CN105713046B - 一种铂类抗肿瘤前体药物,其纳米水凝胶药物及其制备方法 - Google Patents
一种铂类抗肿瘤前体药物,其纳米水凝胶药物及其制备方法 Download PDFInfo
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- CN105713046B CN105713046B CN201610070277.0A CN201610070277A CN105713046B CN 105713046 B CN105713046 B CN 105713046B CN 201610070277 A CN201610070277 A CN 201610070277A CN 105713046 B CN105713046 B CN 105713046B
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
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- A—HUMAN NECESSITIES
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- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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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
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明属于生物医药技术领域,具体为一种铂类抗肿瘤前体药物,其纳米水凝胶药物及其制备方法。本发明的前体药物是利用抗肿瘤的铂类药物经双氧水氧化为Pt(IV)的六配体配合物,再与含有双键的酸酐或羧酸反应得到。该前体药物可以自聚合,或和其他亲水性单体共聚,制备高载药量的药物微球。该微球粒径均匀,大小可调控,通过使用稳定剂可以在水溶液中保持长期的稳定性。本发明制备工艺简洁,得到的纳米水凝胶药物载体具有谷胱甘肽刺激响应性,使得纳米水凝胶在肿瘤细胞外低谷胱甘肽浓度的环境中保持稳定,长时间循环,很少泄露药物,而在肿瘤细胞内还原性环境中快速降解,变为小分子量的线性链,快速释放药物,从而实现对目标肿瘤细胞的靶向杀伤作用。
Description
技术领域
本发明属于生物医药技术领域,具体涉及一种铂类抗肿瘤前体药物,其纳米水凝胶药物及其制备方法。
背景技术
由于癌症对人类生命健康的极大威胁,抗癌药物的研究一直广受关注。顺铂也称顺式二氯二氨合铂(Cisplatin,Pt(NH3)2Cl2),是一种非细胞周期特异性的抗癌药物,具有细胞毒性,能与DNA双螺旋上的鸟嘌呤的N7氮原子结合,形成稳定的交联结构,从而破坏DNA的复制功能,导致细胞凋亡。自从1967年人们发现顺铂的抗癌活性以来,铂类金属抗癌药物的研究和应用得到了极大的发展,除顺铂外,还有一系列具有类似结构和功能的顺铂衍生物,如卡铂、奥沙利铂、赛特铂、奥马铂、异丙铂、乐铂、庚铂以及其他含有单个或多个铂原子的的抗癌药物。这种铂类药物具有抗癌谱广,作用强且无交叉耐药性,尤其对于睾丸癌、卵巢癌有很好的疗效。