CN106074379B - 聚乙二醇化奥沙利铂前药及其制备方法和用途 - Google Patents
聚乙二醇化奥沙利铂前药及其制备方法和用途 Download PDFInfo
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- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 title claims abstract description 76
- 229960001756 oxaliplatin Drugs 0.000 title claims abstract description 74
- 229940002612 prodrug Drugs 0.000 title claims abstract description 32
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 36
- 239000002202 Polyethylene glycol Substances 0.000 claims description 33
- 229920001223 polyethylene glycol Polymers 0.000 claims description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 239000000693 micelle Substances 0.000 claims description 21
- 239000004472 Lysine Substances 0.000 claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
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- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 16
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- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 15
- -1 compound 1 Chemical class 0.000 claims description 15
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
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- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- DCPMPXBYPZGNDC-UHFFFAOYSA-N hydron;methanediimine;chloride Chemical compound Cl.N=C=N DCPMPXBYPZGNDC-UHFFFAOYSA-N 0.000 claims description 8
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- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 5
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- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
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- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 4
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- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 3
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- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
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- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/337—Polymers modified by chemical after-treatment with organic compounds containing other elements
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/34—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from hydroxy compounds or their metallic derivatives
- C08G65/48—Polymers modified by chemical after-treatment
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Abstract
本发明公开了一种聚乙二醇化奥沙利铂前药及其制备方法和用途。所述聚乙二醇化奥沙利铂前药具有如式1或式2所示结构,其中,连接单元L为或者上述聚乙二醇化奥沙利铂前药的用途,主要用于癌症治疗药物的制备。其在水中单独自组装成胶束。此外,本发明还公开了聚乙二醇化奥沙利铂。
Description
技术领域
本发明属于医药化工技术领域,具体涉及一种聚乙二醇化奥沙利铂前药,及其制备方法和用途。
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,奥沙利铂是继顺铂和卡铂之后的第三代铂类抗癌药,也是迄今为止唯一对结直肠癌具有显著活性的络铂类药物。与前两代铂类药物相比,奥沙利铂在体内及体外的抗肿瘤作用效果好,且用药安全。它对结直肠癌、非小细胞肺癌、卵巢癌等实体瘤有明显的抑制作用。但在临床使用过程中,注射入体内后在肿瘤组织蓄积较少,难以达到治疗浓度。而且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递送策略为奥沙利铂化疗提供了新的解决途径。如上海医药工业研究院申报的专利CN101897668A,一种奥沙利铂脂质体及其制备方法和用途;陈祥峰、蔡课霞申报的专利CN101103972A,一种奥沙利铂脂质体葡萄糖制剂及其制备方法、应用,均提出了奥沙利铂脂质体的制备方法。但由于脂质体剂型稳定性较差,易发生聚集和渗漏,同时奥沙利铂易降解,限制其临床应用。
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自组装成胶束的聚乙二醇化奥沙利铂前药,其具有式1或式2所示结构
其中,
n为10-500的整数,优选为10-120的整数,更优选为11、22、45或113;
L为或-o-;
m为6-30的整数,优选为10-20的整数,更优选为12、14或16。
所述聚乙二醇化奥沙利铂前药可通过如下制备方法得到:
或者
其中,n、L和m的定义如前所述;
将1摩尔当量的单羧基化并烷基化奥沙利铂(化合物1)溶于有机溶剂中,加催化剂活化1小时,加入0.1-10摩尔当量的经过修饰的聚乙二醇,在0-40℃之间的任意一个恒定温度避光反应12-72h,旋转蒸发除去溶剂,加水溶解,选用截留分子量为30-100kDa的超滤管离心水洗1-5次,取离心上液冻干即得目标产物(式1或式2所示化合物)。
所述催化剂选自碳二亚胺盐酸盐、二甲基氨基吡啶、二环己基碳二亚胺、1‐羟基苯并三唑、二异丙基乙基胺,三乙胺等催化剂的一种或几种;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。
其中,反应路线1的经过修饰的聚乙二醇为单甲氧基羟基聚乙二醇或单甲氧基氨基聚乙二醇。
反应路线2的经过修饰的聚乙二醇为通过赖氨酸扩展的单甲氧基羟基聚乙二醇或单甲氧基氨基聚乙二醇。其中,赖氨酸选择N2,N6‐双叔丁氧基羧基‐L‐赖氨酸。使用N2,N6‐双叔丁氧基羧基‐L‐赖氨酸制备赖氨酸扩展的单甲氧基羟基聚乙二醇或单甲氧基氨基聚乙二醇的反应路线为:
其中,n、L的定义如前所述;
反应步骤:
a:氨基保护的赖氨酸化聚乙二醇
将N2,N6‐双叔丁氧基羧基‐L‐赖氨酸溶于有机溶剂中,加催化剂活化1小时,加入0.1-10摩尔当量的氨基聚乙二醇,通过酰胺反应连接赖氨酸,或加入0.1-10摩尔当量的羧基聚乙二醇,通过酯化反应连接赖氨酸,其中,酰胺反应得到的产物中L为酯化反应得到的产物中L为-o-。酰胺反应和酯化反应在0-40℃之间的任意一个恒定温度避光反应12-72h,旋转蒸发除去溶剂,加入甲醇溶解所得物质,乙醚沉淀,真空干燥即得氨基保护的赖氨酸化聚乙二醇,即化合物3;
b:脱保护基团的赖氨酸化聚乙二醇
将氨基保护的赖氨酸化聚乙二醇溶于有机溶剂中,加氨基保护基团剪切剂在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,真空干燥即得通过赖氨酸扩展的单甲氧基羟基聚乙二醇或单甲氧基氨基聚乙二醇。
其中,步骤a中的催化剂选自碳二亚胺盐酸盐、二甲基氨基吡啶、二环己基碳二亚胺、1‐羟基苯并三唑、二异丙基乙基胺和三乙胺等催化剂的一种或几种;步骤b中的氨基保护基团剪切剂选自三氟乙酸或盐酸;步骤a和步骤b中的有机溶剂各自独立地选自二氯甲烷、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a和步骤b中在除去溶剂后,还可选择透析法纯化样品,即依据目标产物分子量选择适宜截留分子量的透析袋,加水溶解产物,转移至透析袋内,用去离子水透析24-72小时,冻干袋内样品即得纯化产物。
所述单羧基化并烷基化奥沙利铂是通过以下方法合成,具体步骤如下:
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为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
其中,m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为1:1‐10:1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(即其中m的定义如前所述;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。
