CN114099674A - 一种载二乙基二硫代氨基甲酸前药的铜或锌载体及制备和应用 - Google Patents
一种载二乙基二硫代氨基甲酸前药的铜或锌载体及制备和应用 Download PDFInfo
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- CN114099674A CN114099674A CN202111408982.4A CN202111408982A CN114099674A CN 114099674 A CN114099674 A CN 114099674A CN 202111408982 A CN202111408982 A CN 202111408982A CN 114099674 A CN114099674 A CN 114099674A
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- China
- Prior art keywords
- copper
- prodrug
- zinc
- diethyldithiocarbamate
- photosensitizer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
本发明属于药物制剂和前药化合物领域,具体涉及一种载二乙基二硫代氨基甲酸前药的金属‑光敏剂配位递药系统和制备方法,以及该递药系统在实体瘤中的成像、诊断和治疗应用。本发明的递药系统由外层的高分子亲水二乙基二硫代氨基甲酸前药修饰在金属‑光敏剂配位载体的表面制得,经体内外药效实验证明,具有实体瘤增强的化疗和光动力联合疗效和成像、诊断功能。
Description
技术领域
本发明属于药物制剂和前药化合物领域,具体涉及一种载二乙基二硫代氨基甲酸前药的金属-光敏剂配位递药载体的制备方法,以及该递药系统在实体瘤中的成像、诊断和治疗应用。
背景技术
严峻的肿瘤发病形势对抗癌药物的研发提出了急迫的需求,但是一款新型抗癌药物从实验室研究到上市耗时长,经济成本巨大,失败风险高。从效率和经济成本来看,从已经获批的药物中寻找具有抗癌潜力的药物,由于这类药物制备工艺成熟、临床安全性数据充分,是极具潜力的策略。
戒酒药双硫仑是美国FDA批准的第一款用于酒精成瘾戒断的药物,距今在临床上已经有 60多年的应用历史,有丰富的临床安全性数据积累。二乙基二硫代氨基甲酸是戒酒药物双硫仑的体内代谢产物,其和二价铜或锌离子能络合形成具有强大抗肿瘤活性的铜络合物或锌络合物。上述络合物具有强大且广谱的抗癌效果,其抗癌活性大大强于双硫仑。但由于人体肿瘤部位的铜/锌元素浓度太低,直接递药双硫仑难以在肿瘤部位形成足量的铜或锌络合物发挥理想的抗肿瘤治疗效果。
因此,在现有公开技术中,有报道提出分开给予含铜或锌元素化合物和双硫仑的递药策略,这一方法不仅容易导致金属离子在正常组织的蓄积,导致金属毒性,并且由于铜或锌元素化合物与双硫仑的药动学差异,二者难以同步到达肿瘤组织形成足量的铜或锌络合物。也有报道提出二乙基二硫代氨基甲酸和铜或锌混合共递送,这一递送策略容易在制备和递送过程中形成毒性络合物,造成全身毒副作用。在现有已公开的技术中,尚未有能实现二乙基二硫代氨基甲酸类药物和铜或锌离子在递药载体制备及血液循环中不形成络合物,而在肿瘤组织中特异性生长抗肿瘤络合物的报导。
