一烷基]二硫化物,二[2-(2′-溴异丁酰氧基)乙基]二硫化物,2-溴异丁酸N-羟基琥珀酰亚胺酯,2-溴异丁酸酐,α-溴异丁酰溴,2-(2-溴异丁酰氧基)乙基甲基丙烯酸酯,α-溴异丁酸叔丁酯,2-溴异丁酸3-丁炔酯,二季戊四醇六(2-溴异丁酸酯)),2-溴异丁酸十二烷基酯,α-溴异丁酸乙酯,二(2-溴异丁酸乙烯酯),2-溴异丁酸2-羟基乙酯,1-(DL-1,2-异亚丙基甘油基)2-溴异丁酸酯,α-溴异丁酸甲酯,2-溴异丁酸十八烷基酯,季戊四醇四(2-溴异丁酸酯),1-(邻苯二甲酰亚氨基甲基)2-溴异丁酸酯,聚(乙二醇)二(2-溴异丁酸酯),2-溴异丁酸炔丙酯,1,1,1-三(2-溴异丁酰氧基甲基)乙烷,10-十一碳烯基2-溴异丁酸酯,N-叔丁基-O-[1-[4-(氯甲基)苯基]乙基]-N-(2-甲基-1-苯基丙基)羟胺,N-叔丁基-N-(2-甲基-1-苯基丙基)-O-(1-苯基乙基)羟胺,TEMPO,TEMPO甲基丙烯酸酯,2,2,5-三甲基-4-苯基-3-氮杂己烷-3-氮氧化物,3,5-二(2-十二烷硫基硫代碳酰基硫代1-氧代丙氧基)苯甲酸,3-丁烯基2-(十二烷硫基硫代碳酰基硫代)-2-甲基丙酸酯,4-氰基-4-[(十二烷基硫烷基硫代羰基)硫烷基]戊酸,4-氰基-4-[(十二烷基硫烷基硫代羰基)硫烷基]戊醇,氰基甲基十二烷基,氰基甲基[3-(三甲氧基甲硅烷基)丙基]三硫代碳酸酯,2-氰基-2-丙基十二烷基三硫代碳酸酯,S,S-二苄基三硫代碳酸酯,2-(十二烷硫基硫代碳酰基硫代)-2-甲基丙酸,2-(十二烷硫基硫代碳酰基硫代)-2-甲基丙酸,3-叠氮基-1-丙醇酯,2-(十二烷硫基硫代碳酰基硫代)-2-甲基丙酸N-羟基琥珀酰亚胺酯,2-(十二烷硫基硫代碳酰基硫代)-2-甲基丙酸五氟苯酯,2-(十二烷硫基硫代碳酰基硫代)丙酸,2-(十二烷硫基硫代碳酰基硫代)-2-甲基丙酸甲酯,季戊四醇四[2-(十二烷硫基硫代碳酰基硫代)-2-甲基丙酸酯],邻苯二甲酰亚氨基甲基丁基三硫代碳酸酯,1,1,1-四[(十二烷硫基硫代碳酰基硫代)-2-甲基丙酸酯]乙烷,苯甲基二硫代苯甲酸酯,氰基甲基二硫代苯甲酸酯,4-氰基-4-(苯基硫代碳酰基硫代)戊酸,4-氰基-4-(苯基硫代碳酰基硫代)戊酸N-琥珀酰亚胺酯,2-氰基-2-丙基二硫代苯甲酸酯,2-氰基-2-丙基4-氰基二硫代苯甲酸酯,2-(4-甲氧基苯基硫代碳酰基硫代)乙酸乙酯,2-甲基-2-(苯基硫代羰基硫代)丙酸乙酯,2-(苯基硫代碳酰基硫代)-2-苯基乙酸乙酯,2-(苯基硫代碳酰基硫代)丙酸乙酯,1-(甲氧基羰基)乙基二硫代苯甲酸酯,2-(4-甲氧基苯基硫代碳酰基硫代)乙酸,2-硝基-5-(2-丙炔氧基)苄基,4-氰基-4-(苯基硫代碳酰基硫代)戊酸酯,2-(苯基硫代碳酰基硫代)丙酸,2-苯基-2-丙基二硫代苯甲酸酯,甲基(4-吡啶基)二硫代氨基甲酸氰基甲基酯,氰基丙-2-基N-甲基-N-(吡啶-4-基)氨基二硫代氨基甲酸酯,2-[甲基(4-吡啶基)硫代氨基甲酸基硫代]丙酸甲酯,1-琥珀酰亚胺基-4-氰基-4-[N-甲基-N-(4-吡啶基)硫代氨基甲酸基硫代]戊酸酯或本文所列引发剂的任何片段。
如本文所用的术语“片段”是指由于形成引发剂分子的一个或多个共价键断裂而形成的化合物。
A和/或B可选地为空。
在本发明的一个实施方式中,A为空,B是聚合引发剂或聚合引发剂的片段。在另一个实施方式中,B为空而A为聚合引发剂或聚合引发剂的片段。在另一个实施方式中,A和B都是聚合引发剂的片段,但它们在结构上彼此不同。换句话说,A和B是相同引发剂的不同片段。在另一个实施方式中,A和B都是聚合引发剂的片段,并且它们具有相同的化学结构。
在一些优选的实施方式中,本发明的聚合物药物偶联物包含以下一种或多种:
GFLG作为接头(L),治疗剂选自:多西他奇,培美曲塞,氯喹,考布他汀,吉西他滨,阿霉素,5-FU,5'-脱氧5-氟代胞苷(5'-DFCR)和拉帕替尼。
Val-Cit作为接头(L),治疗剂选自:多西他奇,培美曲塞,氯喹,考布他汀,吉西他滨,阿霉素,5-FU,5'-脱氧5-氟代胞苷(5'-DFCR)和拉帕替尼。
Phe-Lys作为接头(L),治疗剂选自:多西他奇,培美曲塞,氯喹,考布他汀,吉西他滨,阿霉素,5-FU,5'-脱氧5-氟代胞苷(5'-DFCR)和拉帕替尼。
Val-Ala作为接头(L),治疗剂选自:多西他奇,培美曲塞,氯喹,考布他汀,吉西他滨,阿霉素,5-FU,5'-脱氧5-氟代胞苷(5'-DFCR)和拉帕替尼。
Ala-Leu-Ala-Leu作为接头(L),治疗剂选自:多西他奇,培美曲塞,氯喹,考布他汀,吉西他滨,阿霉素,5-FU,5'-脱氧5-氟代胞苷(5'-DFCR)和拉帕替尼。
