CN112011040B - 一种多重纳米传递系统及其制备方法 - Google Patents

一种多重纳米传递系统及其制备方法 Download PDF

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CN112011040B
CN112011040B CN202010699317.4A CN202010699317A CN112011040B CN 112011040 B CN112011040 B CN 112011040B CN 202010699317 A CN202010699317 A CN 202010699317A CN 112011040 B CN112011040 B CN 112011040B
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杨斌
尚同祎
郑国栋
陈晓明
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Guangzhou Medical University
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Abstract

本发明公开了一种多重纳米传递系统，由主体分子和客体分子等摩尔比溶解于水中，充分搅拌反应，透析、冻干后得到。其中客体分子为通过DSPE‑PEG‑NHS在碱性条件下偶联盐酸金刚烷胺得到。其中主体分子的制备方法为：首先以β‑环糊精为起始原料，在碱性条件下开环缩水甘油，得到β‑环糊精接枝超支化聚甘油β‑CD‑HPG；然后以二羰基咪唑为偶联试剂，将三(2‑氨基乙基)胺链接到β‑CD‑HPG的羟基上，得到β‑环糊精接枝超支化聚甘油接枝三(2‑氨基乙基)胺β‑CD‑HPG‑TAEA；然后使用靶向试剂对β‑CD‑HPG‑TAEA进行靶向修饰，得到所述主体分子。该多重纳米传递系统不仅仅可同时负载小分子药物与核酸片段，其所负载的小分子药物与核酸片段可根据使用需求进行灵活调整。