然而,铂类药物存在毒副作用大,溶解性差,在人体内易于和血浆蛋白结合,尤其容易受到含巯基蛋白质(血清蛋白质等)的攻击,从而失去抗癌活性,所以临床效果往往有限。近年来研究发现四价铂配合物(Pt(IV))相对于常用的二价铂配合物(Pt(II))而言,由于在垂直的轴向上增加了两个配体,形成八面体结构,因而具有较低的反应活性和毒副作用。而在药物进入肿瘤细胞后,由于细胞内部的还原性环境,使得迅速转化为具有细胞毒性的Pt(II)结构,从而具有针对性的对肿瘤细胞产生杀伤作用。然而,四价铂配合物(Pt(IV))作为小分子药物,在人体内同样存在循环时间短,代谢速度快,靶向性差的特点,很难在肿瘤部位得到有效的富集,将其运输至肿瘤组织部位仍然是一个很大的挑战。
本发明针对铂类药物的以上特点,对四价铂配合物(Pt(IV))轴向上的羟基进行了修饰,从而第一次得到带有两个双键的新型结构,该铂类抗肿瘤前体药物在有机溶剂中可以自身聚合,也可以与其他单体共聚,形成粒径均一的纳米粒子。通过利用生物相容性的稳定剂对粒子表面进行简单的修饰,使其能够在生物体内保持良好的稳定性,增加长循环时间,在肿瘤细胞内部还原性的条件下可使得微球降解,从而释放出铂类药物。另一方面,稳定剂的外部也可以修饰相应的靶向分子(如叶酸、环RGD肽、转铁蛋白等),从而使其在肿瘤部位得到有效的富集。
发明内容
本发明的目的在于提供一种铂类抗肿瘤前体药物,其纳米水凝胶微球及其制备方法;同时,提供上述纳米水凝胶在肿瘤治疗中的应用。
本发明提供的铂类抗肿瘤前体药物的制备方法,具体步骤如下:将二价的铂类药物与双氧水在避光条件下65-75℃(优选70℃)反应10-12h,得到轴向双羟基配位的四价铂配合物Pt(IV)-(OH)2,产物通过旋蒸除去部分溶剂,过滤后真空烘干,再与含有双键的酸酐或羧酸在避光条件下55-65℃(优选60℃)反应12~24h,得到轴向具有两个双键的铂(IV)类抗肿瘤前体药物。
其中,所述二价的铂类药物可以是顺铂、卡铂、奥沙利铂、赛特铂、奥马铂、异丙铂、乐铂或庚铂等。
其中,所述的酸酐可以为甲基丙烯酸酐、丙烯酸酐、马来酸酐;其中羧酸可以为丙烯酸、甲基丙烯酸、马来酸或富马酸。
其中,所述铂类药物与双氧水的重量比例为1:1~1:10,Pt(IV)-(OH)2与酸酐或羧酸的重量比例为1:1~1:5。
本发明提供的铂类前体药物的水凝胶微球的制备方法,具体步骤为:在有机溶剂中加入亲水性单体,以上述铂类抗肿瘤药物前药作为交联剂,在引发剂的存在下,加热进行反应,反应温度为50~120℃;用蒸馏沉淀法除去一半溶剂,回流溶剂反应时间为0.2~4h;再用离心法除去剩下溶剂和未反应单体,用乙醇和去离子水反复洗涤3-5次;然后在真空烘箱内30~55℃干燥5~24h,即得到纳米水凝胶粒子。
本发明中,所述有机溶剂为单一的乙腈、乙醇、水、四氢呋喃、甲基异丁基酮或甲苯等溶剂;或者为乙腈-乙醇、乙腈-四氢呋喃、乙腈-水、乙腈-甲苯、乙醇-甲苯或甲基异丁基酮-乙腈等的混合溶剂。
本发明中,所述的亲水性单体为甲基丙烯酸(MAA)、丙烯酸(AA)、甲基丙烯酸羟乙酯(HEMA)、丙烯酰胺(AM)、N-异丙基丙烯酰胺(NIPAM)或N-2-羟丙基甲基丙烯酰胺(HPMA)等单体。
本发明中,所述引发剂为偶氮二异丁腈(AIBN)或过氧化二苯甲酰(BPO)等。
本发明中,所述单体在单一或混合溶剂中的浓度为0.5wt%~20.0wt%。
本发明中,所述单体与前体药物的重量比例为10:1~0:1,优选两者比例为10:1~0.5 :1。
