CN110314235A - 一种还原响应型两亲性抗肿瘤药物偶联物及其制备方法和应用 - Google Patents
一种还原响应型两亲性抗肿瘤药物偶联物及其制备方法和应用 Download PDFInfo
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- CN110314235A CN110314235A CN201810296456.5A CN201810296456A CN110314235A CN 110314235 A CN110314235 A CN 110314235A CN 201810296456 A CN201810296456 A CN 201810296456A CN 110314235 A CN110314235 A CN 110314235A
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Abstract
本发明涉及一种还原响应型两亲性抗肿瘤药物偶联物及其制备方法和应用,其具有如式Ⅰ所示的分子结构式:其中,ROH为疏水性抗肿瘤药物;n为5~1000。本发明提供的药物前体能够实现靶向给药,既保留了纳米载药系统的优势,同时又发挥了二硫键在肿瘤部位特异性降解的特点。与常规的2,2′‑二硫代二乙酸、3,3′‑二硫代二丙酸等连接臂相比,无需通过进一步水解就可以得到原药分子形式的抗癌药物。
Description
技术领域
本发明涉及一种抗肿瘤药物偶联物及其制备方法和应用,尤其涉及一种可应用于肿瘤治疗的能够自组装成胶束的两亲性抗肿瘤药物偶联物及其制备方法和应用。
背景技术
化疗是一种基本的肿瘤治疗方法,其主要是利用抗癌药物杀死肿瘤细胞而达到治疗肿瘤的目的。临床上常用的抗癌药物主要包括喜树碱类、紫杉烷类、长春碱和蒽醌类等,但这些抗癌药物理化性质较差(例如难溶于水,选择性差等),对正常细胞和组织有严重的毒副作用,导致肿瘤化疗效果差,因此临床应用受到限制。
通过化学修饰在药物的分子结构中引入亲水性基团,制备得到水溶性的前药,可以有效的解决疏水性药物的水溶性问题。在水溶性高分子聚合物中,聚乙二醇得到了广泛关注。聚乙二醇是一种生物相容性优异的高分子材料,已经被美国FDA批准为可体内注射的药用高分子聚合物之一。疏水性药物经聚乙二醇修饰之后,水溶性和体内稳定性均得以提高,并能显著降低肾脏清除率,大大延长血液循环时间,还能通过EPR效应增强肿瘤处的积聚,这些均对提高肿瘤治疗效果、降低毒副作用具有至关重要的作用。
近年来,纳米给药系统以其优良特性受到了广泛的关注,纳米给药系统具有以下特征:较大程度提高药物的水溶性、通过提高渗透性和保留效应 (EPR效应)来实现对肿瘤的被动靶向、延长体内循环时间、提高药物利用率以及降低毒副作用等。然而,普通的纳米制剂并不能识别肿瘤部位与正常部位,也不能区分细胞内及细胞外的环境,因此如何让纳米制剂在体内选择性的释放出原药仍然是一大难题。
研究发现,细胞内的谷胱甘肽浓度(0.5~10mM)是细胞外谷胱甘肽浓度(2~20μM)的200倍以上,二硫键在一定量的谷胱甘肽(GSH)或二硫苏糖醇(DTT)等还原剂存在下可被还原生成巯基,但是二硫键在人体的正常体温、pH和氧化等环境下则非常稳定,即细胞外的谷胱甘肽浓度不足以还原二硫键,另外,肿瘤组织细胞比正常组织细胞缺氧,更具有还原性环境。因此,可以将亲水性的聚合物和疏水性的药物通过二硫键链接,并在溶剂中自组装成纳米胶束,通过细胞内吞作用进入靶细胞后被GSH还原,即二硫键断裂生成巯基,从而快速有效地释放药物,并扩散到细胞核等结构,从而杀死癌细胞。