Description

一种多重纳米传递系统及其制备方法
技术领域
本发明涉及一种纳米药物载体，特别涉及一种多重纳米传递系统及其制备方法。
背景技术
基于双亲聚合物的纳米药物传递系统，结合自身长循环、靶向、控缓释、透粘膜、透皮和物理化学响应等优势，可以克服现有药物制剂生物利用度低、稳定性差、药理作用时间短、不良反应严重等缺陷，近年来引起了研究人员的广泛关注。
肿瘤组织结构复杂且增殖迅速，造成了肿瘤组织结构的非均质性和复杂的肿瘤微环境，单一的药物疗法效果有限，长期使用还会引发抗药性问题。药物与基因的联合治疗是目前用于肿瘤以及先天性免疫系统疾病治疗的一种新型有效方法，解决了单一药物疗法存在的先天缺陷。该技术实施的关键是构建合适的能够传递药物和基因的载体以及提高该载体的基因转染效率，进而不仅使药物能够在细胞中发挥作用有效释放，同时基因能够在细胞中获得安全、高效且稳定的表达。传统的纳米载药系统由于材料的功能相对单一，仅能实现药物或者基因等单一传递。实现药物和基因共同专递的多重纳米载药系统，对材料的性能提出了更高的要求，材料的制备难度也更大，复杂而繁琐的合成步骤不可避免。
主客体化学是利用分子间非共价作用力，来构建“即插即用”多重纳米传递系统的一种简单有效的策略。环糊精类化合物生物相容性好，易于修饰，通过结合客体分子非常有利于引入功能化模块，避免了复杂的合成步骤。故此，基于环糊精的主客体化学是构建能够同时传递药物和基因的多重纳米传递系统的优先选择。
发明内容
本发明的目的在于克服现有技术有至少一个不足，提供一种多重纳米传递系统及其制备方法。
本发明所采取的技术方案是：
本发明的第一个方面，提供：
一种多重纳米传递系统的主体分子，其结构通式如式Ⅰ所示：
Figure BDA0002592441330000021
式Ⅰ中，R为靶向基团。
在一些实例中，R为靶向肿瘤的基团。
在一些实例中，特别的，R选自：
Figure BDA0002592441330000022
Figure BDA0002592441330000031
等其他可以靶向肿瘤的基团。
本发明的第二个方面，提供：
一种多重纳米传递系统的主体分子，其制备方法包括如下步骤：
S1)以β-环糊精为起始原料，在碱性条件下开环缩水甘油，得到β-环糊精接枝超支化聚甘油β-CD-HPG；
S2)以二羰基咪唑为偶联试剂，将三(2-氨基乙基)胺链接到β-CD-HPG的羟基上，得到β-环糊精接枝超支化聚甘油接枝三(2-氨基乙基)胺β-CD-HPG-TAEA；
S3)使用靶向试剂对β-CD-HPG-TAEA进行靶向修饰，得到所述主体分子。
在一些实例中，所述靶向试剂为肿瘤靶向试剂。
在一些实例中，所述靶向试剂为异硫氰酸苯基α-D-吡喃甘露糖苷、乳糖酸、叶酸、甘草次酸、生物素等其他可以靶向肿瘤的基团。
在一些实例中，所述β-CD-HPG的制备方法包括：
S11)称取β-环糊精溶于溶剂中，在强碱为催化剂条件下，40～60℃下缓慢滴加缩水甘油，然后升温60～100℃继续反应；
S12)反应完成后体系中加入去离子水终止反应并稀释粗产品，纯化、干燥得到所述β-CD-HPG。
在一些实例中，步骤S11)使用的溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二乙基甲酰胺或N-甲基吡咯烷酮。
在一些实例中，步骤S11)使用的强碱催化剂选自金属钾(K)搭配18-冠-6或氢化钾(KH)搭配18-冠-6。
在一些实例中，步骤S11)物料的摩尔投料比，即β-环糊精：钾或氢化钾：18-冠-6：缩水甘油选自1：(5～10)：(5～10)：(20～2000)。
在一些实例中，β-CD-HPG-TAEA的制备方法包括：
S21)称取一定量的羰基二咪唑溶于DMF中，滴加至β-CD-HPG的DMF溶液中，20～30℃反应；
S22)向反应体系中加入一定量催化用三乙胺，接下来将TAEA的DMF溶液缓慢滴加至反应体系中，继续反应；
S23)反应结束后对水透析，MWCO＝1000，冻干，得到β-CD-HPG-TAEA。
本发明的第三个方面，提供：
一种可与本发明第一个方面或第二个方面所述主体分子发生主客体作用的客体分子，其结构通式如式Ⅱ所示：
Figure BDA0002592441330000041
式Ⅱ中，n为23～115的整数；或按如下方法制备得到：
S41)将盐酸金刚烷胺溶解在无水DMF中，并同时往该溶液中滴加一定量三乙胺，20～30℃反应充分；
S42)向反应体系中加入DSPE-PEG-NHS，继续反应充分，对水透析，MWCO＝1000，冻
干，得到所述客体分子；
在一些实例中，所述客体分子的制备过程中，物料的摩尔投料比，即盐酸金刚烷胺：三乙胺：DSPE-PEG-NHS选自(1～2)：(1～2)：1。
在一些实例中，PEG的聚合度为23～115。
本发明的第四个方面，提供：
一种多重纳米传递系统，由主体分子和客体分子等摩尔比溶解于水中，加入待负载药物，充分搅拌反应，透析、冻干后得到，其中，所述主体分子如本发明第一个方面或第二个方面所述，所述客体分子如本发明第三个方面所述。
