CN115252805A - 卡巴他赛-脂肪醇小分子前药及其自组装纳米粒的构建 - Google Patents

卡巴他赛-脂肪醇小分子前药及其自组装纳米粒的构建 Download PDF

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CN115252805A
CN115252805A CN202110478660.0A CN202110478660A CN115252805A CN 115252805 A CN115252805 A CN 115252805A CN 202110478660 A CN202110478660 A CN 202110478660A CN 115252805 A CN115252805 A CN 115252805A
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cabazitaxel
prodrug
fatty alcohol
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罗聪
王永军
杨金诚
马宏达
孙进
何仲贵
冯尧
马志宁
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Suzhou Yutai Pharmaceutical Technology Co ltd
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Abstract

本发明属于药物制剂新辅料和新剂型领域，涉及卡巴他赛脂肪醇前药及其自组装纳米粒的构建，具体涉及二硫键桥连的氧化还原双敏感卡巴他赛脂肪醇前药及其自组装纳米粒的构建，和在制备药物传递系统中的应用。所述的前药通过向卡巴他赛分子中引入长链脂肪醇结构，利用氧化还原双敏感的二硫键将二者连接制成前药，使其在肿瘤细胞内高氧化还原微环境中激活，快速释放母药，其结构如下，其中，R和n如权利要求和说明书所述。此外，长链脂肪醇结构的引入，增加了卡巴他赛的疏水性，从而赋予其自组装能力，可以自组装成纳米粒。本发明的卡巴他赛脂肪醇前药及其自组装纳米粒能够明显提高卡巴他赛的抗肿瘤作用，同时降低其毒性，提高药物的生物利用度。

Description

卡巴他赛-脂肪醇小分子前药及其自组装纳米粒的构建
技术领域
本发明属于药物制剂新辅料和新剂型领域，涉及卡巴他赛脂肪醇小分子前药及其自组装纳米粒的构建，具体涉及二硫键桥连的氧化还原双敏感卡巴他赛脂肪醇前药及其自组装纳米粒的构建，和在制备药物传递系统中的应用。
背景技术
恶性肿瘤严重威胁着全人类的健康。化疗是当前肿瘤治疗中最常用和最有效的策略之一，尤其适用于不能通过手术切除和已转移扩散肿瘤的治疗。卡巴他赛具有超强的细胞毒性和良好的抗肿瘤作用。然而，市售的卡巴他赛溶液剂
Figure BDA0003048291620000011
需要大量辅料助溶、稳定性差、药动学性质不佳、具有极强毒副作用，导致其治疗窗狭窄且疗效不佳。因此，如何改善卡巴他赛的不良性质并提高其药物递送效率是其在当前临床应用中亟待解决的难题。
尽管卡巴他赛具有良好的抗肿瘤效果和临床治疗前景，但具有水溶性很差的缺陷。国内外用于临床试验的卡巴他赛制剂为了克服这一缺陷，一般加入表面活性剂进行增溶处理。尽管这在一定程度上解决了卡巴他赛难溶性的问题，但是增溶剂的引用往往会引起患者产生严重的过敏反应，再加上抗癌药本身具有的毒性，简单的抗癌药物溶液剂会对癌症患者本就虚弱的身体造成进一步的伤害。因此，如何设计出高效低毒的卡巴他赛制剂仍然是其能够在临床发挥良好抗肿瘤效果的关键。
Figure BDA0003048291620000012