光动力疗法(PDT)作为一种全身毒性小,时空高度可控的肿瘤治疗策略近年来受到了广泛的关注。PDT疗法主要由三个关键要素:光敏剂、光、氧气组成。被光激活的光敏剂将其激发态的能量传递给周围环境中的氧气从而产生活性氧和发出特定波长荧光。ROS能够作用于细胞内的关键生物分子如磷脂层、蛋白质和核酸,将其氧化直接杀死肿瘤细胞或者通过诱导损坏肿瘤的脉管系统间接导致肿瘤细胞死亡。由于光敏剂仅能够被特定波长的光激活产生毒性,因此PDT可以选择性杀伤恶性肿瘤而不损害健康的其他组织。同时光敏剂的荧光可以用于肿瘤成像和疾病诊断。但是基于PDT疗法的光敏剂处于实时开启状态,患者注射光敏剂后要进行避光处理,以减少对正常组织的暗毒性。因此,开发一种在正常组织中处于“关闭”状态,而在肿瘤组织中经特异性触发后呈现“开启”状态的可激活型光敏剂也是目前面临的技术难题之一。
发明内容
为了克服现有技术的不足,本发明提供了一种载二乙基二硫代氨基甲酸前药的金属-光敏剂配位递药系统,利用光敏剂分子和金属离子进行配位形成多孔金属有机骨架载体,并进一步将二乙基二硫代氨基甲酸前药共价修饰到高分子亲水长链上,与上述金属有机骨架载体进行组装,实现二乙基二硫代氨基甲酸类药物和金属-光敏剂载体的共递送。该递药载体能在肿瘤部位特异性释放二乙基二硫代氨基甲酸,形成强毒性的金属络合物,并同步触发光敏剂释放,实现肿瘤化疗-光动力协同治疗作用以及成像、诊断功能。
本发明的目的在于克服现有技术的两大缺陷,一是如何使二乙基二硫代氨基甲酸药物与铜离子或锌离子的在制备及血循环中稳定,而在共递送到达肿瘤部位后特异性形成抗肿瘤铜或锌离子络合物的问题。二是如何使光敏剂在正常组织中处于“关闭”状态,而在肿瘤组织中经特异性触发后荧光及光动力活性恢复“开启”状态的问题。
本发明的目的可以通过以下技术方案来实现:
一种载二乙基二硫代氨基甲酸前药的铜或锌递药载体,其特征在于,包含二乙基二硫代氨基甲酸前药以及铜或锌纳米载体,所述二乙基二硫代氨基甲酸前药为共价偶联在亲水高分子链上的聚合物前药;所述铜或锌载体中包含金属离子及光敏剂,其中金属离子可以是以下一种或多种:铜离子、锌离子,光敏剂带有羧基、硼酸基、吡啶、或咪唑等一种或几种配位基团,二者通过铜或锌离子与配体的配位作用制备。
在其中一些实施例中,所述递药载体的制备过程包括以下几个步骤:
A、合成二乙基二硫代氨基甲酸高分子聚合物前药;
B、通过溶剂热法制备铜或锌离子与光敏剂的配位;具体为将铜/锌离子和配体光敏剂分散在N,N二甲基甲酰胺和无水乙醇混合溶剂中,80℃加热4h制备微米级金属有机骨架材料,再通过高压均质及反复超声将粒径缩小至纳米级别;其中铜或锌离子与光敏剂的投料比例大于或等于4∶1;
C、将合成的二乙基二硫代氨基甲酸高分子聚合物前药与纳米级金属有机骨架材料在水溶液中混合搅拌,聚合物前药通过物理吸附或配位相互作用组装在铜离子或锌离子-光敏剂配位纳米载体上;
D、通过多次离心法除去游离的二乙基二硫代氨基甲酸高分子聚合物前药,即制得上述递药载体。
在其中一些实施例中,所述制备的纳米级金属有机骨架材料的粒径为10~500nm。
在其中一些实施例中,所述二乙基二硫代氨基甲酸高分子聚合物前药是通过“二乙基二硫代氨基甲酸-刺激响应敏感键-高分子聚合物”的偶连方式合成的;所述刺激响应敏感键包括但不限于可响应于谷胱甘肽、反应活性氧、肿瘤组织高表达的酶等化学键;所述肿瘤组织高表达的酶包括但不限于组织蛋白酶、基质金属蛋白酶、豆荚蛋白酶等。
在其中一些实施例中,所述高分子聚合物为透明质酸、葡聚糖、海藻酸钠、硫酸软骨素、壳聚糖、羧甲基壳聚糖、右旋糖苷等;所述高分子聚合物的分子量为3k~100w。
在其中一些实施例中,所述光敏剂为近红外光敏剂,最大发射波长为600~800nm,所述激活光敏剂的近红外光激光功率为10~250mW cm-2;所述近红外光持续时间为10秒~10分钟。
本发明的另一目的在于提供一种上述的载二乙基二硫代氨基甲酸前药的金属-光敏剂配位递药载体在制备用于实体肿瘤治疗药物中的用途。
在其中一些实施例中,二乙基二硫代氨基甲酸前药在肿瘤部位刺激响应断键,释放二乙基二硫代氨基甲酸原形药,其争夺铜或锌配位载体中的铜离子或锌离子,形成具有抗肿瘤活性的铜离子或锌离子络合物,与此同时,光敏剂释放出来,实现化疗-光动力治疗的协同。