包含至少一个二硫化物官能团的C1-C10杂取代的烃作为接头(L),治疗剂选自:多西他奇,培美曲塞,氯喹,考布他汀,吉西他滨,阿霉素,5-FU,5'-脱氧5-氟代胞苷(5'-DFCR)和拉帕替尼。
包含至少一个缩醛官能团的C1-C10杂取代的烃作为接头(L),治疗剂选自:多西他奇,培美曲塞,氯喹,考布他汀,吉西他滨,阿霉素,5-FU,5'-脱氧5-氟代胞苷(5'-DFCR)和拉帕替尼。
包含至少一个酯官能团的C1-C10杂取代的烃作为接头(L),治疗剂选自:多西他奇,培美曲塞,氯喹,考布他汀,吉西他滨,阿霉素,5-FU,5'-脱氧5-氟代胞苷(5'-DFCR)和拉帕替尼。
包含至少一个亚胺官能团的C1-C10杂取代的烃作为接头(L),治疗剂选自:多西他奇,培美曲塞,氯喹,考布他汀,吉西他滨,阿霉素,5-FU,5'-脱氧5-氟代胞苷(5'-DFCR)和拉帕替尼。
包含至少一个酰胺官能团的C1-C10杂取代的烃作为接头(L),治疗剂选自:多西他奇,培美曲塞,氯喹,考布他汀,吉西他滨,阿霉素,5-FU,5'-脱氧5-氟代胞苷(5'-DFCR)和拉帕替尼。
包含至少一个碳酸酯官能团的C1-C10杂取代的烃作为接头(L),治疗剂选自:多西他奇,培美曲塞,氯喹,考布他汀,吉西他滨,阿霉素,5-FU,5'-脱氧5-氟代胞苷(5'-DFCR)和拉帕替尼。
包含至少一个氨基甲酸酯官能团的C1-C10杂取代的烃作为接头(L),治疗剂选自:多西他奇,培美曲塞,氯喹,考布他汀,吉西他滨,阿霉素,5-FU,5'-脱氧5-氟代胞苷(5'-DFCR)和拉帕替尼。
包含至少一个腙官能团的C1-C10杂取代的烃作为接头(L),治疗剂选自:多西他奇,培美曲塞,氯喹,考布他汀,吉西他滨,阿霉素,5-FU,5'-脱氧5-氟代胞苷(5'-DFCR)和拉帕替尼。
包含两个或更多个选自缩醛、酯、亚胺、酰胺、二硫化物、碳酸酯、氨基甲酸酯、腙的官能团的C1-C10取代的或杂取代的烃作为接头(L),治疗剂选自:多西他奇,培美曲塞,氯喹,考布他汀,吉西他滨,阿霉素,5-FU,5'-脱氧5-氟代胞苷(5'-DFCR)和拉帕替尼。
包含至少一个选自缩醛、酯、亚胺、酰胺、二硫化物、碳酸酯、氨基甲酸酯、腙的官能团的C1-C10取代的烃以及包含选自GFLG、Val-Cit、Val-Ala、Ala-Leu-Ala-Leu或Phe-Lys的肽链的组合作为接头(L),治疗剂选自:多西他奇,培美曲塞,氯喹,考布他汀,吉西他滨,阿霉素,5-FU,5'-脱氧5-氟代胞苷(5'-DFCR)和拉帕替尼。
本发明的聚合物偶联物中药物量的测量是通过使用本领域熟知的常规技术进行的,例如通过从聚合物-药物偶联物的1H-NMR计算药物比率。
在另一个实施方式中,本发明的聚合物-药物具有20kDa至300kDa的平均分子量。在一个优选的实施方式中,本发明的聚合物-药物偶联物的平均分子量为30Da-270kDa,在最优选的实施方式中,本发明的聚合物-药物偶联物的平均分子量为40kDa-250kDa。
本发明的聚合物-药物偶联物的分子量通过使用本领域已知的常规技术测定,例如通过使用凝胶渗透色谱法(GPC)。
本发明的另一个实施方式是制备本发明的聚合物-药物偶联物(式I)的方法(方法I),其包括使PEG(甲基)丙烯酸酯单体(式II)
与至少一种类型的(甲基)丙烯酸酯-L-D单体(式IIIa)聚合
其中R1和R2独立地选自:H或–CH3,
R3选自:–H或–CH3,
L是可切割接头,
D是至少一种治疗剂,
n是1-200之间的自然数。
另一方面,制备本发明的聚合物-药物偶联物(式I)的方法(方法II)包括:
(i)使PEG(甲基)丙烯酸酯单体(式II)
与(甲基)丙烯酸酯-L单体(式IIIb)聚合
其中R1和R2独立地选自:H或–CH3,
R3选自:–H或–CH3,
L是可切割接头,和
n是1-200之间的自然数,
得到式IV所示的共聚物
其中x是1-100之间的自然数,
y是1-100之间的自然数,
Z选自:-O或-NH,
A是任选为聚合引发剂或其片段的端基或者A可以为空,
B是任选为聚合引发剂或其片段的端基或者B可以为空。
以及然后(ii)使式IV与至少一种类型的治疗剂(D)反应,得到式I所示的聚合物偶联物。
另一方面,制备本发明的聚合物-药物偶联物(式I)的方法(方法III)包括:
(i)使式II所示的PEG(甲基)丙烯酸酯单体
与式IIIc所示的(甲基)丙烯酸酯单体聚合
其中n是1-200之间的自然数,
R1和R2独立地选自:H或–CH3,
R3选自:–H或–CH3,
R4选自:羰基活化基团,例如全氟苯氧基,马来酰亚胺,碳酸酯,噻唑烷酮-2-硫酮,N-氧基苯并三唑,咪唑基,邻/对-硝基苯酚,五氯苯酚,N-羟基琥珀酰亚胺,乙酸酯,甲酸酯,2,3,5-三氯苯酚,8-羟基喹啉,-OCH3,-OCH2CH3,Cl,F,Br,H,-SH,-NH2,-NHR5或–OR5,其中R5是C1-C10饱和或不饱和烃,