在一些实例中，所述药物选自抗肿瘤药物、核酸序列。
本发明的第五个方面，提供：
本发明第四个方面所述的多重纳米传递系统在制备药物载体中的应用。
在一些实例中，所述药物选自抗肿瘤药物、核酸序列。
本发明的有益效果是：
本发明一些实例的主体分子，中间体β-CD-HPG的聚合度可根据使用需要进行灵活调整；同理，中间体β-CD-HPG-TAEA的TAEA接枝率可根据使用需要进行灵活调整；此外，靶向基团的种类以及接枝率，亦可根据使用需要进行灵活调整。
本发明一些实例的客体分子，其PEG链段的分子量也可以根据使用需要进行灵活调整。
本发明一些实例的多重纳米传递系统，不仅仅可同时负载小分子药物(如ICG等)与基因序列(如p53基因)，其所负载的小分子药物与核酸片段可根据使用需求进行灵活调整。
附图说明
图1是实施例1 β-CD-HPG-TAEA-Mannose的核磁谱图；
图2是实施例1 DSPE-PEG-AD的核磁谱图；
图3是实施例1多重纳米传递系统的核磁谱图。
具体实施方式
为了便于理解本发明，下面将对本发明进行更全面的描述。但是，本发明可以以许多不同的形式来实现，并不限于本文所描述的实施例。相反地，提供这些实施例的目的是使对本发明的公开内容的理解更加透彻全面。
除非另有定义，本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本发明。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
实施例1
本实施例一种多重纳米传递系统及其制备方法，包括如下步骤：
(1)在惰性气体保护条件下准确称取5.3mmolβ-环糊精和34.1mmol 18-冠-6，溶于30mL无水DMF中，然后加入42.0mmol KH并持续搅拌使之与环糊精的羟基充分反应。控温50℃，将溶解在10mL无水DMF中的13.4mL缩水甘油缓慢滴加到上述溶液中，约24h滴完。控温80℃继续反应16h结束。待体系温度降至室温后，加少量水终止反应，对水透析(MWCO＝1000)，冻干，得到淡黄色β-CD-HPG固体。
(2)将溶解在10mL无水DMF中的8mmol CDI缓慢滴加入步骤(1)所制备的4mmol β-CD-HPG(溶解于无水DMF中)溶液中，室温下搅拌2h。接着向该体系中加入1mL三乙胺，并缓慢滴加48mmol TAEA(预溶解于5mL无水DMF中)至反应体系中，继续反应24h，对水透析(MWCO＝1000)，冻干，得到β-CD-HPG-TAEA。
(3)将127.7mmol 4-异硫氰酸苯基α-D-吡喃甘露糖苷(Mannose)与步骤(2)所得得117.2mmol β-CD-HPG-TAEA共同溶解在30mL硼砂缓冲液中(pH＝9.0)，室温反应24h，对水透析(MWCO＝1000)，冻干，制得β-CD-HPG-TAEA-Mannose，其核磁谱图见图1。
(4)将117.2mmol盐酸金刚烷胺固体溶解在15mL无水DMF中，滴加1mL三乙胺，室温下搅拌4h后往该体系中加入107.3mmol DSPE-PEG-NHS，继续反应24h，对水透析(MWCO＝1000)，冻干，制得DSPE-PEG-AD，其核磁谱图见图2。
(5)将10.6mmol的步骤(4)所制备的DSPE-PEG-AD分别与步骤(3)中所制备的10.739mmol β-CD-HPG-TAEA-Mannose溶解在去离子水中，50℃条件下反应24h，对水透析(MWCO＝1000)，冻干，得到多重纳米传递系统，其核磁谱图见图3。
实施例2
本实施例一种多重纳米传递系统及其制备方法，包括如下步骤：
(1)在惰性气体保护条件下准确称取5.3mmolβ-环糊精和34.1mmol 18-冠-6，溶于30mL无水DMF中，然后加入42.0mmol KH并持续搅拌使之与环糊精的羟基充分反应。控温50℃，将溶解在20mL无水DMF中的26.8mL缩水甘油缓慢滴加到上述溶液中，约24h滴完。控温80℃继续反应16h结束。待体系温度降至室温后，加少量水终止反应，对水透析(MWCO＝1000)，冻干，得到聚合度更高的主体分子β-CD-HPG固体。
步骤(2)-(5)同实施例1。
实施例3
本实施例一种多重纳米传递系统及其制备方法，包括如下步骤：
将实施例1中步骤(1)、(2)、(4)、(5)保留，去掉靶向甘露糖修饰主体分子的步骤，得到无靶向的多重纳米传递系统。
实施例4
本实施例一种多重纳米传递系统的应用，包括如下步骤：
(1)将20mL吲哚菁绿(ICG,1mg/mL)溶液与20mL实施例1多重纳米传递系统(2mg/mL)溶液在40℃条件下搅拌24h，离心，得到载ICG的纳米传递系统，其ICG的载药量为13.5％。
(2)将7.9μL p53基因序列(1μg/μL)溶液加入至步骤(1)中所制备的载ICG的纳米传递系统溶液中，复合30min，得到同时负载ICG与p53基因的传递系统。
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (12)