本发明所制备的上述纳米水凝胶粒子的粒径为50-950nm,多分散度为0.04-0.16。
上述制备的纳米水凝胶,可以进一步与双亲性的稳定剂相互组装,从而提高其在生理环境中的稳定性和体内的长循环过程。具体操作步骤如下:
将上述制得的纳米水凝胶粒子分散在少量去离子水中,磁力搅拌下缓慢滴入溶解有稳定剂的水溶液中,并超声分散15-20min,这一过程中稳定剂的疏水部分通过非共价疏水作用与纳米粒子交联网络结合,亲水部分伸展在纳米粒子外部,从而实现良好的稳定作用。
所述稳定剂可以是TPGS1000、F127、PVA、PLGA-PEG、DSPE-PEG等。
本发明制得的上述纳米水凝胶作为纳米药物,可对体内的肿瘤组织进行有效的杀伤。其特点在于,纳米药物在正常血液和组织循环中能够保持药物良好的药物密封作用,从而使药物不会释放出来伤害正常的组织和细胞,通过高通透性和滞留效应(EPR effect)富集在肿瘤组织后,纳米粒子被肿瘤细胞吞噬,细胞内的还原性环境使得顺铂药物得以快速的释放出来,从而对肿瘤细胞有针对性的杀伤作用。
本发明中,降解的测试条件为:在25mL的单口烧瓶里加入5mg的纳米水凝胶粒子,分别加入10 mL的三种缓冲溶液中(磷酸盐缓冲溶液pH=7.4、6.0,醋酸盐缓冲溶液pH=5.0,然后加入不同浓度的谷胱甘肽、半胱氨酸或抗坏血酸,放入恒温摇床(200rpm摇速,37.5℃)匀速振荡。并在不同时间取点测试分散液的浊度变化。
释药的条件为:将10 mg载药纳米水凝胶粒子分散在10 mL的两种缓冲溶液中(磷酸盐缓冲溶液,pH=7.4;醋酸盐缓冲溶液,pH=5.0),超声分散均匀,然后分为5份,每份2 mL,将一份凝胶溶液移入透析袋中(透析分子量Mn=14000),再放入80 mL的含不同浓度的谷胱甘肽的缓冲溶液中,即刻开始计时释药。在预订时间,从瓶内取出3 mL释药的缓冲溶液进行紫外测量,再补充3 mL纯的缓冲溶液保持体积恒定。
所制备的纳米水凝胶在还原剂降解后,分子量小于2000且分子量分布均匀(Mn=761,PDI<1.2),远小于代谢阈值(45-50 kDa),可以很好的代谢排出体外。
本发明中,所述的水凝胶纳米药物,由铂类抗肿瘤药物交联聚合形成,其载药率可以方便地用前体药物和共聚单体的不同比例聚合反应加以控制。在上述方案的基础上,所属抗癌药物顺铂的载药率的重量百分比最高可达63.8 %。
顺铂的释放过程可以通过调节环境的谷胱甘肽浓度和pH值加以控制,在高谷胱甘肽浓度和较低pH值条件下(模拟细胞内环境)展现出较快的释放速度,而在低谷胱甘肽浓度和中性的pH值条件下(模拟细胞外环境)保持稳定,释放量小于5%。
本发明中,通过将上述纳米药物和人卵巢癌细胞SKOV-3一起培养进行细胞实验,纳米水凝胶药物载体体现出了很好的释药行为。通过荧光显微镜进行观察,发现5h后载药纳米水凝胶粒子已经进入细胞,24h后顺铂药物对于细胞的杀伤作用已经非常明显,细胞存活率大幅降低,剩余的少量细胞也处于皱缩状态,说明所制备的纳米水凝胶是一种较好的药物载体。
本发明优点在于制备工艺清晰简洁,得到的纳米水凝胶药物载体具有谷胱甘肽刺激响应性,谷胱甘肽响应性可以使得纳米水凝胶在肿瘤细胞外低谷胱甘肽浓度的环境中保持稳定,长时间循环,很少泄露药物,而在肿瘤细胞内高谷胱甘肽浓度的环境中快速降解,变为小分子量的线性链,从而快速释放药物,达到在目标肿瘤细胞内控制释放抗癌药物的效果,体现出与谷胱甘肽的协同效应。而凝胶粒子的可生物降解性和降解后的小分子量又可以使得药物载体迅速代谢排出体外,进一步减少对人体的副作用。