目前最常用的二硫键连接臂主要为2,2′-二硫代二乙酸、3,3′-二硫代二丙酸等,但以这些二硫键连接臂连接亲水性的聚合物与疏水性药物后,在 GSH、DTT等还原条件下,二硫键迅速发生断裂,但是断裂后释放的药物上还连接有巯基和酯键这样的一个“尾巴”,而并非原料分子形式,中国专利 CN102775596所公开的聚合物药物前体在二硫键断裂释放药物的时候即属于上述的情况,要想得到原料分子形式的药物需再经过酯键水解的步骤,而在人体细胞内的弱碱性条件下,酯键的水解缓慢且不完全,直接影响药物的抗肿瘤效果。
发明内容
本发明针对现有抗肿瘤药物水溶性以及靶向释放原药方面存在的不足,提供一种还原响应型且能够自组装成胶束的两亲性抗肿瘤药物偶联物及其制备方法和应用。
本发明解决上述技术问题的技术方案如下:
一种还原响应型两亲性抗肿瘤药物偶联物,具有如式Ⅰ所示的分子结构式:
其中,ROH为疏水性抗肿瘤药物;n为5~1000。
进一步,所述抗肿瘤药物是指紫杉烷类或长春碱类药物中的任意一种。
进一步,所述紫杉烷类药物是指紫杉醇、多烯紫杉醇、卡巴他赛、拉洛他赛中的一种,所述长春碱类药物是指长春碱、长春新碱、长春瑞滨中的一种。
本发明提供的两亲性抗肿瘤药物偶联物释放原药分子的机理为:
本发明采用了肿瘤微环境靶向给药的思路,通过引入对还原环境敏感的自毁式二硫键连接臂,在肿瘤细胞内谷胱甘肽提供的还原条件下,抗肿瘤药物偶联物中的二硫键发生断裂,二硫键断裂后经过系列电子重排迅速释放抗癌药物原药分子,以卡巴他赛为例,其还原响应释放原药分子的机理如下式所示:
本发明提供的两亲性抗肿瘤药物偶联物的有益效果为:
1)本发明提供的两亲性抗肿瘤药物偶联物能够实现靶向给药,既保留了纳米载药系统的优势,同时又发挥了二硫键在肿瘤部位特异性降解的特点。与常规的2,2′-二硫代二乙酸、3,3′-二硫代二丙酸等连接臂相比,无需通过进一步水解就可以得到原药分子形式的抗癌药物。
2)本发明得到的两亲性抗肿瘤药物偶联物,可以在溶剂中自发组装成纳米胶束。
本发明还要求保护由上述的抗肿瘤药物偶联物制备而成的抗肿瘤药物纳米胶束,所述抗肿瘤药物纳米胶束是由如下方法制成的,将前述的抗肿瘤药物偶联物和脂肪酸甘油三酯置于水中溶解得二者的混合溶液,后将溶液超声,过滤膜,向其中加入甘露醇冻干,即得抗肿瘤药物纳米胶束,所得胶束的粒径为10~400nm,载药量为2~70wt%。
本发明还要求保护前述的抗肿瘤药物偶联物以及由本发明的抗肿瘤药物偶联物制备而成的抗肿瘤药物纳米胶束在抗肿瘤药物领域的应用。
进一步,所述肿瘤是指前列腺癌。
本发明还提供了上述两亲性抗肿瘤药物偶联物的制备方法,包括如下步骤:
1)使用对硝基氯甲酸苯酯与紫杉烷类或长春碱类药物于碱性条件下反应制备4-硝基苯基活性酯;
2)使用吡啶二硫基苄醇与步骤1)制备的4-硝基苯基活性酯于碱性条件下反应制备吡啶二硫基药物碳酸酯;
3)将步骤2)制备的吡啶二硫基药物碳酸酯与巯基化聚乙二醇通过巯基 -二硫键交换反应,制得含有二硫键的聚乙二醇化抗肿瘤药物偶联物。
反应路线如下:
进一步,各个步骤的具体反应过程如下:
步骤1):将紫杉烷类或长春碱类药物与4-二甲氨基吡啶溶于有机溶剂中得混合溶液,0℃下将对硝基氯甲酸苯酯滴加至溶液中,其中,对硝基氯甲酸苯酯与药物的摩尔比为(1~3):1,对硝基氯甲酸苯酯与4-二甲氨基吡啶的摩尔比为(1~3):1,0℃下反应2~8小时,反应液经酸洗、分液、干燥、浓缩、硅胶柱纯化、浓缩、真空干燥得4-硝基苯基活性酯;
