CN114642652A - 一种岩藻多糖自组装载药纳米粒制备及应用 - Google Patents
一种岩藻多糖自组装载药纳米粒制备及应用 Download PDFInfo
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Abstract
本发明提供了一种岩藻多糖自组装载药纳米粒的制备方法及其在预防肾损伤中的应用。所述制备方法为在岩藻多糖上通过化学键连接难溶性疏水药物,通过自组装再包载疏水性药物,得自组装纳米粒子,具体为:将岩藻多糖粉末加入到适量去离子水中,超声辅助溶解,搅拌,得到10mg/ml的岩藻多糖溶液,将疏水性药物溶于微量乙醇中(乙醇与水的体积比为1:10~1:20),使用反溶剂法将疏水性药物滴加到岩藻多糖溶液中制备自组装纳米粒,使用溶剂挥发法搅拌挥干乙醇即可得到pH在6~7,粒径在150nm左右,载药量最高可达60%的纳米粒。本发明以具有良好生物相容性的岩藻多糖为运输载体,得到了含阿魏酸、咖啡酸、高聚原花青素等疏水性药物的自组装纳米粒。本方法所选择的载体材料本身具有功能性,可以提高药物稳定性,减少用药量和毒性。本发明操作简单,设备简单,适合于工业化生产,有很好的社会价值和应用前景。
Description
技术领域
本发明涉及生物材料与纳米技术领域,具体涉及疏水性药物自组装成纳米药物的制备方法和应用。
背景技术
纳米载体能通过增加难溶性活性成分的分散度和溶出表面积而增加溶解度,通过小粒径效应改善透膜能力,提高生物利用度,并实现在体内的可控释放。可以解决某些疏水性的药物生物利用度低的问题,同时扩大某些疏水性药物的应用范围。
反溶剂法是利用药物在两种不同溶剂中的溶解度不同来制备纳米粒,先将药物溶于良溶剂中,随后向不良溶剂混合,混合时会在不良溶剂里产生局部过饱和状态,从而引发成核、核增长,聚结和聚集等现象,最终聚沉形成纳米粒。该方法操作简单、反应条件温和。
岩藻多糖(Fucoidan,FU)是在褐藻的细胞壁中广泛发现的一系列复杂的硫酸化多糖,岩藻多糖的结构极其复杂,主要由L-岩藻糖组成。具有抗凝血、抗肿瘤、抗血栓、抗病毒、抗氧化和增强机体免疫机能等多种生物活性,具有良好的生物相容性,而且还可以运载疏水性活性物质,是一种良好的载药纳米粒子构建材料。
阿魏酸(4-羟基-3-甲氧基肉桂酸,Fenilic acid,FA),存在于中药材当归和川芎中,具有广泛的药理作用。FA作为一种强效抗氧化剂,可以通过清除自由基和上调细胞保护系统来增强细胞应激反应。阿魏酸和大多数酚类化合物一样,在体外很容易被氧化降解,通过与岩藻多糖的相互作用,阿魏酸-岩藻多糖纳米粒的构建,极大的增强了阿魏酸在肝肾损伤方面的保护能力。
咖啡酸(caffeic acid,CA),又称“3,4-二羟基肉桂酸”或“3,4-二羟基苯丙烯酸”,是一种具有羟基苯烯酸结构的天然酚类化合物。CA除了应用在食品领域,还具有升高白细胞、血小板以及抗氧化、抗炎、抗癌、调节DNA甲基化水平等多种药理活性,通过与岩藻多糖的相互作用,咖啡酸-岩藻多糖纳米粒的构建,极大的增强了咖啡酸在抗肿瘤方面的应用。
原花青素具有多种生物活性,包括清除自由基离子、抗炎症、抗菌、促进癌细胞凋亡、保护心脑血管、抗糖尿病、抗肥胖、抗抑郁等。极强的自由基离子清除能力赋予了原花青素生物活性发挥的基础,但是高聚原花青素由于其过高的聚合度导致其所具有极低的抗氧化能力以及在水中的溶解度。岩藻多糖-高聚原花青素纳米粒的构建,可以极大的提高高聚原花青素的抗氧化能力以及其在免疫增强方面的应用。