以制备式V所示的共聚物
其中,x是1-100之间的自然数,y是1-100之间的自然数,
Z选自:-O或-NH,
A是任选为聚合引发剂或其片段的端基或者A可以为空,
B是任选为聚合引发剂或其片段的端基或者B可以为空。
以及然后(ii)使式V与连接到接头上的至少一种类型的治疗剂(L-D)反应,
以得到式I所示的聚合物。
本文中术语“羰基活化基团”是指羧基衍生物的离去基团,其容易被进入的亲核试剂取代。
另一方面,制备本发明的聚合物-药物偶联物(式I)的方法(方法IV)包括:
(i)使PEG(甲基)丙烯酸酯单体(式II)
与(甲基)丙烯酸酯单体(式IIIc)聚合
其中n是1-200之间的自然数,
R1和R2独立地选自:H或–CH3,
R3选自:–H或–CH3,
R4选自:羰基活化基团,例如全氟苯氧基,马来酰亚胺,碳酸酯,噻唑烷酮-2-硫酮,N-氧基苯并三唑,咪唑基,邻/对-硝基苯氧基,五氯苯氧基,N-羟基琥珀酰亚胺,乙酸酯,甲酸酯,2,3,5-三氯苯酚,8-羟基喹啉,-OH,-OCH3,-OCH2CH3,Cl,F,Br,H,-SH,-NH2,-NHR5或–OR5,其中R5是C1-C10饱和或不饱和烃,
以得到式V所示的共聚物
其中,x是1-100之间的自然数,y是1-100之间的自然数,
Z选自:-O或-NH,
A是任选为聚合引发剂或其片段的端基或者A可以为空,
B是任选为聚合引发剂或其片段的端基或者B可以为空
以及然后(ii)使式V与接头(L)反应以制备式IV所示的共聚物
其中n,x,y,R1,R2和R3如上文定义,
以及(iii)使式IV与至少一种类型的治疗剂(D)反应以制备式I所示的聚合物偶联物。
在本文中,术语“至少一种治疗剂”和“至少一种类型的治疗剂”可互换使用,并且指使用结构上不同的治疗剂或换句话说是指一种或多种如两种,三种,四种等不同的治疗剂连接到根据本发明的聚合物上,因此该术语不是指聚合物结构中使用的定量。类似地,术语“至少一种类型的(甲基)丙烯酸酯-L-D单体”是指具有一种或多种例如两种,三种或四种等不同治疗剂作为分子D的单体结构。
另一方面,本发明涉及通过方法I,II,III或IV中的任一种制备的式I的聚合物-药物偶联物。通过方法I,II,III或IV制备的式I的聚合物-药物偶联物具有无规共聚物结构,其具有有利的技术效果。
在一个实施方式中,PEG(甲基)丙烯酸酯(式II)优选选自:聚乙二醇甲基醚甲基丙烯酸酯(CAS号:26915-72-0),聚乙二醇甲基丙烯酸酯(CAS号:25736-86-1),聚乙二醇甲基醚丙烯酸酯(CAS号:32171-39-4),和聚乙二醇丙烯酸酯(CAS No:9051-31-4),化合物结构见表1。在本发明的一个优选实施方式中,使用聚乙二醇甲基醚甲基丙烯酸酯,其中R1和R3均为–CH3。
在本发明的一个实施方式中,使用平均分子量为200-2000g/mol的PEG(甲基)丙烯酸酯(式II)。在优选的实施方式中,PEG(甲基)丙烯酸酯(式II)的平均分子量为250-1500g/mol,在最优选的实施方式中,PEG(甲基)丙烯酸酯(式II)的平均分子量为300-1100g/mol。本发明的PEG(甲基)丙烯酸酯(式II)可具有例如200,250,300,350,400,450,500,550,600,650,700,750,800,850,900,950,1000,1050,1100,1150,1200,1250,1300,1350,1400,1450,1500,1550,1600,1650,1700,1750,1800,1850,1900,1950,2000g/mol的平均分子量。
根据本发明的可切割接头可以从商业来源获得,或者可以根据文献中提供的已知方法制备。
另一方面,本发明涉及用于合成式I的聚合物药物偶联物的式IV的共聚物
其中:
x是1-100之间的自然数,
y是1-100之间的自然数,
R1和R2独立地选自:H或–CH3,
R3选自:–H,–CH3或–CH2CH3,
n是1-200之间的自然数,
L是可切割接头,
Z选自:-O或-NH,
A是任选为聚合引发剂或其片段的端基或者A可以为空,
B是任选为聚合引发剂或其片段的端基或者B可以为空
另一方面,本发明涉及用于合成式I的聚合物药物偶联物的式V的共聚物
其中:
x是1-100之间的自然数,
y是1-100之间的自然数,
R1和R2独立地选自:H或–CH3,
R3选自:–H,–CH3或–CH2CH3,
Z选自:-O或-NH,