近年来，前体药物和纳米技术在药物传递领域的广泛应用极大地丰富了抗肿瘤药物的递送策略。对于卡巴他赛的递送，前药策略可以通过巧妙的结构修饰来改善其不良性质，包括溶解度低，稳定性差，毒副作用大等。此外，基于纳米技术构建新型给药系统可以显著改善药物的药动学特征，延长其体内循环时间，利用EPR效应增加药物在肿瘤部位的蓄积，进而提高抗肿瘤效果。基于此，将前体药物和纳米技术的优点合二为一，合理设计构建卡巴他赛前药纳米递送系统，有望克服上述药物递送劣势。近年来新兴的小分子前药自组装纳米粒，将前药策略和纳米技术完美融合，并且具有载药量高，无载体相关毒副作用等优势因此得到广泛研究。现有技术表明，不同结构修饰的卡巴他赛前药，其对于卡巴他赛性质的改变不同，其前药在体内的效果也不同。因此，获得最佳的卡巴他赛前药，使其自组装成纳米粒，从而提高疗效，降低毒性也是医药技术人员正在努力研究的方向。
发明内容
为了克服现有技术的缺陷，本发明提供一种卡巴他赛脂肪醇小分子前药，所述的前药通过向卡巴他赛分子中引入长链脂肪醇结构，并利用氧化还原双敏感的二硫键将二者连接制成前药，使其能够在肿瘤细胞内高氧化还原微环境中激活，快速释放母药。此外，长链脂肪醇结构的引入，增加了卡巴他赛的疏水性，从而赋予其自组装能力。设计氧化还原敏感的卡巴他赛脂肪醇前药自组装纳米粒，可以提高药物的稳定性，增加载药量，并能够在肿瘤部位快速特异性释放母药，进而降低其毒副作用提高肿瘤治疗效果。
本发明通过以下技术方案实现上述目的：
本发明所述的二硫键桥连的卡巴他赛脂肪醇小分子前药或其药学上可接受的盐、异构体、溶剂化物：
Figure BDA0003048291620000021
其中，R为C3-C30饱和或不饱和链烃基；
进一步地，
Figure BDA0003048291620000022
或R为C3-C22烯基；所述烯基中含有1-5个烯键；
p＝7-29；
n＝1-3；
进一步地，当
Figure BDA0003048291620000023
时，p＝11-27；
更进一步地，当
Figure BDA0003048291620000031
时，p＝11-17；
当R为C3-C22烯基时，所述的R包括但不限于丙烯基，烯丙基，2-丁烯基，4-戊烯基，2-己烯基，4-癸烯基，2-十二碳烯基，9-十四碳烯基，9-十六烯基，9-十八烯基,二十碳四烯基，二十二碳五烯基，亚油基。
进一步地，本发明提供如下结构的卡巴他赛硬脂醇前药：
Figure BDA0003048291620000032
n＝1、2或3。
本发明还提供了所述的卡巴他赛脂肪醇小分子前药的合成方法，其合成方法包括如下步骤：
(1)将二元酸(亚二硫基二乙酸、3,3’-亚二硫基二丙酸或4,4’-亚二硫基二丁酸)于乙酸酐中使相应含敏感键二元酸成酸酐，反应完毕后，加入甲苯，旋蒸甲苯并除去乙酸酐；
(2)将步骤(1)所得产物溶于二氯甲烷中，并加入脂肪醇和缩合剂DMAP，室温条件下搅拌12-18小时，通过柱层析分离得到中间产物脂肪醇亚二硫基二乙酸、脂肪醇亚二硫基二丙酸或脂肪醇亚二硫基二丁酸单边酯；
(3)将上述产物与卡巴他赛进行酯化反应：将中间产物、1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐(EDCI)、1-羟基苯并三唑(HOBt)和4-二甲氨基吡啶(DMAP)溶于无水二氯甲烷中，冰浴1-2小时，然后加入卡巴他赛，室温条件下搅拌24-48小时，经制备液相分离纯化得终产物，上述反应全程都在N2保护且干燥无水的条件下进行。
进一步地，
步骤(2)中所述的脂肪醇为C3-C30饱和或不饱和的脂肪醇，如正十二醇、十三醇、十四醇、1-十五醇、十六醇、十七醇、硬脂醇、1-十九烷醇、1-二十醇、二十一醇、1-二十二醇、二十二醇、二十三醇、二十四醇、二十五醇、1-二十六烷醇、9-十六烯醇，9-十八烯醇，亚油醇等。
其反应式如下：
Figure BDA0003048291620000041