所述聚乙二醇化奥沙利铂前药可单独在水中自组装形成胶束。其中,所述胶束的流体力学直径为10-300nm。
所述聚乙二醇化奥沙利铂前药主要用于治疗癌症的药物的制备,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、胃癌等。
附图说明
图1为本发明实施例1中制备的赖氨酸化聚乙二醇的核磁共振氢谱。如核磁图谱所示,a、b、c、d峰为赖氨酸亚甲基的特征峰,e峰为聚乙二醇单甲基的特征峰,证明成功制备赖氨酸化聚乙二醇。
图2为本发明实施例2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3为本发明实施例3中制备的聚乙二醇化单奥沙利铂的核磁共振氢谱。如核磁共振氢谱所示,k、l、m和o峰为聚乙二醇特征峰,a、c峰为奥沙利铂衍生物烷基链特征峰,证明成功制备出聚乙二醇化单奥沙利铂前药。
图4为本发明实施例3中制备的聚乙二醇化双奥沙利铂的核磁共振氢谱。如核磁共振氢谱所示,j、l、m峰为赖氨酸化聚乙二醇特征峰,a、c峰为奥沙利铂衍生物烷基链特征峰,证明成功制备出聚乙二醇化双奥沙利铂前药。
图5为本发明实施例4中聚乙二醇化单奥沙利铂粒径分布图和透射电子显微镜照片(A)和聚乙二醇化双奥沙利铂粒径分布图和透射电子显微镜照片(B)。聚乙二醇化单奥沙利铂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10-30nm。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。聚乙二醇化双奥沙利铂胶束的流体力学粒径由MALVERNNANO 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10-45nm。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18nm的球形粒子。
图6为本发明实施例4中制备的聚乙二醇化单奥沙利铂、聚乙二醇化双奥沙利铂及奥沙利铂原料药对4T1乳腺癌细胞的MTT毒性实验数据。结果表明当药物浓度为10μM时,前药胶束细胞毒性接近奥沙利铂;当药物浓度大于20μM时,前药胶束细胞优于奥沙利铂原料药。表明聚乙二醇化奥沙利铂前药胶束可显著抑制肿瘤细胞生长,当浓度升高细胞毒性优于奥沙利铂原料药。
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。
材料:实施例中所用的单甲氧基氨基聚乙二醇(数均分子量分别为2k和5k,分别简写为mPEG2k和mPEG5k)购自上海西宝生物股份有限公司,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。琥珀酸酐购自梯希爱(上海)化成工业发展有限公司。N2,N6‐双叔丁氧基羧基‐L‐赖氨酸、碳二亚胺盐酸盐、1-羟基苯并三唑,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 G2 F20 S‐TWIN型透射电子显微镜获得。核磁共振氢谱由BrukerAVANCE III 400M核磁共振波谱仪测得。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:赖氨酸化聚乙二醇的制备
依次取mPEG5k 1.0g,N2,N6-双叔丁氧基羧基-L-赖氨酸277mg,碳二亚胺盐酸盐153mg,羟基苯并三氮唑108mg,溶于10ml无水乙腈中,加三乙胺55μl,避光搅拌48小时,旋转抽干有机溶剂,加水10ml溶解,转移至3500Da透析袋中,去离子水透析48小时,取袋内液体冻干。
取上述产物500mg,加5ml二氯甲烷溶解,缓慢滴加三氟乙酸5ml,避光搅拌反应24小时,旋转抽干有机溶剂,加水10ml溶解,转移至3500D透析袋中,透析48小时后冻干即得赖氨酸化聚乙二醇。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:单羧基化并烷基化奥沙利铂的制备
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。
取氧化奥沙利铂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。
取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2所示。
实施例3:聚乙二醇化奥沙利铂前药的制备
1.聚乙二醇化单奥沙利铂前药的制备
取实施例2中制备的单羧基化并烷基化奥沙利铂200mg,mPEG2k1.0g,碳二亚胺盐酸盐95.5mg,羟基苯并三氮唑67.5mg,溶于15ml无水乙腈中,加三乙胺104μl,避光搅拌48小时,旋转抽干有机溶剂,加10ml水溶解,选用截留分子量为30kDa的超滤管离心水洗5次,取上液冻干即得聚乙二醇化单奥沙利铂前药。所得物质采用核磁共振氢谱表征,结果如图3所示。
2.聚乙二醇化双奥沙利铂前药的制备
