CN101831011B - 一种作为药物传输载体的pH响应性环糊精衍生物及其合成方法 - Google Patents
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Abstract
本发明公开了一种作为药物传输载体的pH响应性环糊精衍生物的组成及其合成方法。环糊精衍生物的化学结构为
Description
技术领域
本发明涉及一种作为药物传输载体的pH响应性环糊精衍生物的组成及其合成方法。
背景技术
长期以来，智能响应性药物传输系统是广大药物制剂研究人员所关注的焦点之一[1，2]。相对于一般传输系统，智能传输系统具有以下优点：1)有助于进一步提高药物疗效；2)能有效减缓药物本身的毒副作用；3)通过提高药物的有效利用度来减少给药剂量；4)可控的药物释放。而该类药物传输系统的成功构建开发与新材料的研究制备是息息相关的。因此，智能响应性材料的开发一直是国内外药学、材料学、化学等多学科研究的热点[1-3]。
其中，pH敏感性聚合物是最为深入研究的一类材料[3]。例如，在酸性介质中不溶，而在pH较高溶液中可以溶解的肠溶性包衣材料(虫胶，纤维素衍生物及丙烯酸树脂等)已被广泛用于片剂及微囊的制备[4]。同样地，具有pH响应降解特性的合成聚合物聚酸酐也被深入研究作为微球或植入剂等缓控释传输系统的载体材料[5，6]。另一方面，细胞内内涵体和溶酶体内具有较低的pH微环境(pH-5)；因此，响应于低pH的材料能够作为细胞内药物传输系统的载体材料。美国的Heller研发组多年来致力于可响应于低pH的聚原酸酯材料。到目前为止，该组研究人员已成功开发出四大类具有pH敏感特性的聚原酸酯高分子材料，广泛用于各类系统疾病治疗的药物传输载体以及作为基因治疗的非病毒载体[7]。日本东京大学的Kataoka等人通过pH敏感性腙键将抗癌药物阿霉素键合至嵌段共聚物多肽段得到两亲性的共聚物，通过自组装方法制备了粒径几十纳米的聚合物胶束。在正常pH介质中(pH7.4)，该胶束中的阿霉素几乎无释放；响应于细胞内酸性微环境中，其中的阿霉素可以有效释放，达到治疗的目的[8]。美国加州大学伯克利分校的Fréchet等人通过对葡聚糖的缩醛化制备得到响应于低pH的葡聚糖衍生物，该材料可以作为载体用于小分子药物，蛋白及多聚核苷酸的细胞内传输[9]。
由上述可见，设计并合成pH敏感性材料对于实现药物的可控/靶向传递是一项十分重要而有意义的工作。而国内这一领域的研究起步较晚，目前具有自主知识产权的载体材料品种极少。
发明内容
本发明的目的是提供一种作为药物传输载体的pH响应性环糊精衍生物及其合成方法。
为了达到上述目的，本发明采取以下措施：
作为药物传输载体的pH响应性环糊精衍生物的化学结构为：
其中：n＝6、7或8；分别对应α-，β-，或γ-环糊精衍生物。
上述化学结构的作为药物传输载体的pH响应性环糊精衍生物的合成方法如下：
氮气保护下，将0.001-0.6mmol催化剂加入到含有1.0mmol环糊精的5-80ml有机溶液中，同时加入5-500mmol缩醛化试剂后于-20-80℃磁力搅拌下反应；1-10小时后向该反应体系中加入0.01-10mmol三乙胺停止反应，水中沉淀并真空干燥得到目的产物。
本发明的优点是：
1、所得到的材料具有良好的生物相容性，且可生物降解，降解产物对机体无毒副作用；
2、材料合成过程简单，材料的降解性可以简单地通过环糊精种类及缩醛化时间在一定范围内调控；
3、合成的材料具有良好的pH敏感性，即在正常pH7.4时水解缓慢，而在pH5时较快水解；
4、合成产物易溶于二氯甲烷，氯仿，甲醇，乙醇，丙酮，四氢呋喃等常见溶剂，有利于各种传输系统的制备；
5、通过简单的乳液/溶剂挥发法可以便利的制备粒径大小及分布均可调控的纳米微粒(参见附图1、2)。
附图说明
图1是由α-环糊精衍生物所制备的纳米微粒的透射电镜图片；
图2是由β-环糊精衍生物所制备的纳米微粒的透射电镜图片。
具体实施方式
下面结合实施例对本发明做详细说明。
实施例1
