CN111269332A - 一种壳聚糖-海藻酸钠水凝胶的制备和应用 - Google Patents
一种壳聚糖-海藻酸钠水凝胶的制备和应用 Download PDFInfo
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Abstract
本发明提供了一种壳聚糖‑海藻酸钠水凝胶的制备和应用,本发明提供的壳聚糖‑海藻酸钠水凝胶作为载药载体,具有合成方法简单、包封率高,交联度高等特点,本发明的载体水凝胶具有对生物体亲和性高的两相基团,海藻酸钠具有抗酸性分解的性能,壳聚糖在酸性环境中自动降解,海藻酸钠使壳聚糖‑海藻酸钠水凝胶能够在偏酸性条件会缓慢解链释放里面载的药物,提高药物的作用时间和作用效果,预示其作为一种新的载药载体水凝胶具有广泛的实质性应用。
Description
技术领域
本发明涉及一种壳聚糖-海藻酸钠水凝胶的制备和应用,属于医药领域。
背景技术
药物传递系统是指通过不同给药形式改善药物治疗效果的药物制剂。通常传统的剂型,如注射剂、片剂、胶囊剂等,由于其有效浓度维持时间短的缺陷,已无法满足临床治疗的需求。为克服该缺陷,新型药物传递系统如水凝胶载药引起了科研工作者广泛的关注。
水凝胶聚合物载体降解后的产物分子量低于肾脏的排泄限制(<30kDa),安全性得到提高。其中壳聚糖和海藻酸钠特别值得指出的性质是其生物亲和性和生物可吸收性。也就是说,当把它植入生物体内后,引起的生物组织反应小,且可被组织中的酶慢慢吸收。
根据水凝胶对外界刺激的响应情况可分为传统的水凝胶和环境敏感的水凝胶两大类。传统的水凝胶对环境的变化如温度或pH等的变化不敏感,而环境敏感的水凝胶是指自身能感知外界环境(如温度、pH、光、电、压力等)微小的变化或刺激,并能产生相应的物理结构和化学性质变化。此类凝胶的突出特点是在对环境的响应过程中其溶胀行为有显著的变化,利用这种刺激响应特性可将其用做传感器、控释开关等。
为了解决药物在肿瘤部位的作用时间和作用效果,设计一类能缓慢释放肿瘤药物的高生物亲和性水凝胶具有重要的实际价值。
发明内容
本发明涉及一种壳聚糖-海藻酸钠水凝胶的制备和应用,本发明提供的壳聚糖-海藻酸钠水凝胶为载药载体,具有合成方法简单、操作方便、可以包封和输送富含吸电子基团的抗肿瘤药物、提高药物的靶向性、减缓药物的释放速率来提高药物的疗效。该载药壳聚糖-海藻酸钠水凝胶本身具有容易在生物体内安全无毒能降解的疏水基团和亲水基团,可以作为一种新的水凝胶载药载体,对治疗肿瘤有非常重要的实用价值。
本发明一目的是提供一种壳聚糖-海藻酸钠水凝胶的制备。
本发明再一目的是提供了一种壳聚糖-海藻酸钠水凝胶载药的应用,所述药物为富含吸电子基团的抗肿瘤药物,所述肿瘤细胞为PC3前列腺癌细胞和HepG2肝癌细胞。
本发明再一目的是提供了一种壳聚糖-海藻酸钠水凝胶的应用,所述壳聚糖-海藻酸钠水凝胶中的海藻酸钠具有抗酸性分解的性能,而壳聚糖在酸性环境中自动降解,海藻酸钠的存在使得壳聚糖-海藻酸钠水凝胶能够在酸性条件下缓慢解开交联链,达到缓慢释放药物的效果。
一种壳聚糖-海藻酸钠水凝胶的制备,其制备方法为:
(1)4.0g式(Ⅱ)溶于100mL去离子水中,然后放入30℃的水浴锅中磁力搅拌,待式(Ⅱ)全部分散于水中,逐滴加入2mL冰醋酸溶液,10分钟后,400μL式(Ⅲ)加入上述壳聚糖溶液中,30℃下继续搅拌8~10h,反应结束后将得到的溶液(Ⅳ)透析48小时,每8小时换一次水(透析袋截留分子量为10000),最后将透析袋里溶液真空冷冻干燥得到产物式(Ⅳ)。
