CN106046062B - 两亲性奥沙利铂前体,其制备方法及用途 - Google Patents
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Abstract
本发明公开了一种式1所示的两亲性奥沙利铂前体、其制备方法及用途。所述两亲性奥沙利铂前体包含奥沙利铂单元,以及疏水性和亲水性官能团。所述两亲性奥沙利铂前体可在水中单独自组装成胶束。其中,上述两亲性奥沙利铂前体的疏水性官能团可通过疏水相互作用构成疏水内核,亲水性官能团形成亲水壳层,以保持自组装胶束的胶体稳定性。此外,本发明还公开了所述两亲性奥沙利铂前体的用途,主要用于癌症治疗药物的制备。
Description
技术领域
本发明属于医药化工技术领域,具体涉及两亲性奥沙利铂前体,其制备方法及用途。
背景技术
化疗是当前癌症治疗的主要手段之一,其中(二价)铂类药物具有抗癌效果好、适应症广等特点,因此目前临床主要使用顺铂(Cisplatin),卡铂(Carboplatin)以及奥沙利铂(Oxaliplatin)来治疗多种恶性肿瘤。但是铂类抗肿瘤药物在临床使用过程中大都易引起严重的胃肠道反应、肾毒性、耳毒性以及神经毒性和骨髓毒性。同时,奥沙利铂易导致获得性耐药,使奥沙利铂的实际疗效严重降低,适应症范围明显缩小,进而限制了奥沙利铂的临床使用效果。近年来,基于纳米技术的药物共递送策略为联合化疗提供了新型药物递送系统。纳米药物递送系统可以有效延长小分子的血液清除时间,提高小分子药物的瘤内分布,并显著改善小分子药物的化疗效果,正受到广泛关注。
发明内容
基于以上背景,本发明的目的是提供一种在水中可以构成自组装胶束的两亲性奥沙利铂前体,所述两亲性奥沙利铂前体具有以下结构式1所示结构:
其中,R1选自C2~C16饱和烷基,二硫二乙基(CH3-CH2-S-S-CH2-CH2-)或含有甘氨酸-苯丙氨酸-亮氨酸-甘氨酸(GFLG)序列的短肽链(与亮氨酸连接的甘氨酸为靠近奥沙利铂母体结构的一端);R2为仲氨基,选自羟基乙氨基(-NH-CH2-CH2-OH)和(2-氨基乙基)三甲基氯化铵基团。
所述两亲性奥沙利铂前体通式中R1为疏水性基团,R2为亲水性基团。
所述两亲性奥沙利铂前体的制备方法包括如下步骤:
步骤a:氧化奥沙利铂的制备
取奥沙利铂混悬于去离子水中,以双氧水:奥沙利铂20-100:1的摩尔比向溶液中加入质量分数为30%的双氧水,置于0-40℃之间的任意一个恒定温度避光反应6-48h,旋转蒸发除去溶剂,加入甲醇溶解所得物质,乙醚沉淀,真空干燥即得氧化奥沙利铂;
步骤b:单羧化氧化奥沙利铂的制备
取步骤a中制得的氧化奥沙利铂溶于二甲基亚砜中,加入等摩尔量的琥珀酸酐,在0-40℃之间的任意恒定温度反应1-24h后,乙醚沉淀,所得物质用甲醇溶解,旋转蒸发除去甲醇,所得沉淀用乙醚洗涤,真空干燥即得单羧化氧化奥沙利铂;
步骤c:单羧基化并烷基化奥沙利铂的制备
其中,R1的定义如前所述;
将单羧化氧化奥沙利铂溶于有机溶剂中,以烷基化试剂与单羧化氧化奥沙利铂1-10:1的摩尔比向溶液中加入烷基化试剂,在20-60℃之间的任意恒定温度反应6-48h后,旋转蒸发浓缩,所得物质用乙醚洗涤,真空干燥,即得单羧基化并烷基化奥沙利铂;
其中,所述烷基化试剂选自烷基异氰酸酯(R1-N=C=O)或者饱和及不饱和酸酐(O=C(R1)-O-C(R1)=O)中的一种;所述有机溶剂选自二氯甲烷、乙腈、四氢呋喃、丙酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺和二甲基亚砜中的至少一种;