取实施例2中制备的单羧基化并烷基化奥沙利铂500mg,实施例1中的赖氨酸化聚乙二醇1065.5mg,碳二亚胺盐酸盐161mg,羟基苯并三氮唑113.4mg,溶于18ml无水乙腈中,加三乙胺150μl,避光搅拌48小时,旋转抽干有机溶剂,加12ml水溶解,选用截留分子量为30kDa的超滤管离心水洗5次,取上液冻干即得聚乙二醇化双奥沙利铂前药。所得物质采用核磁共振氢谱表征,结果如图4所示。
实施例4:聚乙二醇化奥沙利铂前药胶束的制备
取实施例3中制备的聚乙二醇化单奥沙利铂(mPEG2k‐奥铂)前药5mg,溶解于2ml乙醇溶液中,缓慢旋转蒸发除去溶剂,加2ml去离子水溶解,即得mPEG2k‐奥铂前药胶束。所得胶束采用粒度仪和电镜表征,结果如图5(A)所示。
取实施例3中制备的聚乙二醇化双奥沙利铂(mPEG5k‐奥铂‐2)前药5mg,溶解于2ml乙醇溶液中,缓慢旋转蒸发除去溶剂,加2ml去离子水溶解,即得mPEG5k‐奥铂‐2前药胶束。所得胶束采用粒度仪和电镜表征,结果如图5(B)所示。
实施例5:聚乙二醇化奥沙利铂前药胶束的细胞毒性评价
将实施例4中制备的聚乙二醇化单奥沙利铂、聚乙二醇化双奥沙利铂及奥沙利铂原料药按40μmol/ml等摩尔浓度配制,然后用两倍稀释法依次配制9个梯度浓度,即400、200、100、50、25、12.5、6.25、3.125、1.562μmol/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(180μl/孔)。在细胞培养板中加入20μL稀释后的上述溶液,与癌细胞共同孵育48h后利用标准MTT法测定细胞代谢活性。
Claims (13)
1.一种聚乙二醇化奥沙利铂前药,其具有式1或式2所示结构,
其中,
n为10-500的整数;
L为或-O-;
m为6-30的整数。
2.根据权利要求1所述的聚乙二醇化奥沙利铂前药,其特征在于:n为10-120的整数,m为10-20的整数。
3.根据权利要求1所述的聚乙二醇化奥沙利铂前药,其特征在于:n为11、22、45或113;m为12、14或16。
4.根据权利要求1~3中任一项所述的聚乙二醇化奥沙利铂前药的制备方法,其包括如下步骤:
反应路线1
或者
反应路线2
其中,n、L和m的定义如权利要求1所述;
将1摩尔当量的单羧基化并烷基化奥沙利铂,即化合物1,溶于有机溶剂中,加催化剂活化1小时,加入0.1-10摩尔当量的经过修饰的聚乙二醇,在0-40℃之间的任意一个恒定温度避光反应12-72h,旋转蒸发除去溶剂,加水溶解,选用截留分子量为30-100kDa的超滤管离心水洗1-5次,取离心上液冻干即得目标产物,即式1或式2所示化合物。
5.根据权利要求4所述的制备方法,其特征在于:所述催化剂选自碳二亚胺盐酸盐、二甲基氨基吡啶、二环己基碳二亚胺、1-羟基苯并三唑、二异丙基乙基胺、N-羟基琥珀酰亚胺和三乙胺催化剂的中一种或几种;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。
6.根据权利要求4所述的制备方法,其特征在于:反应路线1中所述的经过修饰的聚乙二醇为单甲氧基羟基聚乙二醇或单甲氧基氨基聚乙二醇。
7.根据权利要求4所述的制备方法,其特征在于:反应路线2中所述的经过修饰的聚乙二醇为通过赖氨酸扩展的单甲氧基羟基聚乙二醇或单甲氧基氨基聚乙二醇。
8.根据权利要求7所述的制备方法,其特征在于:所述赖氨酸为N2,N6-双叔丁氧基羧基-L-赖氨酸,使用N2,N6-双叔丁氧基羧基-L-赖氨酸制备赖氨酸扩展的单甲氧基羟基聚乙二醇或单甲氧基氨基聚乙二醇的反应路线为:
反应路线3
其中,n、L的定义如权利要求1所述;
a:氨基保护的赖氨酸化聚乙二醇
将N2,N6-双叔丁氧基羧基-L-赖氨酸溶于有机溶剂中,加催化剂活化1小时,加入0.1-10摩尔当量的氨基聚乙二醇,通过酰胺反应连接赖氨酸,或加入0.1-10摩尔当量的羧基聚乙二醇,通过酯化反应连接赖氨酸;酰胺反应和酯化反应在0-40℃之间的任意一个恒定温度避光反应12-72h,旋转蒸发除去溶剂,加入甲醇溶解所得物质,乙醚沉淀,真空干燥即得氨基保护的赖氨酸化聚乙二醇,即化合物3;
b:脱保护基团的赖氨酸化聚乙二醇
将氨基保护的赖氨酸化聚乙二醇溶于有机溶剂中,加氨基保护基团剪切剂在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,真空干燥即得通过赖氨酸扩展的单甲氧基羟基聚乙二醇或单甲氧基氨基聚乙二醇。
9.根据权利要求8所述的制备方法,其特征在于:步骤a中的催化剂选自碳二亚胺盐酸盐、二甲基氨基吡啶、二环己基碳二亚胺、1-羟基苯并三唑、二异丙基乙基胺和三乙胺催化剂中的一种或几种;步骤b中的氨基保护基团剪切剂选自三氟乙酸或盐酸;步骤a和步骤b中的有机溶剂各自独立地选自二氯甲烷、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。
10.一种胶束,由权利要求1~3中任一项所述的聚乙二醇化奥沙利铂前药单独在水中自组装形成。
11.根据权利要求10所述的胶束,其流体力学直径为10-300nm。
12.权利要求1~3中任一项所述的聚乙二醇化奥沙利铂前药在癌症治疗药物的制备中的用途。
13.根据权利要求12所述的用途,其特征在于: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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