1.一种可与主体分子发生主客体作用的客体分子，其结构通式如式Ⅱ所示：
Figure FDA0003143019450000011
式Ⅱ中，n为23～115的整数；
所述主体分子的结构通式如式Ⅰ所示：
Figure FDA0003143019450000012
式Ⅰ中，R为靶向基团，R选自：
Figure FDA0003143019450000021
2.根据权利要求1所述的客体分子，其特征在于：所述客体分子按如下方法制备得到：
S41)将盐酸金刚烷胺溶解在无水DMF中，并同时往该溶液中滴加一定量三乙胺，20～30℃反应充分；
S42)向反应体系中加入DSPE-PEG-NHS，继续反应充分，对水透析，MWCO＝1000，冻干，得到所述客体分子。
3.根据权利要求2所述的客体分子，其特征在于：所述客体分子的制备过程中，物料的摩尔投料比，即盐酸金刚烷胺：三乙胺：DSPE-PEG-NHS选自(1～2)：(1～2)：1。
4.根据权利要求1所述的客体分子，其特征在于：所述主体分子的制备方法包括如下步骤：
S1)以β-环糊精为起始原料，在碱性条件下开环缩水甘油，得到β-环糊精接枝超支化聚甘油β-CD-HPG；
S2)以二羰基咪唑为偶联试剂，将三(2-氨基乙基)胺TAEA链接到β-CD-HPG的羟基上，得到β-环糊精接枝超支化聚甘油接枝三(2-氨基乙基)胺β-CD-HPG-TAEA；
S3)使用靶向试剂对β-CD-HPG-TAEA进行靶向修饰，得到所述主体分子。
5.根据权利要求4所述的客体分子，其特征在于：所述靶向试剂为肿瘤靶向试剂，所述肿瘤靶向试剂选自异硫氰酸苯基α-D-吡喃甘露糖苷、乳糖酸、叶酸、甘草次酸或生物素。
6.根据权利要求4所述的客体分子，其特征在于：所述β-CD-HPG的制备方法包括：
S11)称取β-环糊精溶于溶剂中，在强碱为催化剂条件下，40～60℃下缓慢滴加缩水甘油，然后升温60～100℃继续反应；所述强碱选自金属钾搭配18-冠-6或氢化钾搭配18-冠-6；
S12)反应完成后体系中加入去离子水终止反应并稀释粗产品，纯化、干燥得到所述β-CD-HPG。
7.根据权利要求6所述的客体分子，其特征在于：步骤S11)使用的溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二乙基甲酰胺或N-甲基吡咯烷酮。
8.根据权利要求6所述的客体分子，其特征在于：步骤S11)物料的摩尔投料比，即β-环糊精：钾或氢化钾：18-冠-6：缩水甘油选自1：(5～10)：(5～10)：(20～2000)。
9.根据权利要求4所述的客体分子，其特征在于：β-CD-HPG-TAEA的制备方法包括：
S21)称取一定量的羰基二咪唑溶于DMF中，滴加至β-CD-HPG的DMF溶液中，20～30℃反应；
S22)向反应体系中加入一定量催化用三乙胺，接下来将TAEA的DMF溶液缓慢滴加至反应体系中，继续反应；
S23)反应结束后对水透析，MWCO＝1000，冻干，得到β-CD-HPG-TAEA。
10.一种多重纳米传递系统，由主体分子和客体分子等摩尔比溶解于水中，加入待负载药物，充分搅拌反应，透析、冻干后得到，其中，所述主体分子如权利要求1～9任一项所述，所述客体分子如权利要求1所示。
11.权利要求10所述的多重纳米传递系统在制备药物载体中的应用。
12.根据权利要求11所述应用，其特征在于：所述药物选自抗肿瘤药物、核酸序列。
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1717209A (zh) * 2002-10-09 2006-01-04 植入疗法公司 以环糊精为基础的材料、其相关的组合物和用途
CN105412936A (zh) * 2015-12-23 2016-03-23 中南大学 一种刺激响应型聚吡咯纳米管靶向药物载体及制备方法
CN109395092A (zh) * 2018-10-29 2019-03-01 广东省医疗器械研究所 一种基于主客体相互作用的载体及其应用
CN110064057A (zh) * 2018-01-22 2019-07-30 北京大学 一种透过血脑屏障的载药纳米颗粒的制备及其联合聚焦超声靶向微泡破坏技术的应用
WO2019165149A1 (en) * 2018-02-22 2019-08-29 Wisconsin Alumni Research Foundation Polyplex delivery system for proteins, nucleic acids and protein/nucleic acid complexes
CN110917215A (zh) * 2019-12-04 2020-03-27 陕西佰傲再生医学有限公司 复合体、组织修复材料及其制备方法和应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8697667B2 (en) * 2010-10-18 2014-04-15 Rutgers, The State University Of New Jersey Cyclodextrin-modified polyamines for delivery of therapeutic molecules
CN108339124B (zh) * 2018-01-10 2020-12-22 湖北中医药大学 一种双级脑靶向聚合物胶束递药系统的制备方法和应用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1717209A (zh) * 2002-10-09 2006-01-04 植入疗法公司 以环糊精为基础的材料、其相关的组合物和用途
CN105412936A (zh) * 2015-12-23 2016-03-23 中南大学 一种刺激响应型聚吡咯纳米管靶向药物载体及制备方法
CN110064057A (zh) * 2018-01-22 2019-07-30 北京大学 一种透过血脑屏障的载药纳米颗粒的制备及其联合聚焦超声靶向微泡破坏技术的应用
WO2019165149A1 (en) * 2018-02-22 2019-08-29 Wisconsin Alumni Research Foundation Polyplex delivery system for proteins, nucleic acids and protein/nucleic acid complexes
CN109395092A (zh) * 2018-10-29 2019-03-01 广东省医疗器械研究所 一种基于主客体相互作用的载体及其应用
CN110917215A (zh) * 2019-12-04 2020-03-27 陕西佰傲再生医学有限公司 复合体、组织修复材料及其制备方法和应用

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Chain conformation transition induced host–guest assembly between triple helical curdlan and β-CD for drug delivery;Qingye Liu;《Biomaterials Science》;20200106;全文 *
Fabrication and characterization of hyperbranched polyglycerol modified carbon nanotubes through the host-guest interactions;Hongye Huang;《Materials Science & Engineering C》;20180503;全文 *
Host−Guest Interaction-Based Self-Engineering of Nano-Sized Vesicles for Co-Delivery of Genes and Anticancer Drugs;Bin Yang;《ACS Appl. Mater. Interfaces》;20150923;正文第2页第2栏第2-3段，第4页图2 *

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