氮气保护下，将0.01mmol吡啶对甲苯磺酸盐加入到含有1.0mmol α-环糊精的10ml N，N-二甲基甲酰胺溶液中，同时加入20mmol 2，2-二甲氧基丙烷后于0℃磁力搅拌下反应；2.5小时后向该反应体系中加入0.02mmol三乙胺停止反应，水中沉淀并真空干燥得到目的产物。
实施例2
氮气保护下，将0.015mmol吡啶对甲苯磺酸盐加入到含有1.0mmol β-环糊精的15ml N，N-二甲基甲酰胺溶液中，同时加入25mmol 2，2-二甲氧基丙烷后于0℃磁力搅拌下反应；2.5小时后向该反应体系中加入0.03mmol三乙胺停止反应，水中沉淀并真空干燥得到目的产物。
实施例3
氮气保护下，将0.02mmol吡啶对甲苯磺酸盐加入到含有1.0mmol γ-环糊精的15ml N，N-二甲基甲酰胺溶液中，同时加入50mmol 2，2-二甲氧基丙烷后于0℃磁力搅拌下反应；4.0小时后向该反应体系中加入0.05mmol三乙胺停止反应，水中沉淀并真空干燥得到目的产物；
实施例4
氮气保护下，将0.1mmol对甲苯磺酸加入到含有1.0mmol β-环糊精的20ml N，N-二甲基甲酰胺溶液中，同时加入50mmol 2-甲氧基丙烯后于20℃磁力搅拌下反应；3.0小时后向该反应体系中加入0.2mmol三乙胺停止反应，水中沉淀并真空干燥得到目的产物，收率91％。
实施例5
氮气保护下，将0.05mmol对甲苯磺酸加入到含有1.0mmol β-环糊精的20ml N，N-二甲基乙酰胺溶液中，同时加入50mmol 2-甲氧基丙烯后于20℃磁力搅拌下反应；3.5小时后向该反应体系中加入0.1mmol三乙胺停止反应，水中沉淀并真空干燥得到目的产物；收率90％。
实施例6
氮气保护下，将0.15mmol对甲苯磺酸加入到含有1.0mmol α-环糊精的20ml二甲基亚砜溶液中，同时加入50mmol 2-甲氧基丙烯后于20℃磁力搅拌下反应；2.0小时后向该反应体系中加入0.3mmol三乙胺停止反应，水中沉淀并真空干燥得到目的产物；收率87％
实施例7
氮气保护下，将0.1mmol吡啶对甲苯磺酸盐加入到含有1.0mmol α-环糊精的20ml二甲基亚砜溶液中，同时加入100mmol 2-乙氧基丙烯后于25℃磁力搅拌下反应；5.0小时后向该反应体系中加入0.2mmol三乙胺停止反应，水中沉淀并真空干燥得到目的产物。收率83％
实施例8
氮气保护下，将0.05mmol吡啶对甲苯磺酸盐加入到含有1.0mmol β-环糊精的30ml二甲基亚砜溶液中，同时加入200mmol 2-乙氧基丙烯后于23℃磁力搅拌下反应；4.5小时后向该反应体系中加入0.2mmol三乙胺停止反应，水中沉淀并真空干燥得到目的产物。
实施例9
氮气保护下，将0.1mmol吡啶对甲苯磺酸盐加入到含有1.0mmol γ-环糊精的20ml N，N-二甲基甲酰胺溶液中，同时加入300mmol 2-甲氧基丙烯后于30℃磁力搅拌下反应；6.0小时后向该反应体系中加入0.3mmol三乙胺停止反应，水中沉淀并真空干燥得到目的产物，收率85％。
实施例10
氮气保护下，将0.08mmol对甲苯磺酸加入到含有1.0mmol γ-环糊精的15ml N，N-二甲基甲酰胺溶液中，同时加入400mmol 2-乙氧基丙烯后于25℃磁力搅拌下反应；5.5小时后向该反应体系中加入0.2mmol三乙胺停止反应，水中沉淀并真空干燥得到目的产物，收率88％
实施例11
氮气保护下，将0.05mmol对甲苯磺酸加入到含有1.0mmol β-环糊精的20ml N，N-二甲基甲酰胺和二甲基亚砜为混合溶剂(体积比1∶1)的溶液中，同时加入350mmol 2-甲氧基丙烯后于25℃磁力搅拌下反应；6.0小时后向该反应体系中加入0.2mmol三乙胺停止反应，水中沉淀并真空干燥得到目的产物，收率80％
主要参考文献：
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[2].Kost，J.；Langer，R.Responsive polymeric delivery systems.Adv.Drug Deliv.Rev.2001，46，125-148.