步骤d:两亲性奥沙利铂前体的制备
其中,R2的定义如前所述;
将单羧基化并烷基化奥沙利铂溶于有机溶剂中得到溶液,以羟基活化剂与单羧基化并烷基化奥沙利铂为1-10:1的摩尔比向溶液中加入羟基活化剂,在0-40℃之间的任意恒定温度下反应1-5h;向反应液中以亲水性试剂R2H与单羧基化并烷基化奥沙利铂1-10:1摩尔比加入亲水性试剂R2H;之后在0-40℃之间的任意恒定温度下搅拌反应6-48h;旋转蒸发浓缩,乙醚沉淀,真空干燥,即得两亲性奥沙利铂前体。
其中,所述羧基活化剂为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、1-羟基苯并三唑、或N-羟基琥珀酰亚胺中的一种或几种;所述有机溶剂选自二氯甲烷、乙腈、四氢呋喃、丙酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺和二甲基亚砜中的至少一种。
本发明的另一方面是提供所述两亲性奥沙利铂前体在制备癌症治疗药物中的用途。
所述癌症包括乳腺癌、肺癌、卵巢癌、前列腺癌、胰腺癌、肝癌、头颈部癌或胃癌等。
本发明的另一方面是提供一种胶束,所述胶束是由单羧化并烷基化奥沙利铂在水中自组装形成。且所述胶束的平均流体力学粒径优选为10-300nm。
本发明的另一方面是提供上述胶束在制备癌症治疗药物中的用途,上述胶束容易进入肿瘤细胞内部,经过谷胱甘肽还原后,四价奥沙利铂前体被还原成二价奥沙利铂,胶束解离,使肿瘤细胞内药物浓度迅速提高杀死肿瘤细胞,从而有效改善肿瘤化疗效果。
所述癌症包括乳腺癌、肺癌、卵巢癌、前列腺癌、胰腺癌、肝癌、头颈部癌或胃癌等。
附图说明
图1为本发明实施例1中制备的氧化奥沙利铂的核磁共振氢谱。如核磁共振氢谱所示,f峰为奥沙利铂氧化后羟基的特征峰,证明成功制备出氧化奥沙利铂
图2为本发明实施例2中制备的单羧化奥沙利铂的核磁共振氢谱(A)和质谱(B)。如核磁共振氢谱所示,f1和f2峰为琥珀酸酐的亚甲基特征峰,证明成功制备出单羧化奥沙利铂;质谱图所示合成产物的分子量为530,与理论分子量吻合,证明成功制备出单羧化奥沙利铂。
图3为本发明实施例3中制备的单羧化并烷基化奥沙利铂的核磁共振氢谱(A)和质谱(B)。如核磁共振氢谱所示,g、h、和i峰为十六烷基异氰酸酯的亚甲基特征峰,j峰为十六烷基异氰酸酯的末端甲基峰,证明成功制备出单羧化并烷基化奥沙利铂;如质谱图所示合成产物的分子量为797,符合预测结果,进一步证明成功制备出单羧化并烷基化奥沙利铂。
图4为本发明实施例4中制备的两亲性奥沙利铂前体的核磁共振氢谱(A)和质谱(B)。如核磁共振氢谱所示,l1和l2峰为(2-氨基乙基)三甲基氯化铵的亚甲基特征峰,k峰为(2-氨基乙基)三甲基氯化铵的三个甲基峰,证明成功制备出两亲性奥沙利铂前体;质谱图所示合成产物的分子量为883,进一步证明成功制备出两亲性奥沙利铂前体。
图5为本发明实施例5中两亲性奥沙利铂前体胶束的流体力学粒径分布图(A)和透射电子显微镜照片(B)。两亲性奥沙利铂前体胶束的流体力学粒径由MALVERN NANO SIZER型激光粒径测定仪测得,结果显示两亲性奥沙利铂前体胶束的直径为10-250nm。透射电镜结果显示两亲性奥沙利铂前体胶束能够在水中形成直径为20nm的球形粒子。