(2)2.5g式(Ⅴ)溶于100mL去离子水中,然后放入30℃的水浴锅中磁力搅拌,全部分散于水中,逐滴加入0.5g DCC,30℃搅拌半小时,然后加入式(Ⅳ)2.0g,60℃反应8小时,反应结束后将得到的溶液透析48小时,每8小时换一次水(透析袋截留分子量为10000),最后将透析袋里溶液真空干燥成蓝色固体式(Ⅰ)。
有益效果:本发明提供了一种壳聚糖-海藻酸钠水凝胶的制备和应用,本发明提供的聚合物作胞内囊泡室的酸性环境中(pH值6~6.5)则变得不稳定。壳聚糖的酸易分解性和为载药载体,在细胞外基质微环境中(pH值7~7.5)中保持稳定,而当其被肿瘤细胞内吞后,在细海藻酸钠的耐酸性使得水凝胶在肿瘤细胞内解链速度变缓,使得里面的药物被缓慢释放出来,延长了药物的作用时间和作用效果,本发明的壳聚糖-海藻酸钠水凝胶本身具备无毒性,可以包封和输送富含吸电子基团的抗肿瘤药物、提高药物的靶向性、减缓药物的释放速率来提高药物的疗效,在小鼠实体肿瘤实验中,载奈达铂壳聚糖-海藻酸钠水凝胶后对HepG2肿瘤抑制效果比单纯注射奈达铂高60%,通过临界胶束浓度计算,药物负载量很大,药物负载效率较高。此外,该聚合物直径在120nm级,是一种优秀的纳米载药载体,综合以上,本发明提供的该壳聚糖-海藻酸钠水凝胶可作为抗肿瘤药物的理想载体,对癌症的治疗具有商业价值和科学研究意义。
下面将结合本发明实施例的技术方案进行清楚、完整地描述。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
附图说明
图1为TEM捕获壳聚糖-海藻酸钠水凝胶的形貌图片。
图2为DLS测定壳聚糖-海藻酸钠水凝胶的尺寸大小分布图。
图3为载奈达铂壳聚糖-海藻酸钠水凝胶(1~50mg/mL)与PC3前列腺癌细胞和Hacat表皮细胞的细胞毒性柱状图。
图4为壳聚糖-海藻酸钠水凝胶(1~50mg/mL)与PC3前列腺癌细胞和Hacat表皮细胞的细胞毒性柱状图。
具体实施例子
实施例1
壳聚糖-海藻酸钠水凝胶的合成方法:
(1)4.0g式(Ⅱ)溶于100mL去离子水中,然后放入30℃的水浴锅中磁力搅拌,待式(Ⅱ)全部分散于水中,逐滴加入2mL冰醋酸溶液,10分钟后,400μL式(Ⅲ)加入上述壳聚糖溶液中,30℃下继续搅拌8~10h,反应结束后将得到的溶液(Ⅳ)透析48小时,每8小时换一次水(透析袋截留分子量为10000),最后将透析袋里溶液真空冷冻干燥得到产物式(Ⅳ)。
(2)2.5g式(Ⅴ)溶于100mL去离子水中,然后放入30℃的水浴锅中磁力搅拌,全部分散于水中,逐滴加入0.5g DCC,30℃搅拌半小时,然后加入式(Ⅳ)2.0g,60℃反应8小时,反应结束后将得到的溶液透析48小时,每8小时换一次水(透析袋截留分子量为10000),最后将透析袋里溶液真空干燥成蓝色固体式(Ⅰ)。
实施例2
载奈达铂壳聚糖-海藻酸钠水凝胶的制备
奈达铂被包封到壳聚糖-海藻酸钠水凝胶的交联网中。50mg壳聚糖-海藻酸钠水凝胶,10mg奈达铂溶于体积比为1:9的二甲亚砜/水的体系中,在室温下搅拌24小时脱盐后,将其缓慢滴加到大量超纯水(500mL)中,然后在室温下快速搅拌1小时后。将溶液用超纯水透析,并通过0.45μm针式过滤器过滤,以获得载奈达铂水凝胶。
实施例3
载奈达铂壳聚糖-海藻酸钠水凝胶的药物负载量(DLC)和药物负载效率(DLE)
形貌:将一滴水凝胶溶液均匀地滴在有碳膜的铜网上,然后待其在室温下干燥后,用TEM去捕获胶束的形貌图片。粒径:用DLS测定胶束的平均尺寸和尺寸分布。图1为TEM捕获载奈达铂壳聚糖-海藻酸钠水凝胶的形貌图片,图2为DLS测定载奈达铂壳聚糖-海藻酸钠水凝胶的尺寸大小分布图。