其中，R为C3-C30饱和或不饱和链烃基，n＝1-3。
本发明还提供了卡巴他赛脂肪醇小分子前药的自组装纳米粒，所述的卡巴他赛脂肪醇小分子前药纳米粒可以是非PEG化的小分子前药纳米粒、PEG修饰的小分子前药纳米粒、包载荧光物质或疏水性药物的小分子前药纳米粒和主动靶向的小分子前药纳米粒。
所述的卡巴他赛脂肪醇小分子前药自组装纳米粒的制备方法如下：
将卡巴他赛-脂肪醇小分子前药溶解到适量无水乙醇中，搅拌下，将该乙醇溶液缓慢滴加到水中，前药可以自发地组装成粒径均匀的纳米粒；
也可以采用微流控设备进行超小纳米粒的制备：配制含有卡巴他赛硬酯醇前药的乙醇溶液作为有机相；以超纯水作为水相，按照水相和有机相混合制备，最终得到卡巴他赛硬酯醇前药纳米粒。。
具体地，所述的制备方法包括：
非PEG化的小分子前药自组装纳米粒的制备方法:将一定量的前药溶解到适量的乙醇中,于搅拌下将该乙醇溶液缓缓滴加到水中，前药自发形成均匀的纳米粒。
PEG修饰或主动靶向制剂修饰的小分子前药自组装纳米粒的制备方法:将一定量的PEG修饰剂和前药溶解到适量的乙醇中，搅拌下，将该乙醇溶液缓缓滴加到水中，前药自发形成均匀的纳米粒。其中，PEG修饰剂可以为DSPE-PEG、TPGS、PLGA-PEG、PE-PEG或DSPE-PEG-AA等两亲性聚合物或靶向基团。其中，卡巴他赛-脂肪醇小分子前药与PEG修饰剂的质量比为90:10～70:30。
包载疏水性荧光物质或药物的小分子前药自组装纳米粒的制备方法，以PEG化纳米粒为例:将一定量的PEG修饰剂、香豆素-6或DiR以及前药溶解到适量的乙醇中，搅拌下,将该乙醇溶液缓缓滴加到水中，前药自发形成均匀的纳米粒。
在上述纳米粒形成以后，采用透析法或旋蒸法除去制剂中的乙醇，得到不含任何有机溶剂的纳米胶体溶液。
本发明的有益技术效果：本发明提供了二硫键桥连的卡巴他赛脂肪醇小分子前药，该前药可以自组装纳米粒，能够明显提高卡巴他赛的抗肿瘤活性，降低毒性。
附图说明
图1为本发明实施例1的二硫键(n＝1)相连的卡巴他赛硬脂醇前药的MS谱图。
图2为本发明实施例1的二硫键(n＝1)相连的卡巴他赛硬脂醇前药1HNMR谱图。
图3为本发明实施例3的PEG修饰的小分子前药自组装纳米粒的血药浓度--时间曲线图。
图4为本发明实施例3的PEG修饰的小分子前药自组装纳米粒的在体抗肿瘤实验肿瘤体积变化曲线图。
图5为本发明实施例3的PEG修饰的小分子前药自组装纳米粒的在体抗肿瘤实验结束后肿瘤体积直观对比图。
图6为本发明实施例3的PEG修饰的小分子前药自组装纳米粒的在体抗肿瘤实验小鼠体重变化图。
图7为本发明实施例3的PEG修饰的小分子前药自组装纳米粒的在体抗肿瘤实验结束后脾脏体积直观对比图。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将发明限制在所述的实施例范围之中。
实施例1：二硫键(n＝1)桥连的卡巴他赛硬脂醇前药的合成
Figure BDA0003048291620000051
n＝1。
将适量的二硫代二乙酸溶于乙酸酐，置于100mL茄形瓶中，25℃磁力搅拌3h，加入三倍量甲苯，减压蒸馏除去甲苯并带除乙酸酐，加入10-15mL二氯甲烷溶解所形成的二硫代二乙酸酐,加入溶解好的硬脂醇，并逐滴滴加二氯甲烷溶解的DMAP溶液，25℃磁力搅拌12h，得到中间产物硬脂醇二硫代二乙酸单边酯，采用环己烷-丙酮(30：1-15：1)洗脱体系进行分离提纯；纯化后加入EDCI、HOBt作为催化剂，0℃冰浴活化1～2h，缓慢滴加用二氯甲烷溶解的硬脂醇二硫代二乙酸单边酯和DMAP，室温搅拌24～48h。反应结束后采用制备液相对初产物进行分离。所述的脂肪醇与二硫代二乙酸的摩尔比为0.5：1；DMAP与二硫代二乙酸的摩尔比为0.5：1；中间产物：EDCI：HOBt：DMAP的摩尔比为1：1：3：2。采用MS和1H-NMR对产物结构进行确证，结果如图1，图2所示。