[3].Schmaljohann，D.Thermo-and pH-responsive polymers in drugdelivery.Adv.Drug Deliv.Rev.2006，58，1655-1670.
[4].Heller，J.Controlled release of biologically active compoundsfrom bioerodible polymers.Biomaterials 1980，1，51-57.
[5].Gopferich，A.；Tessmar，J.Polyanhydride degradation and erosion.Adv.Drug Deliv.Rev.2002，54，911-931.
[6].Jain，J.P.；Modi，S.；Domb，A.J.；Kumar，N.Role ofpolyanhydrides as localized drug carriers J.Control.Release 2005，103，541-563.
[7].Heller，J.；Barr，J.；Ng，S.Y.；Abdellauoi，K.S.；Gurny，R.Poly(ortho esters)：synthesis，characterization，properties and uses.Adv.Drug Deliv.Rev.2002，54，1015-1039.
[8].Bae，Y.；Fukushima，S.；Harada，A.；Kataoka，K.Design ofenvironment-sensitive supramolecular as semblies for intracellulardrug delivery：Polymeric micelles that are responsive to intracellularpH change.Angew.Chem.Int.Ed.2003，42，4640-4643.
[9].Bachelder，E.M.；Beaudette，T.T.；Broaders，K.E.；Dashe，J.；Frechet，J.M.J.Acetal-Derivatized Dextran：An Acid-ResponsiveBiodegradable Material for Therapeutic Applications.J.Am.Chem.Soc.2008，130，10494-10495.
Claims (4)
1.一种作为药物传输载体的pH响应性环糊精衍生物，其特征在于：它的化学结构为：
其中：n＝6、7或8；分别对应α-环糊精、β-环糊精或γ-环糊精。
2.一种作为药物传输载体的pH响应性环糊精衍生物，其特征在于：它的化学结构为：
其中：R＝-CH2CH3；n＝6、7或8；分别对应α-环糊精、β-环糊精或γ-环糊精。
3.一种权利要求1所述作为药物传输载体的pH响应性环糊精衍生物的合成方法，其特征在于：氮气保护下，将0.001-0.6mmol催化剂加入到含有1.0mmol环糊精的5-80ml有机溶剂中，同时加入5-500mmol缩醛化试剂后于-20-80℃磁力搅拌下反应；1-10小时后向该反应体系中加入0.01-10mmol三乙胺停止反应，水中沉淀并真空干燥得到目的产物；所述催化剂为吡啶对甲苯磺酸盐或对甲苯磺酸；所述有机溶剂选自N，N-二甲基甲酰胺、N，N-二甲基乙酰胺或二甲基亚砜；所述环糊精为α-环糊精、β-环糊精或γ-环糊精；所述缩醛化试剂选自2，2-二甲氧基丙烷或2-甲氧基丙烯。
4.一种权利要求2所述作为药物传输载体的pH响应性环糊精衍生物的合成方法，其特征在于：氮气保护下，将0.001-0.6mmol催化剂加入到含有1.0mmol环糊精的5-80ml有机溶剂中，同时加入5-500mmol缩醛化试剂后于-20-80℃磁力搅拌下反应；1-10小时后向该反应体系中加入0.01-10mmol三乙胺停止反应，水中沉淀并真空干燥得到目的产物；所述催化剂为吡啶对甲苯磺酸盐或对甲苯磺酸；所述有机溶剂选自N，N-二甲基甲酰胺、N，N-二甲基乙酰胺或二甲基亚砜；所述环糊精为α-环糊精、β-环糊精或γ-环糊精；所述缩醛化试剂为2-乙氧基丙烯。
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