药物负载量(DLC)和药物负载效率(DLE):将载奈达铂壳聚糖-海藻酸钠水凝胶冷冻后得到成淡黄色固体粉末,将粉末溶解在甲醇中,重复制备4批载奈达铂壳聚糖-海藻酸钠水凝胶,通过UV-vis记录488nm处的吸光度值。同样,制备梯度DOX溶液,重复制备4批载奈达铂壳聚糖-海藻酸钠水凝胶,并将获得的吸光度值绘制成标准工作曲线以计算载药水凝胶的DLC和DLE。下表1为载药水凝胶包封率和载药量测量结果。
DLC%=(水凝胶中DOX的质量/聚合物的质量)×100% (1)
DLE%=(水凝胶中DOX的质量/DOX投料的质量)×100% (2)
表1:壳聚糖-海藻酸钠水凝胶包封率和载药量测量
批次 | 1 | 2 | 3 | 4 |
包封率% | 62.8 | 64.2 | 63.6 | 61.9 |
载药量% | 12.65 | 12.03 | 12.74 | 12.96 |
实施例4
载奈达铂壳聚糖-海藻酸钠水凝胶的细胞毒性实验
细胞培养:将PC3前列腺癌细胞和HepG2肝癌细胞接种于细胞培养瓶中放于37℃,5%CO2环境中培养,培养基选用含10%胎牛血清和0.5%的双抗的1640培养基。细胞接种:将培养的细胞接种于96孔板中,细胞密度为8000个/mL,继续在37℃,5%CO2环境中培养48h。加梯度化合物溶液:去除96孔板中的培养基,用预冷的PBS洗涤3次,加入含不同梯度载奈达铂壳聚糖-海藻酸钠水凝胶的1640完全培养基,继续在37℃,5%CO2环境中培养24h。加MTT溶液:去除96孔板中的培养基,加入用完全培养基稀释成5mg/ml的MTT溶液每个孔200μL,用锡纸包裹继续培养4小时后,除去溶液,加入DMSO 100μL,充分溶解附着在96孔板中的甲臜。测量细胞存活率:将96孔板转移到酶标仪中,设定扫描波长为577nm,测量其吸光度,然后根据吸光度的数值来确定细胞存活率。
图3为载奈达铂壳聚糖-海藻酸钠水凝胶(1~50mg/mL)与PC3前列腺癌细胞和HepG2肝癌细胞的细胞毒性柱状图。本发明的载奈达铂壳聚糖-海藻酸钠水凝胶快速穿透细胞膜,将药物带入肿瘤细胞内,在肿瘤偏酸性条件下水凝胶缓慢解链,使得药物作用肿瘤时间变长,达到杀死肿瘤细胞的目的。
实施例5
壳聚糖-海藻酸钠水凝胶浸提液对细胞的毒性测试
首先将正常表皮细胞Hacat和前列腺癌细胞PC3种植在96孔板内,密度为104个/孔,每孔含200μL的完全培养基。将上述培养板置于二氧化碳培养箱(37℃,5%CO2)中培养24h待细胞贴壁后,吸弃旧的培养基,向每孔分别加入200μL的壳聚糖-海藻酸钠水凝胶浸提液,放入CO2培养箱中继续孵育。在预定时间点取出培养板,吸弃旧的培养基,用PBS清洗两次,然后每孔加360μL不含血清的DMEM细胞培养基和40μL MTT,放入培养箱继续培养4h。当细胞与MTT充分反应后,吸去培养基,每孔加入400μL的DMSO,避光37℃条件下震荡30min,使沉淀完全溶解。然后用酶标仪在577nm波长下检测吸光值,每个样品重复三次。
图4为壳聚糖-海藻酸钠水凝胶(1~50mg/mL)与PC3前列腺癌细胞和Hacat表皮细胞的细胞毒性柱状图。本发明的壳聚糖-海藻酸钠水凝胶在不载药物的条件下,自身对肿瘤细胞和正常细胞都没有细胞毒性,表明该壳聚糖-海藻酸钠水凝胶自身无毒。
实施例6
动物抗肿瘤分析
实验选取五周大的雄性小鼠进行右前肢皮下注射HepG2细胞,对药递送系统的体内抗肿瘤效果进行了测试研究。注射HepG2癌细胞后,当小鼠的肿瘤体积达到约100mm3时,将小鼠称重并随机分为5组(每组5只小鼠)进行后续动物实验。组别为PBS(100μL,pH 7.4),纯可注射壳聚糖-海藻酸钠水凝胶(200mg/kg),纯可注射壳聚糖-海藻酸钠水凝胶(400mg/kg),载奈达铂壳聚糖-海藻酸钠水凝胶(200mg/kg),载奈达铂壳聚糖-海藻酸钠水凝胶(400mg/kg)。将水凝胶准确注入到肿瘤组织周围并包围肿瘤以获得最大的治疗效果。实验过程中,每2天用游标卡尺对小鼠肿瘤进行体积大小测量,肿瘤体积计算公式为V=L×W2/2,其中L为最长肿瘤直径,W是垂直于L的最短肿瘤直径。