与现有技术相比,本发明具有以下有益效果:
本发明设计并合成了刺激响应型二乙基二硫代氨基甲酸聚合物前药,以及铜离子或锌离子与有机光敏剂配位的金属有机骨架材料,实现了二乙基二硫代氨基甲酸与铜离子或锌离子的稳定、同步递送问题,克服了二者分开单独给药以及直接给予铜离子或锌离子络合物的局限。此外,本发明设计的递药载体可特异性响应肿瘤微环境,于肿瘤组织中原位生成具有强效抗肿瘤活性的铜离子或锌离子络合物。与此同时,与金属配位的光敏剂得到释放,恢复其荧光及光动力活性,实现化疗-光动力联合治疗。
附图说明
下面结合附图对本发明的具体实施方式作进一步详细的说明,其中:
图1为实施例1中二乙基二硫代氨基甲酸前药核磁氢谱图。
图2实施例2或3中铜/锌载体载药前和载药后的透射电镜图;
其中A是载药前的铜载体,B是载二乙基二硫代氨基甲酸前药的铜载体。
图3为实施例2或3中铜载体载药前后的粒径分布和电位变化示意图;
其中A是粒径分布示意图,B是表面电位分布示意图。MOF未载药铜载体,HA-DQ@MOF指最终载二乙基二硫代氨基甲酸前药的铜载体。载药前后粒径变化不大,载药后表面负电性明显增强。
图4为实施例4中递药系统在肿瘤细胞和正常细胞中的细胞杀伤作用;
其中,A图为最终递药系统在非光照条件下在肿瘤细胞4T1及正常细胞3T3中的细胞毒作用,B图为最终递药系统在光照条件下在肿瘤细胞4T1及正常细胞3T3中的细胞毒作用。
图5为实施例5中递药系统的肿瘤治疗药效图;
本发明的最终递药系统具有良好的抗实体瘤治疗效果。
具体实施方式
以下结合附图对发明的优选实施例进行说明,应当理解,此处所描述的优选实施例仅用于说明和解释本发明,并不用于限定本发明。
实施例1:制备二乙基二硫代氨基甲酸透明质酸前药(HA-DQ)
称取0.172g(1mmol)二乙基二硫代氨基甲酸钠与0.214g(1mmol)4-(溴甲基)苯硼酸,加入乙腈与乙醇混合溶液(乙腈∶乙醇=2∶1)15mL中,超声15分钟后,于室温搅拌反应过夜至溶液澄清。减压加热旋干溶剂后,加入50ml乙酸乙酯复溶,转移到分液漏斗,并用超纯水洗涤萃取3次,仅收集有机层,减压加热旋干乙酸乙酯,得目标物DTC-PBA。
称取0.283g(1mmol)DTC-PBA,加入10mL甲苯与2mL四氢呋喃溶解后,加入3-氨基 -1,2-丙二醇乙醇溶液(2mmol/mL)1mL,搅拌下滴入5滴乙二胺,然后加入0.086g(0.5mmol),于110℃油浴冷凝回流12小时。取出,待反应液稍冷却后,减压加热旋干溶剂,冷却至室温后,加入50mL乙酸乙酯复溶,转移到分液漏斗,并用超纯水洗涤萃取3次,仅收集有机层,减压加热旋干乙酸乙酯,得目标物DQ-NH2。
称取0.200g透明质酸(3-10k),加入200μL水溶胀,搅拌下滴加1mL 1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐DMSO溶液(0.05mmol/mL),1mL N,N-二异丙基乙胺DMSO溶液(0.05mmol/mL)与4mL DTC-NH2 DMSO溶液(0.25mmol/mL),室温搅拌过夜。反应液转移到1k透析袋中,用乙醇水溶液(1∶1)透析3天,收集透析袋内溶液冷冻干燥,得目标物HA-DQ。
核磁共振结果显示(图1),合成产物在1H-NMR 7.25-8.0ppm之间有苯硼酸苯环上的特征峰,在1.5-2.0ppm之间有透明质酸链上甲基上的特征峰,在1.0-1.5ppm之间有二乙基二硫代氨基甲酸甲基上的特征峰,表明二乙基二硫代氨基甲酸前药已成功合成。
实施例2:制备铜-光敏剂配位载体(Cu-MOF)