实施例2：非PEG化的卡巴他赛硬脂醇小分子前药自组装纳米粒的制备
精密称取实施例1的前药8mg，用800μL乙醇将其溶解，搅拌下，将该乙醇溶液缓缓滴加到4mL去离子水中，自发形成均匀的纳米粒。
实施例3：PEG修饰的卡巴他赛硬脂醇小分子前药自组装纳米粒的制备
精密称取DSPE-PEG2K 1.4mg和实施例1的前药8mg，用800μL乙醇将其溶解,搅拌下将该乙醇溶液缓缓滴加到4mL去离子水中，自发形成粒径均匀的PEG修饰的纳米粒。其粒径为91nm，粒径多分散系数0.156。
改变前药与DSPE-PEG2K的比例，结果表明，当DSPE-PEG2K用量在10％-30％时，即前药与DSPE-PEG2K的比例为90：10-70：30时，所制备的纳米粒粒径均为70～100nm，粒径多分散系数＜0.2。
所述的DSPE-PEG2K也可以以TPGS、PLGA-PEG、PE-PEG或DSPE-PEG-AA等两亲性聚合物或靶向基团代替。
实施例4：使用微流控设备来制备超小型拉洛他赛硬酯醇小分子前药纳米粒：
配制含有DSPE-PEG2000和卡巴他赛硬酯醇小分子前药的乙醇溶液作为有机相，其中，卡巴他赛硬酯醇前药浓度为10mg/ml，DSPE-PEG2000的浓度2mg/ml；以超纯水作为水相，按照水相和有机相流速比为5：1的比例来混合制备，最终得到卡巴他赛硬酯醇小分子前药纳米粒。
实施例5：小分子前药自组装纳米粒的药代动力学研究
取10只健康雄性大鼠，体重200-250g，随机分为2组，给药前禁食12h，自由饮水。两组分别尾静脉注射卡巴他赛溶液剂和实施例3中制备的PEG化修饰的卡巴他赛硬脂醇前药自组装纳米粒(粒径为91nm)。其剂量为5mg/kg(以卡巴他赛计)。于规定的时间点眼眶取血，分离获得血浆。通过液相色谱-质谱联用仪测定血浆中的药物浓度。结果如图3,卡巴他赛溶液剂循环时间很短，给药后在体内迅速代谢清除。相比之下，PEG化的小分子前药自组装纳米粒循环时间明显延长,生物利用度明显提高。实验结果表明,PEG化的小分子前药自组装纳米粒能显著延长卡巴他赛在血液中的循环时间。
5只大鼠静脉给予前药CTX-SS-SAl-DSPE-PEG2K NPs(给药计量：以母药计5mg/kg)前药CTX-Pro的药动学参数
Figure BDA0003048291620000061
Figure BDA0003048291620000071
5只大鼠静脉给予前药CTX-SS-SAl-DSPE-PEG2K NPs(给药计量：以母药计5mg/kg)母药CTX的药动学参数
Figure BDA0003048291620000072
5只大鼠静脉给予前药CTX-Pro的solution剂型后(给药计量：以母药计5mg/kg)母药CTX的药动学参数
Figure BDA0003048291620000073
实施例6：PEG化的小分子前药自组装纳米粒的在体抗肿瘤实验
将小鼠乳腺癌细胞悬液(4T1,1x106cells/100uL)接种于雌性Balb/c背侧皮下。待肿瘤体积生长至100-120mm3，将荷瘤小鼠随机分为7组，每组五只：空白对照组(PBS)，卡巴他赛溶液剂5mg/kg组，卡巴他赛溶液剂10mg/kg组，卡巴他赛溶液剂20mg/kg组，CTX-SS-SAl/DSPE-PEG2K纳米粒5mg/kg组，CTX-SS-SAl/DSPE-PEG2K纳米粒10mg/kg组，CTX-SS-SAl/DSPE-PEG2K纳米粒20mg/kg组。给药所用的纳米粒为实施例3中制备的PEG修饰的小分子前药自组装纳米粒(粒径为91nm)。每隔1d给药1次，连续给药5次。给药后，每天检测小鼠的存活状态和体重变化情况，测量肿瘤体积。最后一次给药后一天将小鼠处死，获取器官和肿瘤，进行进一步分析评价。结果如图4和图5所示，在空白对照组中，肿瘤体积迅速增长，在第10天达到700-800mm3。