图6为奥沙利铂原药、本发明实施例5中制备的两亲性奥沙利铂前体胶束对4T1乳腺癌细胞的MTT毒性实验数据。结果表明当药物浓度为20μM时,奥沙利铂原药组的细胞存活率为53%,两亲性奥沙利铂前体胶束组的细胞存活率为30%,表明由两亲性奥沙利铂前体纳米粒可显著抑制肿瘤细胞生长,且细胞毒性优于奥沙利铂原药。
具体实施方式
通过以下具体实施例对本发明进行说明,但本发明不受这些具体实施例限定。
实施例中所用的(2-氨基乙基)三甲基氯化铵、十六烷基异氰酸酯购自西格玛奥德里奇(中国)公司。奥沙利铂购自山东铂源公司。琥珀酸酐、1-乙基-(3-二甲氨基丙基)碳二亚胺盐酸盐、1-羟基苯并三唑购自梯希爱(上海)化成工业发展有限公司。溶剂N,N-二甲基甲酰胺、二甲基亚砜购自上海百灵威科技有限公司。4T1乳腺癌细胞购自美国ATCC细胞库,细胞培养用RPIM1640培养基和胎牛血清均购自Gibco公司。
本申请中,如无特殊说明,其余所用试剂和溶剂均购自国药集团(上海)化学试剂有限公司。
本申请中,如无特殊说明,所用设备及测试方法均为本领域常规的设备和方法。透射电镜照片由Tecnai G2F20S-TWIN型透射电子显微镜获得。胶束胶束的流体力学粒径由MALVERN NANO SIZER型激光粒径测定仪测得。
实施例1.氧化奥沙利铂的制备
称取奥沙利铂500mg,混悬于10ml去离子水中,加入3ml 30%双氧水,置于50ml圆底烧瓶中,30摄氏度避光搅拌反应12小时,旋转蒸发除去溶剂,加入甲醇溶解所得物质,乙醚沉淀,真空干燥即得氧化奥沙利铂。所得物质采用核磁共振氢谱表征,结果如图1所示。
实施例2.单羧化奥沙利铂的制备
取实施例1中制备的氧化奥沙利铂215mg,溶于5ml无水二甲基亚砜中,加入50mg琥珀酸酐,25℃下反应12h,乙醚沉淀,所得物质用甲醇溶解,之后旋转蒸发除去甲醇,所得沉淀用乙醚洗涤,真空干燥即得单羧化氧化奥沙利铂。所得物质采用核磁共振氢谱和质谱表征,结果如图2所示。
实施例3.单羧化奥沙利铂的烷基化
取实施例2中制备的单羧化氧化奥沙利铂60mg,溶于3ml无水N,N-二甲基甲酰胺中,再加入45.33mg十六烷基异氰酸酯,置于25℃下搅拌反应过夜,旋转蒸发浓缩,所得物质用乙醚洗涤,真空干燥,即得单羧基化并烷基化奥沙利铂。所得物质采用核磁共振氢谱和质谱表征,结果如图3所示。
实施例4.两亲性奥沙利铂前体的制备
取实施例3中制备的单羧化并烷基化奥沙利铂200mg,溶于5mlN,N-二甲基甲酰胺中,加入1-乙基-(3-二甲氨基丙基)碳二亚胺盐酸盐72mg、1-羟基苯并三唑50.8mg,置于25℃下搅拌反应活化2h后,再加入(2-氨基乙基)三甲基氯化铵52.2mg反应过夜,旋转蒸发浓缩,乙醚沉淀,真空干燥,即得两亲性奥沙利铂前体。所得物质用核磁共振氢谱和质谱表征,结果如图4所示。
实施例5.两亲性奥沙利铂前体胶束的制备
称取实施例4中制备的两亲性奥沙利铂前体5mg,溶解于2ml甲醇溶液中,缓慢旋转蒸发除去溶剂,加5ml去离子水溶解,即得两亲性奥沙利铂前体胶束。
实施例6.两亲性奥沙利铂前体胶束的细胞毒性评价
将实施例5中制备的胶束,按10μmol/ml等摩尔浓度配制,然后用两倍稀释法依次配制7个梯度浓度,即9.6、4.8、2.4、1.2、0.6、0.3和0.15μmol/ml。4T1乳腺癌细胞接种于96孔细胞培养板中(3000细胞/孔),每孔加入0.1ml RPIM1640培养基(含10%血清)。培养24h后换液,补加培养基(190μl/孔)。在细胞培养板中加入10μL稀释后的上述溶液,与癌细胞共同孵育48h后MTT法测定细胞活性。