R4选自:羰基活化基团,例如全氟苯氧基,马来酰亚胺,碳酸酯,噻唑烷酮-2-硫酮,N-氧基苯并三唑,咪唑基,邻/对-硝基苯氧基,五氯苯氧基,N-羟基琥珀酰亚胺,乙酸酯,甲酸酯,2,3,5-三氯苯酚,8-羟基喹啉,-OH,-OCH3,-OCH2CH3,Cl,F,Br,H,-SH,-NH2,-NHR5或–OR5,
R5是C1-C10饱和或不饱和烃,
n是1-200之间的自然数。
A是任选为聚合引发剂或其片段的端基或者A可以为空,
B是任选为聚合引发剂或其片段的端基或者B可以为空。
如上所述,制备式I的聚合物药物偶联物(方法I,II,III和IV)的方法包括至少一个聚合步骤,其中式II的单体和式IIIa或IIIb或IIIc的单体聚合。在本发明的一个实施方式中,这些聚合步骤还包含引发剂和/或溶剂。
本发明的聚合物-药物偶联物可通过任何已知的聚合方法制备。本领域已知的任何合适的引发剂和/或催化剂可用于制备本发明的聚合物-药物偶联物。当使用聚合引发剂时,引发剂或其片段可以存在于所得聚合物-药物偶联物中。
本发明的聚合物-药物偶联物的聚合物主链可以通过例如本领域已知的本体聚合,溶液聚合和/或悬浮聚合技术获得。
用于制备本发明的聚合物-药物偶联物的聚合技术可以通过自由基聚合或受控/活性自由基聚合进行增长。本文中术语“受控/活性自由基聚合”是指原子转移自由基聚合(ATRP),可逆加成断裂链转移(RAFT)聚合,碘转移聚合(ITP),硒中心自由基介导的聚合,碲化物介导的聚合(TERP),氮氧化物介导的聚合(NMP)。在本发明的一个优选实施方式中,使用RAFT聚合制备本发明的聚合物-药物偶联物。
如本文所用的聚合引发剂是指与单体反应形成能够与大量其它单体连续连接成聚合化合物的中间体化合物的化合物。
在本发明的一个实施方式中,聚合引发剂选自:4,4′-偶氮二(4-氰基戊酸),4,4′-偶氮二(4-氰基戊酸),1,1′-偶氮二(环己腈),2,2′-偶氮二(2-甲基丙脒)二盐酸盐,2,2′-偶氮二(2-甲基丙腈)(也称为AIBN),过硫酸铵,羟基甲烷亚磺酸单钠二水合物,过硫酸钾,过硫酸钠,叔丁基过氧化氢,过氧乙酸叔丁酯,过氧化氢异丙苯(Cumenehydroperoxide),2,5-二(叔丁基过氧)-2,5-二甲基-3-己炔,二枯基过氧化物,2,5-二(叔丁基过氧)-2,5-二甲基己烷,1,1-二(叔丁基过氧)-3,3,5-三甲基环己烷,1,1-二(叔戊基过氧)环己烷,过氧化苯甲酰,过氧化2-丁酮,叔丁基过氧化物,二叔戊基过氧化物,过氧化月桂酰,过氧化苯甲酸叔丁酯,叔丁基过氧化2-乙基己基碳酸酯,叔丁基过氧化氢,2-叠氮基乙基2-溴异丁酸酯,二[2-(2-溴异丁酰氧基)十一烷基]二硫化物,二[2-(2′-溴异丁酰氧基)乙基]二硫化物,2-溴异丁酸N-羟基琥珀酰亚胺酯,2-溴异丁酸酐,α-溴异丁酰溴,2-(2-溴异丁酰氧基)乙基甲基丙烯酸酯,α-溴异丁酸叔丁酯,2-溴异丁酸3-丁炔酯,二季戊四醇六(2-溴异丁酸酯)),2-溴异丁酸十二烷基酯,α-溴异丁酸乙酯,二(2-溴异丁酸乙烯酯),2-溴异丁酸2-羟基乙酯,1-(DL-1,2-异亚丙基甘油基)2-溴异丁酸酯,α-溴异丁酸甲酯,2-溴异丁酸十八烷基酯,季戊四醇四(2-溴异丁酸酯),1-(邻苯二甲酰亚氨基甲基)2-溴异丁酸酯,聚(乙二醇)二(2-溴异丁酸酯),2-溴异丁酸炔丙酯,1,1,1-三(2-溴异丁酰氧基甲基)乙烷,10-十一碳烯基2-溴异丁酸酯,N-叔丁基-O-[1-[4-(氯甲基)苯基]乙基]-N-(2-甲基-1-苯基丙基)羟胺,N-叔丁基-N-(2-甲基-1-苯基丙基)-O-(1-苯基乙基)羟胺,TEMPO,TEMPO甲基丙烯酸酯,2,2,5-三甲基-4-苯基-3-氮杂己烷-3-氮氧化物,3,5-二(2-十二烷硫基硫代碳酰基硫代1-氧代丙氧基)苯甲酸,3-丁烯基2-(十二烷硫基硫代碳酰基硫代)-2-甲基丙酸酯,4-氰基-4-[(十二烷基硫烷基硫代羰基)硫烷基]戊酸,4-氰基-4-[(十二烷基硫烷基硫代羰基)硫烷基]戊醇,氰基甲基十二烷基,氰基甲基[3-(三甲氧基甲硅烷基)丙基]三硫代碳酸酯,2-氰基-2-丙基十二烷基三硫代碳酸酯,S,S-二苄基三硫代碳酸酯,2-(十二烷硫基硫代碳酰基硫代)-2-甲基丙酸,2-(十二烷硫基硫代碳酰基硫代)-2-甲基丙酸,3-叠氮基-1-丙醇酯,2-(十二烷硫基硫代碳酰基硫代)-2-甲基丙酸N-羟基琥珀酰亚胺酯,2-(十二烷硫基硫代碳酰基硫代)-2-甲基丙酸五氟苯酯,2-(十二烷硫基硫代碳酰基硫代)丙酸,2-(十二烷硫基硫代碳酰基硫代)-2-甲基丙酸甲酯,季戊四醇四[2-(十二烷硫基硫代碳酰基硫代)-2-甲基丙酸酯],邻苯二甲酰亚氨基甲基丁基三硫代碳酸酯,1,1,1-四[(十二烷硫基硫代碳酰基硫代)-2-甲基丙酸酯]乙烷,苯甲基二硫代苯甲酸酯,氰基甲基二硫代苯甲酸酯,4-氰基-4-(苯基硫代碳酰基硫代)戊酸,4-氰基-4-(苯基硫代碳酰基硫代)戊酸N-