相比之下，溶液剂和纳米粒组均能显著抑制肿瘤生长，其抗肿瘤能力无显著差异。而从安全性角度来看，如图6所示，溶液剂组能够引起小鼠体重的显著降低，而纳米粒组小鼠体重仅发生微小变化。此外，还可以通过在体抗肿瘤实验结束后小鼠脾脏萎缩情况来间接反映药物毒性。由图7所示，在体内药效试验结束后，溶液剂组小鼠脾脏发生十分明显的萎缩，而纳米粒组脾脏体积虽然也有减小，但其体积缩减程度明显降低。结果表明PEG化的小分子前药自组装纳米粒在具有明显的抗肿瘤效果的同时，没有对机体造成显著的非特异性毒性，明显降低了卡巴他赛的毒性，是一种疗效确切且安全的药物递送系统。

Claims (10)

1.具有如下结构的卡巴他赛脂肪醇小分子前药或其药学上可接受的盐、异构体、溶剂化物：
Figure FDA0003048291610000011
其中，R为C3-C30饱和或不饱和链烃基；
优选
Figure FDA0003048291610000012
或R为C3-C22烯基；所述烯基中含有1-5个烯键；
p＝7-29；
n＝1-3。
2.权利要求1所述的卡巴他赛脂肪醇小分子前药或其药学上可接受的盐、异构体、溶剂化物：
其中，
Figure FDA0003048291610000013
且p＝11-27，优选为p＝11-17；或R为丙烯基，烯丙基，2-丁烯基，4-戊烯基，2-己烯基，4-癸烯基，2-十二碳烯基，9-十四碳烯基，9-十六烯基，9-十八烯基,二十碳四烯，二十二碳五烯，亚油基。
3.权利要求1或2所述的卡巴他赛脂肪醇小分子前药或其药学上可接受的盐、异构体、溶剂化物：
Figure FDA0003048291610000014
其中，n＝1-3，优选为1。
4.如权利要求1所述的卡巴他赛脂肪醇小分子前药的制备方法，其特征在于，采用如下步骤制备：
Figure FDA0003048291610000021
其中，R和n如权利要求1所述。
5.权利要求1-3任何一项所述的卡巴他赛脂肪醇小分子前药的自组装纳米粒，其特征在于，所述的卡巴他赛脂肪醇小分子前药纳米粒是非PEG化的小分子前药纳米粒、PEG修饰剂修饰的小分子前药纳米粒、包载荧光物质或疏水性药物的小分子前药纳米粒或主动靶向的小分子前药纳米粒，所述的PEG修饰剂优选为TPGS、DSPE-PEG、PLGA-PEG、PE-PEG或DSPE-PEG-AA，小分子前药与PEG修饰剂的比例为90:10～70:30。
6.如权利要求4所述的卡巴他赛脂肪醇小分子前药的自组装纳米粒的制备方法，其特征在于，
将卡巴他赛脂肪醇小分子前药或卡巴他赛脂肪醇小分子前药与PEG修饰剂溶解到适量的乙醇中，搅拌下，将该乙醇溶液缓缓滴加到水中，前药自发形成粒径均匀的PEG修饰的纳米粒，最后，采用透析法或旋蒸法除去制剂中的乙醇，得到不含任何有机溶剂的纳米胶体溶液；
或以含有PEG修饰剂和卡巴他赛硬酯醇小分子前药的乙醇溶液作为有机相，以超纯水作为水相，采用微流控设备制备。
7.权利要求1-3任何一项所述的卡巴他赛脂肪醇前药或其药学上可接受的盐、异构体、溶剂化物或权利要求5所述的卡巴他赛脂肪醇小分子前药的自组装纳米粒在制备药物传递系统中的应用。
8.权利要求1-3任何一项所述的卡巴他赛脂肪醇前药或其药学上可接受的盐、异构体、溶剂化物或权利要求5所述的卡巴他赛脂肪醇小分子前药的自组装纳米粒在制备抗肿瘤药物中的应用。
9.权利要求1-3任何一项所述的卡巴他赛脂肪醇前药或其药学上可接受的盐、异构体、溶剂化物或权利要求5所述的卡巴他赛脂肪醇前药的自组装纳米粒在制备提高疗效、降低毒性药物中的应用。
10.权利要求1-3任何一项所述的卡巴他赛脂肪醇前药或其药学上可接受的盐、异构体、溶剂化物或权利要求5所述的小分子前药的自组装纳米粒在制备注射给药、口服给药或局部给药系统中的应用。
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