通过溶剂热法制备Zn-TCPP/Cu2+MOF,称取3.6mg Cu(NO3)2·3H2O,10mg PVP100,10μL三氟乙酸溶解分散在12mL DMF/EtOH(DMF∶EtOH=3∶1)混合溶液中,转移到20mL 聚氟乙烯高压反应釜中,超声10分钟。称取4.5mg Zn-TCPP溶解到4mL DMF/EtOH(DMF∶ EtOH=3∶1)混合溶液中,加入上述反应釜,混匀再超声15分钟。将高压反应釜封闭紧密,置于80℃烘箱加热4小时。取出冷却至室温,离心收集固体,用无水乙醇洗涤3-5次,真空干燥箱烘干得微米级Cu-MOF。再通过高压均质及反复超声将粒径缩小至纳米级别。
透射电镜结果显示(图2A),所得超声后的Cu-MOF的粒径约为30~100nm。
实施例3:制备载二乙基二硫代氨基甲酸前药的铜-光敏剂配位递药系统(HA-DQ@
MOF)
HA-DQ通过物理吸附修饰到MOF表面,具体操作方法如下:将上文制备好的干燥Cu-MOF粉末分散在无水乙醇溶液中配成2mg/mL浓度待用。将制备好的HA-DQ材料溶解在去离子水中配成2mg/mL共10mL,将配制好的MOF溶液1mL加入到10mL HA-DQ溶液中,在室温条件下避光搅拌3h。结束后取出进行高速离心(10000rpm/20min)取沉淀,然后用去离子水反复洗涤3次,除去游离的HA-DQ。制得的HA-DQ@MOF分散在NaCl生理盐水和去离子水溶液中待用。
透射电镜结果显示(图2B),所得超声后的载药HA@DQ-MOF的粒径及形态与未载药Cu-MOF基本相同,约为30~100nm,可能原因为HA前药在透射电镜图中难以被观察到。动态光散射粒径结果显示(图3A),载药HA@DQ-MOF的粒径略大于未载药Cu-MOF。电位测定结果表明(图3B),Cu-MOF表面裹上高分子聚合物后电位变负,由于HA是带负电荷的聚合物,该结果表明HA成功包裹在Cu-MOF表面。
实施例4:HA-DQ@MOF体外细胞毒性实验
将4T1和NIH-3T3细胞以5×104个/孔的密度分别接种于96孔板中,细胞培养箱中培养过夜,待细胞贴壁后,加入HA-DQ@MOF(浓度从0-100μg/mL,倍半稀释)与细胞孵育,药物孵育4h后对细胞分别给予不光照及630nm NIR(100mW/cm2)光照射10min处理,孵育24h后各组均加入20μL MTT(5mg/mL in PBS buffer),于细胞培养箱中避光孵育4h,弃去培养液加入150μL DMSO,置于摇床100rpm避光震摇15min,立即用酶标仪测定其在490 nm处各孔的吸光值。根据结果以不加药物组为对照组,不加细胞孔为空白组,按照以下公式计算细胞的存活率:细胞存活率(%)=(OD样品-OD空白)/(OD对照-OD空白)×100%。
结果显示(图4),在4T1肿瘤细胞中,HA-DQ@MOF具有较强的细胞杀伤作用,可能是由于前药在响应肿瘤细胞上调的ROS后释放二乙基二硫代氨基甲酸,进而生成具有抗肿瘤活性的金属铜络合物。经光照处理后,HA-DQ@MOF的细胞杀伤作用较不光照时显著增强,可能为铜金属络合物的同时,触发光敏剂的释放,进而实现化疗-光动力治疗的协同。与之形成鲜明对比的是,在NIH 3T3正常细胞中,由于活性氧含量较低,难以触发二乙基二硫代氨基甲酸原形药物释放,进而难以形成足量抗肿瘤金属铜络合物及光敏剂,因而其细胞毒作用显著低于4T1细胞系。
实施例5:体内药效学评价
4T1小鼠皮下乳腺癌模型的构建,用配置好的DMEM培养液(含10%胎牛血清,1%青霉素链霉素双抗)培养4T1细胞,待细胞密度、数量及状态符合实验要求时,用胰酶消化、收集后分散于PBS溶液中,进行细胞计数,稀释适当倍数至浓度为1*107个/ml。用注射器吸取按100uL/只将4T1细胞混悬液接种至5-6周雌性BALB/c小鼠右后背段皮下,构建BALB/c 小鼠异位皮下移植4T1乳腺癌模型。隔日观察肿瘤细胞接种部位,记录肿瘤的生长状态,用游标卡尺测定皮下肿瘤的长径(L)和短径(W),按照体积公式(V)=L*W2/2计算.