琥珀酰亚胺酯,2-氰基-2-丙基二硫代苯甲酸酯,2-氰基-2-丙基4-氰基二硫代苯甲酸酯,2-(4-甲氧基苯基硫代碳酰基硫代)乙酸乙酯,2-甲基-2-(苯基硫代羰基硫代)丙酸乙酯,2-(苯基硫代碳酰基硫代)-2-苯基乙酸乙酯,2-(苯基硫代碳酰基硫代)丙酸乙酯,1-(甲氧基羰基)乙基二硫代苯甲酸酯,2-(4-甲氧基苯基硫代碳酰基硫代)乙酸,2-硝基-5-(2-丙炔氧基)苄基,4-氰基-4-(苯基硫代碳酰基硫代)戊酸酯,2-(苯基硫代碳酰基硫代)丙酸,2-苯基-2-丙基二硫代苯甲酸酯,甲基(4-吡啶基)二硫代氨基甲酸氰基甲基酯,氰基丙-2-基N-甲基-N-(吡啶-4-基)氨基二硫代氨基甲酸酯,2-[甲基(4-吡啶基)硫代氨基甲酸基硫代]丙酸甲酯,1-琥珀酰亚胺基-4-氰基-4-[N-甲基-N-(4-吡啶基)硫代氨基甲酸基硫代]戊酸酯或它们的组合。在本发明的一个实施方式中,AIBN用作引发剂。因此,在本发明的一个实施方式中,用于制备式I的聚合物-偶联物的方法I,II,III和/或IV包括在聚合反应中使用AIBN作为引发剂。
在本发明的一个实施方式中,本发明的聚合物-药物偶联物可以进一步包含靶向基团。本文中术语“靶向基团”是指与细胞特异性结合的肿瘤特异性配体,优选具有互补受体的肿瘤细胞。
术语“靶向基团”是指用于将本发明的聚合物-药物偶联物递送至特定位点以获得所需活性的分子,即它提供化合物的定位。该定位可以通过分子决定簇的特异性识别,靶向剂或偶联物的分子大小,离子相互作用,疏水相互作用等介导。将药剂靶向特定组织或区域的其他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结合的分子。示例性靶向配体包括抗体,抗体片段,小有机分子,肽,拟肽,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式中,靶向系统包括将靶向配体如RGDfK,EPPT1肽,双膦酸或叶酸共价连接至载体分子或接头。
在某些实施方式中,本发明的特征在于具有或不具有靶向配体的聚合物-药物偶联物。在一些实施方式中,靶向配体可以是RGDfK,EPPT1,双膦酸或叶酸。
本发明的另一个实施方式提供了递送治疗剂的方法,包括给予对象有效量的式I所示的聚合物-药物偶联物。
本发明的另一个实施方式本发明的聚合物-药物偶联物,其用于治疗需要递送抗癌剂或类似药剂的各种病症的。
在一个优选的实施方式中,本发明涉及式I所示的聚合物-药物偶联物,其用作治疗癌症的药物。
如本文所用,“治疗”或“处理”意指抑制,减少,调节,改善或阻断表征为在受病症威胁或患有病症的对象中的病理状况的至少一种症状。不同类型癌症的非限制性列表如下:癌,实体组织癌,鳞状细胞癌,腺癌,肉瘤,神经胶质瘤,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,黑素瘤,腺瘤,缺氧肿瘤,骨髓瘤,转移性癌症或一般癌症。所公开的组合物可用于治疗的癌症的具体实例包括:B细胞淋巴瘤,T细胞淋巴瘤,蕈样真菌病,霍奇金病,膀胱癌,脑癌,神经系统癌,头颈癌,头部鳞状细胞癌和颈部,肾脏癌症,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,口腔鳞状细胞癌,咽喉癌,喉癌,结肠癌,宫颈癌症,宫颈癌,乳腺癌,上皮癌,肾癌,泌尿生殖系统癌,肺癌,食道癌,头颈癌,大肠癌,造血系统癌症;睾丸癌;结肠和直肠癌,前列腺癌或胰腺癌。
本发明的聚合物-药物偶联物还可用于治疗癌前病症,例如宫颈和肛门发育不良,其他发育不良,严重发育异常,增生,非典型增生和瘤形成。
本文所用的术语“癌症”和“癌性”是指恶性肿瘤或描述以不受调节的细胞生长为特征的生理状况。
如本文所讨论的,本发明的聚合物-药物偶联物可用于治疗和/或预防癌症。对于这种用途,本发明的聚合物-药物偶联物通常以药物组合物的形式给药。
因此,根据本发明,提供了药物组合物,其包含根据式I的聚合物-药物偶联物和至少一种药学上可接受的稀释剂,赋形剂和/或载体。术语“治疗”包括治疗性或预防性治疗。
包含本发明的聚合物-药物偶联物的组合物可以是任何合适的形式,这取决于将其给予患者的所需方法。包含本发明的聚合物药物偶联物的组合物可以配制成口服给药,例如液体分散体或水性或油性悬浮液的形式,或者它们可以配制用于胃肠外给药,例如用于皮下,静脉内,肌内,胸骨内,腹膜内,皮内,透皮或其它输注技术。包含本发明的聚合物药物偶联物的组合物还可以配制成通过气溶胶或溶液形式的用于与吸入器或喷雾器一起吸入给药。本发明的聚合物-药物偶联物优选透皮,皮下,鼻内,静脉内,肌内,肿瘤内或通过吸入给予对象。在任何给定情况下,最合适的给药途径将取决于本发明的聚合物-药物偶联物中存在的具体治疗剂,对象,疾病的性质和严重性,以及对象的身体状况。