步骤2):将吡啶二硫基苄醇与步骤1)所得的4-硝基苯基活性酯按摩尔比(1~3):1溶于有机溶剂中,室温搅拌条件下向其中加入4-二甲氨基吡啶,控制4-二甲氨基吡啶与4-硝基苯基活性酯的摩尔比为(1~3):1,回流反应12~36小时,反应液依次经碱洗、酸洗、分液、干燥、浓缩、硅胶柱纯化、浓缩、真空干燥得吡啶二硫基药物碳酸酯;
步骤3):惰性氛围中,搅拌条件下将巯基化聚乙二醇滴加到步骤2)所得的吡啶二硫基药物碳酸酯的溶液中,控制巯基化聚乙二醇与吡啶二硫基药物碳酸酯的摩尔比为1:(1~3),室温下反应12~48小时,反应液经浓缩、硅胶柱纯化、浓缩、真空干燥得含有二硫键的聚乙二醇化抗肿瘤药物偶联物。
本发明提供的还原响应型两亲性抗肿瘤药物偶联物的制备方法的有益效果是:原料易得、反应条件温和、产率和产物纯度高等优点,利于批量生产。
附图说明
图1为实施例1所得抗肿瘤药物偶联物的核磁共振氢谱;
图2为实施例1所得抗肿瘤药物偶联物在DTT条件下还原响应释药结果图;
图3为实施例2所得胶束的粒径分布图;
图4为实施例2所得胶束与卡巴他赛对前列腺癌细胞DU145的增殖抑制活性比较。
具体实施方式
以下结合实例对本发明的原理和特征进行描述,所举实例只用于解释本发明,并非用于限定本发明的范围。
本发明实施例中所采用的溶液浓度单位M=mol/L。
实施例1:
一种还原响应释放原药的卡巴他赛的两亲性抗肿瘤药物偶联物,具有如下结构式:
上述卡巴他赛的两亲性抗肿瘤药物偶联物的制备方法如下:
(1)4-(2-吡啶基二硫基)苯甲醇的制备:
将氢化铝锂(740mg,19.4mmol)混悬于15mL四氢呋喃中,氮气保护下,0℃保温。将4-巯基苯甲酸(1.0g,6.48mmol)的四氢呋喃溶液(15 mL)缓慢滴加至氢化铝锂四氢呋喃体系中,保温过夜。以0.5mL水淬灭反应后,以2M盐酸调节pH=2,以乙酸乙酯萃取。有机相以水,饱和食盐水洗,无水硫酸钠干燥,减压浓缩。经硅胶柱纯化得到4-巯基苯甲醇(440mg,54%)。
将二硫二吡啶(1.3g,5.7mmol)溶于10mL二氯甲烷中,4-巯基苯甲醇(400mg,2.86mmol)溶于10mL二氯甲烷中,混合后室温搅拌过夜。旋蒸除去溶剂后,硅胶柱纯化得到4-(2-吡啶基二硫基)苯甲醇(589mg,82%)。
(2)4-硝基苯基-2’-卡巴他赛活性酯的制备:
将卡巴他赛(1.0g,1.2mmol)和4-二甲氨基吡啶DMAP(0.22g,1.8 mmol)溶于50mL二氯甲烷DCM中,0℃下滴加氯甲酸对硝基苯酯(0.38 g,1.8mmol)的DCM溶液(15mL)后,0℃保温反应2小时。以0.1M 的HCl溶液洗有机相后,无水硫酸钠干燥,减压浓缩,经硅胶柱纯化得到1.1g白色固体,收率为93%。对产物进行1H NMR和MS测试,表明得到式a所示结构的4-硝基苯基-2’-卡巴他赛活性酯。
(3)4-(2-吡啶基二硫基)苄基-2’-卡巴他赛碳酸酯的制备:
将4-硝基苯基-2′-卡巴他赛活性酯(2.0g,2.0mmol)和4-(2-吡啶基二硫基)苯甲醇(498mg,2.0mmol)溶于100mL二氯甲烷中,加入4-二甲氨基吡啶(DMAP,244mg,2.0mmol),回流过夜。反应液依次以1M 的碳酸氢钠溶液和0.1M的稀盐酸洗,干燥后,减压蒸去溶剂,粗品经硅胶柱纯化得到1.8g白色固体,收率为82%。对产物进行1H NMR和MS测试,表明得到式b所示结构的4-(2-吡啶基二硫基)苄基-2’-卡巴他赛碳酸酯。
(4)聚乙二醇-二硫键(BnO)-卡巴他赛的制备:
将mPEG2000-SH(1.6g,1.0mmol)溶于50mL DMF中,氮气保护、搅拌下,滴加4-(2-吡啶基二硫基)苄基-2’-卡巴他赛碳酸酯(1.1g,1.0mmol) 的DMF(50mL)溶液,室温下反应12小时。减压蒸去DMF,经硅胶柱纯化,浓缩得到1.48g白色固体,收率为56%。对产物进行1HNMR测试,表明得到式c所示结构的聚乙二醇-二硫键(BnO)-卡巴他赛(图1)。
合成路线如下所示:
为了验证实施例1所得的两亲性抗肿瘤药物偶联物在还原条件下是否释放原药分子,我们将实施例1所得抗肿瘤药物偶联物分别置于PBS 7.4溶液和10mM的还原剂DTT溶液中后对不同时间的产物均进行了HPLC测试,结果如图2所示,由图2我们可以看出,实施例1所得抗肿瘤药物偶联物在 PBS 7.4溶液中稳定,而在DTT溶液中放置10min后,产物中已经出现了大量原药分子卡巴他赛,表明已经有一部分的抗肿瘤药物偶联物分解释放出了原药,因而本申请提供的抗肿瘤药物偶联物在还原条件下可以迅速分解释放原药。
实施例2:
一种含有实施例1所得两亲性抗肿瘤药物偶联物的纳米胶束,采用如下方法制成:将20mg抗肿瘤药物偶联物和10μL中链脂肪酸甘油三酯置于水中,然后超声1min,过滤膜,向其中加入甘露醇冻干,即得还原响应型抗肿瘤药物偶联物纳米胶束冻干粉。利用动态光散射(Dynamic Light Scattering,DLS)测定得到纳米胶束的粒径及分布,如图3所示。
实施例3:
一种还原响应释放原药的长春瑞滨的两亲性抗肿瘤药物偶联物,具有如下结构式:
上述长春瑞滨的两亲性抗肿瘤药物偶联物的制备方法如下:
(1)4-硝基苯基-长春瑞滨活性酯的制备:
将长春瑞滨(500mg,0.64mmol)和4-二甲氨基吡啶DMAP(78mg, 0.64mmol)溶于20mL二氯甲烷中,0℃下滴加氯甲酸对硝基苯酯(387mg, 1.92mmol)的DCM溶液(10mL)后,0℃保温反应8小时。以0.1M的 HCl溶液洗有机相后,无水硫酸钠干燥,减压浓缩,经硅胶柱纯化得到490mg 白色固体,收率为81%。对产物进行1H NMR和MS测试,表明得到式d 所示结构的4-硝基苯基长春瑞滨碳酸酯。
(2)4-(2-吡啶基二硫基)苄基-长春瑞滨碳酸酯的制备:
将4-硝基苯基长春瑞滨活性酯(490mg,0.52mmol)和4-(2-吡啶基二硫基)苯甲醇(390mg,1.56mmol)溶于20mL二氯甲烷中,加入4-二甲氨基吡啶(DMAP,192mg,1.56mmol),回流过夜。反应液依次以1M 的碳酸氢钠溶液和0.1M的稀盐酸洗,干燥后,减压蒸去溶剂,粗品经硅胶柱纯化得到380mg白色固体,收率为70%。对产物进行1H NMR和MS测试,表明得到式e所示结构的4-(2-吡啶基二硫基)苄基-长春瑞滨碳酸酯。
(3)聚乙二醇-二硫键(BnO)-长春瑞滨的制备:
将mPEG5000-SH(1.8g,0.36mmol)溶于50mL DMF中,氮气保护、搅拌下,滴加4-(2-吡啶基二硫基)苄基-长春瑞滨碳酸酯(1140mg,1.08 mmol)的DMF(10mL)溶液,室温下反应48小时。减压蒸去DMF,经硅胶柱纯化,浓缩得到850mg白色固体,收率为40%。对产物进行1HNMR 测试,表明得到式f所示结构的聚乙二醇-二硫键(BnO)-长春瑞滨。
合成路线如下所示:
为了验证本发明所得抗肿瘤药物偶联物对肿瘤细胞的增殖抑制效果,我们取实施例2所得的胶束以及卡巴他赛进行了体外抗肿瘤细胞的效果对比实验,我们以前列腺癌DU145为例分别进行了实施例2所得的胶束与卡巴他赛对肿瘤细胞的增殖抑制效果实验,具体操作过程如下:
取对数生长期的细胞,调整适当的细胞密度,接种于96孔板内,100 μl/well,培养于37℃,5%CO2的培养箱内。培养过夜后给药,分别加药作用 48h。分设空白组、给药组,每组设4个复孔。体外抗前列腺癌细胞效果如图4所示。从图4中可以看出,聚乙二醇-二硫键(BnO)-卡巴他赛与卡巴他赛具有近似的细胞毒性,聚乙二醇-二硫键(BnO)-卡巴他赛对前列腺癌 DU145的半数抑制率IC50<0.001μM,有较强的抗肿瘤活性。
综上所述,本发明提供的两亲性抗肿瘤药物偶联物不仅水溶性好,并且能够在肿瘤细胞内的还原条件下1h内释放出原药,实现了靶向释放,且经过实验证明与原药具有基本相同的抗肿瘤活性,可以于48h内发挥出其对肿瘤细胞的抑制作用。
以上所述仅为本发明的较佳实施例,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (9)
1.一种还原响应型两亲性抗肿瘤药物偶联物,其特征在于,具有如式Ⅰ所示的分子结构式:
其中,ROH为疏水性抗肿瘤药物;n为5~1000。
2.根据权利要求1所述的抗肿瘤药物偶联物,其特征在于,所述抗肿瘤药物是指紫杉烷类或长春碱类药物中的任意一种。
3.根据权利要求2所述的抗肿瘤药物偶联物,其特征在于,所述紫杉烷类药物是指紫杉醇、多烯紫杉醇、卡巴他赛、拉洛他赛中的一种,所述长春碱类药物是指长春碱、长春新碱、长春瑞滨中的一种。
4.一种抗肿瘤药物纳米胶束,其特征在于,所述抗肿瘤药物纳米胶束是由如下方法制成的,将权利要求1-3中任一项所述的抗肿瘤药物偶联物和脂肪酸甘油三酯置于水中溶解得二者的混合溶液,后将溶液超声,过滤膜,向其中加入甘露醇冻干,即得抗肿瘤药物纳米胶束。
5.根据权利要求4所述的抗肿瘤药物纳米胶束,其特征在于,所述抗肿瘤药物纳米胶束的粒径为10~400nm,载药量为2~70wt%。
6.一种权利要求1-3中任一项所述的抗肿瘤药物偶联物和权利要求4、5中任一项所述的抗肿瘤药物纳米胶束在抗肿瘤药物领域的应用。
7.根据权利要求6所述的应用,其特征在于,所述肿瘤是指前列腺癌。
8.一种权利要求1-3中任一项所述的抗肿瘤药物偶联物的制备方法,其特征在于,包括如下步骤:
1)使用对硝基氯甲酸苯酯与紫杉烷类或长春碱类药物于碱性条件下反应制备4-硝基苯基活性酯;
2)使用吡啶二硫基苄醇与步骤1)制备的4-硝基苯基活性酯于碱性条件下反应制备吡啶二硫基药物碳酸酯;
3)将步骤2)制备的吡啶二硫基药物碳酸酯与巯基化聚乙二醇通过巯基-二硫键交换反应,制得含有二硫键的聚乙二醇化抗肿瘤药物偶联物;
反应路线如下:
9.根据权利要求8所述的制备方法,其特征在于,各个步骤的具体反应过程如下:
步骤1):将紫杉烷类或长春碱类药物与4-二甲氨基吡啶溶于有机溶剂中得混合溶液,0℃下将对硝基氯甲酸苯酯滴加至溶液中,其中,对硝基氯甲酸苯酯与药物的摩尔比为(1~3):1,对硝基氯甲酸苯酯与4-二甲氨基吡啶的摩尔比为(1~3):1,0℃下反应2~8小时,反应液经后处理得4-硝基苯基活性酯;
步骤2):将吡啶二硫基苄醇与步骤1)所得的4-硝基苯基活性酯按摩尔比(1~3):1溶于有机溶剂中,室温搅拌条件下向其中加入4-二甲氨基吡啶,控制4-二甲氨基吡啶与4-硝基苯基活性酯的摩尔比为(1~3):1,回流反应12~36小时,反应液经后处理得吡啶二硫基药物碳酸酯;
步骤3):惰性氛围中,搅拌条件下将巯基化聚乙二醇滴加到步骤2)所得的吡啶二硫基药物碳酸酯的溶液中,控制巯基化聚乙二醇与吡啶二硫基药物碳酸酯的摩尔比为1:(1~3),室温下反应12~48小时,反应液经后处理得含有二硫键的聚乙二醇化抗肿瘤药物偶联物。
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