Claims (10)
1.一种两亲性奥沙利铂前体,其具有式1所示结构:
其中,R1选自C2~C16饱和烷基或CH3-CH2-S-S-CH2-CH2-;R2为仲氨基,选自-NH-CH2-CH2-OH和
2.权利要求1所述的两亲性奥沙利铂前体的制备方法,该方法具体包括如下步骤:
步骤a:氧化奥沙利铂的制备
取奥沙利铂混悬于去离子水中,以双氧水与奥沙利铂20:1~-100:1的摩尔比向溶液中加入质量分数30%的双氧水,置于0-40℃之间的任意一个恒定温度避光反应6-48h,旋转蒸发除去溶剂,加入甲醇溶解所得物质,乙醚沉淀,真空干燥即得氧化奥沙利铂;
步骤b:单羧化氧化奥沙利铂的制备
取步骤a中制得的氧化奥沙利铂溶于二甲基亚砜中,加入等摩尔量的琥珀酸酐,在0-40℃之间的任意恒定温度反应1-24h后,乙醚沉淀,所得物质用甲醇溶解,旋转蒸发除去甲醇,所得沉淀用乙醚洗涤,真空干燥即得单羧化氧化奥沙利铂;
步骤c:单羧基化并烷基化奥沙利铂的制备
将单羧化氧化奥沙利铂溶于有机溶剂中,以烷基化试剂与单羧化氧化奥沙利铂1-10:1的摩尔比向溶液中加入烷基化试剂,在20-60℃之间的任意恒定温度反应6-48h后,旋转蒸发浓缩,所得物质用乙醚洗涤,真空干燥,即得单羧基化并烷基化奥沙利铂;
其中,所述烷基化试剂为R1-N=C=O;
其中,R1的定义如权利要求1所述;
步骤d:两亲性奥沙利铂前体的制备
将单羧基化并烷基化奥沙利铂溶于有机溶剂中,以羧基活化剂与单羧基化并烷基化奥沙利铂1-10:1的摩尔比向溶液中加入羟基活化剂,在0-40℃之间的恒定温度下反应1-5h;向反应液中以亲水性试剂R2H与单羧基化并烷基化奥沙利铂1-10:1摩尔比加入亲水性试剂R2H;之后在0-40℃之间的任意恒定温度下搅拌反应6-48h;旋转蒸发浓缩,乙醚沉淀,真空干燥,即得两亲性奥沙利铂前体;其中,R2的定义如权利要求1所述。
3.根据权利要求2所述的制备方法,其特征在于:步骤c中所述有机溶剂选自二氯甲烷、乙腈、四氢呋喃、丙酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺和二甲基亚砜中的至少一种。
4.根据权利要求2所述的制备方法,其特征在于:步骤d中所述羧基活化剂选自1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、1-羟基苯并三唑和N-羟基琥珀酰亚胺中的一种或几种。
5.根据权利要求2所述的制备方法,其特征在于:步骤d中有机溶剂选自二氯甲烷、乙腈、四氢呋喃、丙酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺和二甲基亚砜中的至少一种。
6.权利要求1所述的两亲性奥沙利铂前体在制备癌症治疗药物中的用途。
7.根据权利要求6所述的用途,所述癌症选自乳腺癌、肺癌、卵巢癌、前列腺癌、胰腺癌、肝癌、头颈部癌、胃癌。
8.一种胶束,其由权利要求1所述两亲性奥沙利铂前体在水中自组装形成。
9.根据权利要求8所述的胶束,其特征在于,所述胶束的流体力学直径为10-300nm。
10.权利要求8或9所述的胶束在制备癌症治疗药物中的用途;所述癌症选自乳腺癌、肺癌、卵巢癌、前列腺癌、胰腺癌、肝癌、头颈部癌、胃癌。
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