本发明的聚合物-药物偶联物可以组合给药,例如,与一种或多种其他治疗活性化合物同时、依次或分开给予,所述一种或多种其他治疗活性化合物可以是抗癌剂,或者是免疫调节剂,抗病毒剂,抗感染剂,抗微生物剂,抗感染剂或麻醉剂或其组合。
所述第二治疗剂可以选自上面列出的治疗剂,只要其不同于本发明的聚合物-药物偶联物中存在的治疗剂。
在本说明书的上下文中包含意指包括。
在技术上合适的情况下,本发明的实施方式可以组合。
这里将实施方式描述为包括某些特征/元素。本发明还扩展到由所述特征/元素组成或基本上由所述特征/元素组成。
诸如专利和申请的技术参考文献通过引用结合在此。
本文具体和明确地叙述的任何实施方式可单独或与一个或多个其他实施方式组合形成免责声明的基础。
现在将参考以下实施例描述本发明,这些实施例仅是说明性的,不应以任何方式解释为限制本发明的范围。
实施例
实施例1:具有甲基丙烯酸酯官能团的甘氨酸-苯丙氨酸-亮氨酸-甘氨酸(GFLG)可切割接头的制备
根据K.Ulbrich等,Journal of Controlled Release,64,2000,63-79中描述的文献方法制备GFGL-MA接头。
实施例2:多西他奇-GFGL-甲基丙烯酸酯(MA)单体的制备
根据Ghandehari等人,Mol.Pharm.,2011,8(4),1090-1099中描述的文献方法,将多西他奇(DTX)与GFGL-MA接头偶联,得到DTX-GFLG-MA。
将多西他奇(0.335g,4.1mmol),4-(二甲基氨基)吡啶(DMAP,0.049g,4.0mmol)和MA-GFLG-OH(0.188g,4.0mmol)在真空下干燥。将反应混合物在氮气下溶于无水N,N-二甲基甲酰胺(DMF,5mL)中,用<0℃的冰浴(盐/冰)冷却,并逐滴加入二异丙基碳二亚胺(DIPC,76μL,4.89mmol)。
随后将反应混合物搅拌1小时,然后移去冰浴,将混合物温热至室温,搅拌过夜,通过薄层色谱法(TLC,洗脱液二氯甲烷(DCM):甲醇(MeOH)(95:5))监测进程,用于原料消失以及MA-GFLG-多西他奇的形成。使用旋转蒸发器在真空下除去DMF。通过硅胶色谱法纯化产物。
实施例3:在侧链中包含多西他奇和PEG的聚合物-药物偶联物的制备
聚乙二醇甲基醚甲基丙烯酸酯(PEGMEMA)(Mn:300)和DTX-GFGL-MA在作为引发剂的AIBN和作为溶剂的DMF存在下聚合,得到PEGMEMA-DTX。
方案1:PEGMEMA和DTX-GFLG-MA单体共聚的示意图。
在上图中,(*)表示AIBN片段作为聚合物-药物偶联物的端基。
通过改变PEGMEMA的比例,可以获得具有不同分子量的PEGMEMA-DTX偶联物。
为了证明本发明适用于各种分子量的PEGMEMA-DTX偶联物,本发明人制备了50kDa和85kDa PEGMEMA-DTX聚合物-药物偶联物并对它们进行药代动力学测试。
实施例4:药代动力学研究的结果
将具有50kDa和85kDa分子量的PEGMEMA-DTX偶联物进行药代动力学测试,并将其药代动力学特征与游离DTX的药代动力学特征进行比较。
使用聚合物药物偶联物和游离DTX的血浆总DTX浓度值计算总DTX的药代动力学参数。计算半衰期,分布容积(VDβ),清除率(CL)和曲线下的总面积(总AUC)。
为了与已知的现有技术进行比较,申请人根据Ghandehari等,Mol.Pharm.,2011,8(4),1090-1099公开的已知现有技术方法制备了分子量为52kDa和85kDa的N-(2-羟丙基)甲基丙烯酰胺(HPMA)-GFLG-DTX聚合物。为了提供相似性,制备不含RGDfK靶向基团的HPMA-GFLG-DTX聚合物。
药代动力学试验的结果如表1所示。
表1:PEGMEMA-GFLG-DTX偶联物,HPMA-GFLG-DTX偶联物和游离DTX的药代动力学参数
当考虑表1时,可以看出,与游离治疗剂和HPMA-DTX偶联物相比,两种PEGMEMA-DTX偶联物都具有优异的药代动力学性质。该结果表明,本发明的聚合物-药物偶联物提供了优异的聚合物-药物偶联物,其相对于游离DTX和与HPMA聚合物结合的DTX具有更长的半衰期,更低的清除率和更大的AUC。
实施例5:PEGMEMA-DTX偶联物和游离DTX对BxPC3细胞的细胞毒性结果
将人胰腺腺癌(BxPC3)细胞用偶联物和游离DTX在DMEM培养基中处理72小时。进行CCK-8测定以测量细胞活力。与期望的游离DTX偶联物相比,PEGMEMA-DTX偶联物显示出较低的细胞毒性。聚合物药物偶联物和游离DTX的EC 50值显示在表2中。
表2:游离DTX和PEGMEMA-DTX偶联物的EC50值