附图说明
图1:顺铂前体药物纳米水凝胶微球的透射电镜照片。
图2:顺铂前体药物纳米水凝胶微球的***细胞SKOV-3毒性实验(24h)。
具体实施方式
下面将通过实例进一步对本发明进行描述,但不限于这些实施例。
实施例1:顺铂类抗肿瘤前体药物的制备
在100ml的三口圆底烧瓶中加入顺铂2g,去离子水50ml和过氧化氢(30%)11.4ml,在氮气气氛下,70℃避光反应6h后降至室温再反应12h,旋蒸掉部分水后冰水冷却析出产物,抽滤,用冰水、乙醇、***一次洗涤反应产物后真空干燥,得到轴向两端羟基修饰的Pt(IV)前驱体,记做Pt(IV)-(OH)2-1。
取上述2g前驱体Pt(IV)-(OH)2-1加入到50ml三口圆底烧瓶中,然后加入与其摩尔比为1:2的甲基丙烯酸酐和10ml预先干燥的二甲基亚砜(DMSO),在氮气气氛和60℃避光下反应24h,反应后冷冻干燥除去溶剂,产物用***和丙酮重结晶,干燥,得到两端双键修饰的Pt(IV)交联剂,记做Pt(IV)-1。
实施例2:奥沙利铂类抗肿瘤前体药物的制备
在100ml的三口圆底烧瓶中加入奥沙利铂2g,去离子水50ml和过氧化氢(30%)11.4ml,在氮气气氛下,70℃避光反应6h后降至室温再反应12h,旋蒸掉部分水后冰水冷却析出产物,抽滤,用冰水、乙醇、***一次洗涤反应产物后真空干燥,得到轴向两端羟基修饰的Pt(IV)前驱体,记做Pt(IV)-(OH)2-2
取上述2g前驱体Pt(IV)-(OH)2-1加入到50ml三口圆底烧瓶中,然后加入与其摩尔比为1:2的甲基丙烯酸酐和10ml预先干燥的二甲基亚砜(DMSO),在氮气气氛和60℃避光下反应24h,反应后冷冻干燥除去溶剂,产物用***和丙酮重结晶,干燥,得到两端双键修饰的Pt(IV)交联剂,记做Pt(IV)-2。
实施例3:奥沙利铂类抗肿瘤前体药物纳米水凝胶微球的制备
MAA单体400 mg,ZDMA交联剂100mg, AIBN 引发剂16.7 mg,乙腈40 mL,加热到95℃,回流溶剂反应2小时,离心除去溶剂和未反应单体,用乙醇和去离子水洗涤3次,真空烘箱干燥24 h。
实施例4:顺铂类抗肿瘤前体药物纳米水凝胶微球的制备
AA单体400 mg,Pt(IV)-1交联剂100mg,15.3 mg BPO 引发剂,40 mL乙腈-乙醇混合溶剂(V乙腈:V乙醇=1:1),加热到95℃,回流溶剂反应2小时,离心除去溶剂和未反应单体,用丙酮和去离子水洗涤3次,真空烘箱干燥24 h。
实施例5:奥沙利铂前体药物交联的PMAA-co-PHPMA纳米水凝胶的制备
MAA单体200 mg,HPMA 200mg, Pt(IV)-2交联剂100mg,16.7 mg AIBN 引发剂,40mL乙腈-甲苯混合溶剂(V乙腈:V甲苯=4:1),加热到95℃,回流溶剂反应2小时,离心除去溶剂和未反应单体,用丙酮和去离子水洗涤3次,真空烘箱干燥24 h。
实施例6:稳定剂TPGS1000稳定的铂交联纳米水凝胶制备
将顺铂类抗肿瘤前体药物纳米水凝胶微球均匀分散于0.5ml的去离子水中,在磁力搅拌的条件下缓慢滴加于TPGS1000的水溶液中,之后超声15min后,用去离子水离心洗涤3次,得到TPGS1000稳定的铂交联纳米水凝胶。