Claims (5)
1.一种壳聚糖-海藻酸钠水凝胶的制备,其特征在于:所述的壳聚糖-海藻酸钠水凝胶由壳聚糖、2,3-二羟基丙醛、海藻酸钠合成:
所述壳聚糖-海藻酸钠水凝胶结构式如式(Ⅰ)所示:
其中,n=100~200;m=50~100;
所述壳聚糖结构式如(Ⅱ)所示;
其中,n=100~200;
所述海藻酸钠的结构式如式(Ⅴ)所示:
其中,m=50~100;
所述2,3-二羟基丙醛的结构式如式(Ⅲ)所示:
所述壳聚糖-海藻酸钠水凝胶的合成步骤为:
(1)将式(Ⅱ)结构的化合物与式(Ⅲ)结构化合物反应,得到式(Ⅳ)结构的如下化合物:
其中,n=100~200;
式(Ⅳ)结构化合物反应:4.0g式(Ⅱ)溶于100mL去离子水中,然后放入30℃的水浴锅中磁力搅拌,待式(Ⅱ)全部分散于水中,逐滴加入2mL冰醋酸溶液,10分钟后,400μL式(Ⅲ)加入上述壳聚糖溶液中,25~35℃下继续搅拌8~10h,反应结束后将得到的溶液(Ⅳ)透析48小时,每8小时换一次水(透析袋截留分子量为10000),最后将透析袋里溶液真空冷冻干燥得到产物式(Ⅳ);
(2)将式(Ⅳ)结构的化合物与式(Ⅴ)反应,得到式(Ⅰ)结构的化合物:
式(Ⅰ)结构化合物反应:2.5g式(Ⅴ)溶于100mL去离子水中,然后放入30℃的水浴锅中磁力搅拌,全部分散于水中,逐滴加入0.5g DCC,20~40℃搅拌半小时,然后加入式(Ⅳ)2.0g,50~70℃反应8小时,反应结束后将得到的溶液透析48小时,每8小时换一次水(透析袋截留分子量为10000),最后将透析袋里溶液真空干燥成蓝色固体式(Ⅰ)。
2.根据权利要求1所述的一种壳聚糖-海藻酸钠水凝胶的制备,其特征在于:所述壳聚糖-海藻酸钠水凝胶的合成步骤优选为:
(1)将式(Ⅱ)结构的化合物与式(Ⅲ)结构化合物反应,得到式(Ⅳ)结构的化合物:
式(Ⅳ)结构化合物反应:4.0g式(Ⅱ)溶于100mL去离子水中,然后放入30℃的水浴锅中磁力搅拌,待式(Ⅱ)全部分散于水中,逐滴加入2mL冰醋酸溶液,10分钟后,400μL式(Ⅲ)加入上述壳聚糖溶液中,30℃下继续搅拌8~10h,反应结束后将得到的溶液(Ⅳ)透析48小时,每8小时换一次水(透析袋截留分子量为10000),最后将透析袋里溶液真空冷冻干燥得到产物式(Ⅳ);
(2)将式(Ⅳ)结构的化合物与式(Ⅴ)反应,得到式(Ⅰ)结构的化合物:
式(Ⅰ)结构化合物反应:2.5g式(Ⅴ)溶于100mL去离子水中,然后放入30℃的水浴锅中磁力搅拌,全部分散于水中,逐滴加入0.5g DCC,30℃搅拌半小时,然后加入式(Ⅳ)2.0g,60℃反应8小时,反应结束后将得到的溶液透析48小时,每8小时换一次水(透析袋截留分子量为10000),最后将透析袋里溶液真空干燥成蓝色固体式(Ⅰ)。
3.一种壳聚糖-海藻酸钠水凝胶的应用,其特征在于:所述壳聚糖-海藻酸钠水凝胶作为富含吸电子基团抗癌药的载药体。
4.根据权利要求3所述一种壳聚糖-海藻酸钠水凝胶的应用,其特征在于:所述壳聚糖-海藻酸钠水凝胶能抗酸降解,缓慢释放药物。
5.根据权利要求3所述一种壳聚糖-海藻酸钠水凝胶的应用,其特征在于:所述的富含吸电子基团抗癌药为长春碱,阿霉素。
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