实施例6:PEGMEMA-DTX和游离DTX的血液毒性
在注射24小时之前和之后收集血样(200μL)。全血计数器用于测量样品的血象值。与注射前相比,注射24小时后的相对变化如图1所示。评估白细胞(WBC)红细胞(RBC)血红蛋白(HGB)和血细胞比容(HCT)值。与高分子量偶联物相比,低分子量偶联物对WBC具有更低的毒性。与游离DTX相比,所有偶联物对RBC的毒性较小。这些结果也用HGB和HCT验证。
总而言之,药代动力学测试以及细胞和血液毒性测试的结果表明,相对于已知的现有技术,本发明的聚合物-药物偶联物具有更好和意想不到的性质,因此本发明超过了现有技术水平。
附图说明
图1是显示PEGMEMA-DTX偶联物和游离DTX的血液百分比值的图。
序列表
<110> RS研究教育咨询医学工业贸易股份有限公司(RS Arastirma EgitimDanismanlik Ilac Sanayi Ticaret Ltd. A.S.)
<120> 可切割的聚合物药物偶联物
<130> RS-01-GB
<160> 2
<170> BiSSAP 1.3.6
<210> 1
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 1
Gly Phe Leu Gly
1
<210> 2
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 2
Ala Leu Ala Leu
1
Claims (21)
1.一种用于递送治疗剂的聚合物-药物偶联物,其包含基于(甲基)丙烯酸酯的聚合物主链,其特征在于所述聚合物包含至少两种类型的侧链,其中一种侧链是PEG链,例如–CO-Z-CH2CH2(OCH2CH2)nOR3,其中n是1-200之间的自然数,R3选自H或-CH3,Z选自-O或-NH,另一种侧链包含与可切割接头共价键合的至少一种治疗剂。
2.如权利要求1所述的式I的聚合物-药物偶联物
其中:
R1和R2独立地选自:H或–CH3,
R3选自:–H或–CH3,
x是1-100之间的自然数,
y是1-100之间的自然数,
n是1-200之间的自然数,
L是可切割接头,
D是至少一种治疗剂,
Z选自:-O或-NH,
A是任选为聚合引发剂或其片段的端基或者A为空,
B是任选为聚合引发剂或其片段的端基或者B为空。
3.如权利要求1或2所述的聚合物-药物偶联物,其中,接头选自:聚(乙二醇),氨基酸,聚(氨基酸),多肽和短肽。
4.如权利要求3所述的聚合物-药物偶联物,其中,所述接头是对组织蛋白酶B不稳定的短肽。
5.如权利要求4所述的聚合物-药物偶联物,其中,短肽选自:Gly-Phe-Leu-Gly(SEQ IDNO:1),Val-Cit(SEQ ID NO:2),Phe-Lys(SEQ ID NO:3),Val-Ala(SEQ ID NO:4),Ala-Leu-Ala-Leu(SEQ ID NO:5)。
6.如权利要求1或2所述的聚合物-药物偶联物,其中,所述接头是C1-C10烃或C1-C10取代的或杂取代的烃,其包含在生理条件下解离的官能团。
7.如权利要求6所述的聚合物药物偶联物,其中,所述官能团选自:缩醛,酯,亚胺,酰胺,二硫化物,碳酸酯,肼,氨基甲酸酯。
8.如权利要求1-7所述的聚合物-药物偶联物,其中,治疗剂选自:核苷类似物,抗叶酸剂,其他代谢物,拓扑异构酶I抑制剂,蒽环类,鬼臼毒素,紫杉烷,长春花生物碱,烷化剂,铂化合物,抗激素,放射性药物,单克隆抗体,酪氨酸激酶抑制剂,哺乳动物雷帕霉素靶蛋白(mTOR)抑制剂,类维生素A,免疫调节剂,组蛋白去乙酰化酶抑制剂和其他药剂。
9.如权利要求8的聚合物-药物偶联物,其中,所述治疗剂选自:紫杉烷类,抗叶酸剂,酪氨酸激酶抑制剂,蒽环类,核苷类似物和其他药剂。
10.如权利要求8或9所述的聚合物-药物偶联物,其中,所述治疗剂选自:多西他奇,培美曲塞,氯喹,考布他汀,吉西他滨,阿霉素,5-FU,5'-脱氧5-氟代胞苷(5'-DFCR),拉帕替尼。
11.如权利要求1-10所述的聚合物-药物偶联物,其中,所述治疗剂的存在量为聚合物-药物偶联物重量的1%至40%。
12.如权利要求1-11所述的聚合物-药物偶联物,其中,所述聚合物-药物偶联物的平均分子量为20kDa至300kDa。
13.一种制备式I的聚合物-药物偶联物的方法,包括使PEG(甲基)丙烯酸酯单体(式II)
与至少一种类型的(甲基)丙烯酸酯-L-D单体(式IIIa)聚合以提供式I
其中R1和R2独立地选自:H或–CH3,R3选自:–H或–CH3,L是可切割接头,D是治疗剂,n是1-200之间的自然数。
14.一种制备式I的聚合物-药物偶联物的方法,包括:
(i)使PEG(甲基)丙烯酸酯单体(式II)与(甲基)丙烯酸酯-L单体(式IIIb)聚合
其中R1和R2独立地选自:H或–CH3,R3选自:–H或–CH3,L是可切割接头,n是1-200之间的自然数,
以得到式IV所示的共聚物
其中x是1-100之间的自然数,y是1-100之间的自然数,
Z选自:-O或-NH,
A是任选为聚合引发剂或其片段的端基或者A可以为空,
B是任选为聚合引发剂或其片段的端基或者B可以为空,
以及然后(ii)使式IV与至少一种类型的治疗剂(D)反应,以得到式I。
15.一种制备式I的聚合物-药物偶联物的方法,包括:
(i)使PEG(甲基)丙烯酸酯单体(式II)与(甲基)丙烯酸酯单体(式IIIc)聚合
其中R1和R2独立地选自:H或–CH3,R3选自:–H或–CH3,R4选自:羰基活化基团,例如全氟苯氧基,马来酰亚胺,碳酸酯,噻唑烷酮-2-硫酮,N-氧基苯并三唑,咪唑基,邻/对-硝基苯酚,五氯苯酚,N-羟基琥珀酰亚胺,乙酸酯,甲酸酯,2,3,5-三氯苯酚,8-羟基喹啉,-OH,-OCH3,-OCH2CH3,Cl,F,Br,H,-SH,-NH2,-NHR5或–OR5,R5是C1-C10饱和或不饱和烃,n是1-200之间的自然数,
以得到式V的共聚物
其中,x是1-100之间的自然数,y是1-100之间的自然数,
Z选自:-O或-NH,
A是任选为聚合引发剂或其片段的端基或者A可以为空,
B是任选为聚合引发剂或其片段的端基或者B可以为空,
以及然后(ii)使式V与连接到接头上的至少一种类型的治疗剂(L-D)反应,以得到式I。
16.一种制备式I的聚合物-药物偶联物的方法,包括:
(i)使PEG(甲基)丙烯酸酯单体(式II)与(甲基)丙烯酸酯单体(式IIIc)聚合
其中R1和R2独立地选自:H或–CH3;R3选自:–H或–CH3;R4选自:羰基活化基团,例如全氟苯氧基,马来酰亚胺,碳酸酯,噻唑烷酮-2-硫酮,N-氧基苯并三唑,咪唑基,邻/对-硝基苯氧基,五氯苯氧基,N-羟基琥珀酰亚胺,乙酸酯,甲酸酯,2,3,5-三氯苯酚,8-羟基喹啉,-OH,-OCH3,-OCH2CH3,Cl,F,Br,H,-SH,-NH2,-NHR5或–OR5,R5是C1-C10饱和或不饱和烃,n是1-200之间的自然数,
以得到式V的共聚物
其中,x是1-100之间的自然数,y是1-100之间的自然数,
A是任选为聚合引发剂或其片段的端基或者A可以为空,
B是任选为聚合引发剂或其片段的端基或者B可以为空,
以及然后(ii)使式V与接头(L)反应,以得到式IV的共聚物,
以及(iii)使式IV与至少一种类型的治疗剂(D)反应,以得到式I的聚合物偶联物。
17.如权利要求13-16所述的制备式I的聚合物-药物偶联物的方法,其中,所述方法还包括用于式II与式IIIa或IIIb或IIIc的聚合的引发剂。
18.一种药物组合物,其包含如权利要求1-12所述的式I的聚合物-药物偶联物。
19.如权利要求1-12所述的式I的聚合物-药物偶联物,其用作治疗和/或预防癌症的药物。
20.用于合成式I的聚合物-药物偶联物的式IV的共聚物
其中
x是1-100之间的自然数,
y是1-100之间的自然数,
R1和R2独立地选自:H或–CH3,
R3选自:–H或–CH3,
n是1-200之间的自然数,
L是可切割接头,
Z选自:-O或-NH,
A是任选为聚合引发剂或其片段的端基或者A可以为空,
B是任选为聚合引发剂或其片段的端基或者B可以为空。
21.用于合成式I的聚合物-药物偶联物的式V的共聚物
其中
x是1-100之间的自然数,
y是1-100之间的自然数,
Z选自:-O或-NH,
R1和R2独立地选自:H或–CH3,
R3选自:–H或–CH3,
R4选自:羰基活化基团,例如全氟苯氧基,马来酰亚胺,碳酸酯,噻唑烷酮-2-硫酮,N-氧基苯并三唑,咪唑基,邻/对-硝基苯氧基,五氯苯氧基,N-羟基琥珀酰亚胺,乙酸酯,甲酸酯,2,3,5-三氯苯酚,8-羟基喹啉,N-羟基邻苯二甲酰亚胺,-OH,-OCH3,-OCH2CH3,Cl,F,Br,H,-SH,-NH2,-NHR5或–OR5,
R5是C1-C10饱和或不饱和烃,
n是1-200之间的自然数。
A是任选为聚合引发剂或其片段的端基或者A可以为空,
B是任选为聚合引发剂或其片段的端基或者B可以为空。
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CN108752507A (zh) * | 2018-05-12 | 2018-11-06 | 辽宁大学 | 一种酶敏感和氧化还原敏感双重响应型共聚物及其制备方法和应用 |
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