本发明制备的上述纳米水凝胶微,球粒径均匀,形态规整,大小可调控,通过使用稳定剂稳定之后可以在水溶液中保持长期的稳定性。另一方面,交联键合的Pt(IV)配合物易于在还原性的条件下被还原成Pt(II),从而导致微球的交联骨架解体,并快速释放出铂类药物分子。本发明能够使铂类抗肿瘤药物在不依赖载体的情况下自身交联成纳米粒子,从而运输至肿瘤部位,并在肿瘤细胞内的还原性氛围下进行Pt(IV)→Pt(II)的转化,使轴向的两个羟基断裂,交联键打开使药物被定向的释放于肿瘤细胞内部,从而实现无载体的高载药模式,降低辅料浓度以及药物在正常组织和细胞的毒副作用。
Claims (8)
1.一种基于铂类抗肿瘤前体药物的水凝胶微球的制备方法,其特征在于,具体步骤为:在有机溶剂中加入亲水性单体,以所述铂类抗肿瘤前体药物作为交联剂,在引发剂的存在下,加热进行反应,反应温度为50~120℃;用蒸馏沉淀法除去一半溶剂,回流溶剂反应时间为0.2~4h;再用离心法除去剩下溶剂和未反应单体,用乙醇和去离子水反复洗涤3-5次;然后在真空烘箱内30~55℃干燥5~24h,即得到纳米水凝胶粒子;
所述铂类抗肿瘤前体药物制备的具体步骤如下:将二价的铂类药物与双氧水在避光条件下65-75℃反应10-12h,得到轴向双羟基配位的四价铂配合物Pt(IV)-(OH)2,产物通过旋蒸除去部分溶剂,过滤后真空烘干,再与含有双键的酸酐或羧酸在避光条件下55-65℃反应12~24h,得到轴向具有两个双键的铂(IV)类抗肿瘤前体药物;
所述二价的铂类药物为顺铂、卡铂、奥沙利铂、乐铂或庚铂;
所述的酸酐为甲基丙烯酸酐、丙烯酸酐、马来酸酐;所述羧酸为丙烯酸、甲基丙烯酸、马来酸或富马酸;
铂类药物与双氧水的重量比例为1:1~1:10,Pt(IV)-(OH)2与酸酐或羧酸的重量比例为1:1~1:5。
2.根据权利要求1所述的制备方法,其特征在于,所述溶解单体的溶剂为乙腈、乙醇、四氢呋喃、甲基异丁基酮或甲苯单一的溶剂;或者为乙腈-乙醇、乙腈-四氢呋喃、乙腈-水、乙腈-甲苯、乙醇-甲苯或甲基异丁基酮-乙腈的混合溶剂。
3.根据权利要求1所述的制备方法,其特征在于,所述的亲水性单体为甲基丙烯酸、丙烯酸、甲基丙烯酸羟乙酯、丙烯酰胺、N-异丙基丙烯酰胺或N-2-羟丙基甲基丙烯酰胺;所述引发剂为偶氮二异丁腈或过氧化二苯甲酰。
4.根据权利要求1所述的制备方法,其特征在于,所述单体在单一或混合溶剂中的浓度为0.5wt%~20.0wt%。
5.根据权利要求1所述的制备方法,其特征在于,所述单体与铂类抗肿瘤药物前药的重量比例为10:1~0.5 :1。
6.根据权利要求1所述的制备方法,其特征在于,所述纳米水凝胶粒子的粒径为50-950nm,多分散度为0.04-0.16。
7.由权利要求1-6之一所述制备方法制备得到的基于铂类抗肿瘤前体药物的水凝胶微球药物。
8.一种提高权利要求7所述的基于铂类抗肿瘤前体药物的水凝胶微球药物稳定性的方法,其特征在于,具体步骤如下:将所述的水凝胶微球药物分散在去离子水中,磁力搅拌下缓慢滴入溶解有稳定剂的水溶液中,并超声分散15-20min,这一过程中稳定剂的疏水部分通过非共价疏水作用与纳米粒子交联网络结合,亲水部分伸展在纳米粒子外部,从而实现良好的稳定作用;其中,所述稳定剂是TPGS1000、F127、PVA、PLGA-PEG或DSPE-PEG。
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