待BALB/c小鼠4T1乳腺癌皮下肿瘤生长至100mm3时,将小鼠随机分为3组(n=6),分别为:1)仅注射生理盐水+光照组;2)注射HA-DQ@MOF(200ug/只)不加光照组;3) 注射HA-DQ@MOF(200ug/只)加光照组。按照以上分组进行给药,以上组别注射操作均为尾静脉注射,注射后4h光照第一次,24h后照射第二次,以上光照均按(100mW/cm2630 nm)NIR照射10min,仅在肿瘤部位给予光照操作。在分组第1、3、5天进行共3次给药,分别于给药当天及次日进行共计6次光照。以给药当天为起始第一天,隔日观察各组测量小鼠的肿瘤大小,按照体积公式计算肿瘤体积值同时纪录小鼠的体重变化。待实验进行至21天,进行颈椎脱臼法处死小鼠。
结果显示(图5),生理盐水+光照组肿瘤生长迅速,HA-DQ@MOF非光照组具有中等程度的肿瘤抑制作用,可能是由于前药在响应肿瘤细胞上调的ROS后释放二乙基二硫代氨基甲酸,进而生成具有抗肿瘤活性的金属铜络合物。经光照后,由于抗肿瘤金属铜络合物以及光动力的协同作用,肿瘤抑制作用显示增强。
Claims (8)
1.一种载二乙基二硫代氨基甲酸前药的铜或锌递药载体,其特征在于,包含二乙基二硫代氨基甲酸前药以及铜或锌纳米载体,所述二乙基二硫代氨基甲酸前药为共价偶联在亲水高分子链上的聚合物前药;所述铜或锌载体中包含金属离子及光敏剂,其中金属离子可以是以下一种或多种:铜离子、锌离子,光敏剂带有羧基、硼酸基、吡啶、或咪唑等一种或几种配位基团,二者通过铜或锌离子与配体的配位作用制备。
2.根据权利要求1所述的一种载二乙基二硫代氨基甲酸前药的铜或锌递药载体,其特征在于,其制备过程包括以下几个步骤:
A、合成二乙基二硫代氨基甲酸高分子聚合物前药;
B、通过溶剂热法制备铜或锌离子与光敏剂的配位;具体为将铜/锌离子和配体光敏剂分散在N,N二甲基甲酰胺和无水乙醇混合溶剂中,80℃加热4h制备微米级金属有机骨架材料,再通过高压均质及反复超声将粒径缩小至纳米级别;其中铜或锌离子与光敏剂的投料比例大于或等于4∶1;
C、将合成的二乙基二硫代氨基甲酸高分子聚合物前药与纳米级金属有机骨架材料在水溶液中混合搅拌,聚合物前药通过物理吸附或配位相互作用组装在铜离子或锌离子-光敏剂配位纳米载体上;
D、通过多次离心法除去游离的二乙基二硫代氨基甲酸高分子聚合物前药,即制得上述递药载体。
3.根据权利要求2所述的一种载二乙基二硫代氨基甲酸前药的铜或锌递药载体,其特征在于,所述制备的纳米级金属有机骨架材料的粒径为10~500nm。
4.根据权利要求1所述的一种载二乙基二硫代氨基甲酸前药的铜或锌递药载体,其特征在于,所述二乙基二硫代氨基甲酸高分子聚合物前药是通过“二乙基二硫代氨基甲酸-刺激响应敏感键-高分子聚合物”的偶连方式合成的;所述刺激响应敏感键包括但不限于可响应于谷胱甘肽、反应活性氧、肿瘤组织高表达的酶等化学键;所述肿瘤组织高表达的酶包括但不限于组织蛋白酶、基质金属蛋白酶、豆荚蛋白酶等。
5.根据权利要求3所述的一种载二乙基二硫代氨基甲酸前药的铜或锌递药载体,其特征在于,所述高分子聚合物为透明质酸、葡聚糖、海藻酸钠、硫酸软骨素、壳聚糖、羧甲基壳聚糖、右旋糖苷等;所述高分子聚合物的分子量为3k~100w。
6.根据权利要求1所述的一种载二乙基二硫代氨基甲酸前药的铜或锌递药载体,其特性在于,所述光敏剂为近红外光敏剂,最大发射波长为600~800nm,所述激活光敏剂的近红外光激光功率为10~250mW cm-2;所述近红外光持续时间为10秒~10分钟。
7.根据权利要求1-7任一项所述的一种载二乙基二硫代氨基甲酸前药的铜或锌递药载体在制备用于实体肿瘤治疗药物中的用途。
8.根据权利要求7所述的用途,其特征在于,二乙基二硫代氨基甲酸前药在肿瘤部位刺激响应断键,释放二乙基二硫代氨基甲酸原形药,其争夺铜或锌配位载体中的铜离子或锌离子,形成具有抗肿瘤活性的铜离子或锌离子络合物,与此同时,光敏剂释放出来,实现化疗-光动力治疗的协同。
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