作为一种天然聚合物,纯岩藻多糖基自组装纳米粒的构建不需要其他可能存在安全隐患的辅料,还可以提高药物的吸收,减少给药刺激性,具有很好的经济前景。
发明内容
本发明为一种对人体无毒性,无刺激性,生物相容性好,生物降解性好的载药纳米载体的构建。
本发明所要解决的技术问题是提供一种岩藻多糖自组装载药纳米粒及其制备方法,该方法制备简单,适合于工业化生产。
本发明中的岩藻多糖自组装载药纳米粒由岩藻多糖与疏水性药物如阿魏酸相互作用在水中自发组装形成。
所述纳米粒中岩藻多糖与药物(如咖啡酸)的最高质量比为10:1
所述纳米粒中岩藻多糖与药物(如阿魏酸)的最高质量比为10:3
所述纳米粒中岩藻多糖与药物(如高聚原花青素)的质量比为5:3
本发明的一种岩藻多糖自组装载药纳米粒的制备方法,包括:
1)将200mg岩藻多糖加入到20ml的去离子水中,超声2min溶解后,以500r/min 速度搅拌2h;将20mg的阿魏酸溶解于1ml的无水乙醇中,超声溶解,得到均匀溶液;
2)使用反溶剂沉淀法,在700r/min搅拌速度下,使用注射器将阿魏酸-乙醇溶液逐滴滴入到岩藻多糖-水溶液中;
3)滴加结束后,继续在500r/min下搅拌1h即得岩藻多糖-阿魏酸自组装纳米颗粒;
4)使用溶剂挥发法,在500r/min以下的转速下,继续搅拌2h即可挥干乙醇;
5)220nm微孔滤膜过滤匀化粒径。
上述岩藻多糖自组装载药纳米粒的制备方法,制得的载药纳米粒平均粒径为136nm。
本发明制备的自组装载药纳米粒降低了阿魏酸、高聚原花青素等疏水性药物的给药刺激性、还提高了药物的吸收、减少了给药次数、增加了药物的生物相容性,具有良好的经济效益。
本发明与现有技术相比具有以下优点:本发明采用以上技术方案,用纯天然聚合物岩藻多糖为运输载体,有效地改善了阿魏酸和高聚原花青素的水溶性。该方法操作方便,简单易行,制得的纳米颗粒粒径小,载药效率高,稳定性好,提高了阿魏酸和高聚原花青素的利用度。更重要的是解决了传统纳米载体潜在毒性,为纳米技术在药物的运输方面提供了新途径。
附图说明
图1为阿魏酸、岩藻多糖、阿魏酸-岩藻多糖SEM ;图1-1阿魏酸扫描电子显微镜分析图;图1-2岩藻多糖扫描电子显微镜分析图;图1-3岩藻多糖-阿魏酸扫描电子显微镜分析图
图2为肾损伤后小鼠体重变化,顺铂-肾损伤小鼠体重变化
图3为肾损伤小鼠体内尿素氮含量变化情况,顺铂-肾损伤小鼠体重变化情况。
具体实施方式
下面结合具体实施案例对本发明所述的技术方案做进一步阐述,但本发明不限于此。
实施例1
阿魏酸-岩藻多糖自组装纳米粒的制备
精确称取岩藻多糖粉末0.200g,将其溶于20ml去离子水中,超声2min溶解, 500r/min速度搅拌2h,待用;精确称取阿魏酸粉末0.020g,将其溶于1ml的乙醇中,超声1 min溶解,在700r/min搅拌速度下,使用注射器将阿魏酸-乙醇溶液逐滴滴入到岩藻多糖-水溶液中;滴加结束后,继续在500r/min下搅拌1h即得岩藻多糖-阿魏酸自组装纳米颗粒;使用溶剂挥发法,在500r/min以下的转速下,继续搅拌2h即可挥干乙醇,220nm微孔滤膜过滤匀化粒径。得到的阿魏酸-岩藻多糖自组装纳米粒溶液的平均粒径为136nm。
实施例2
顺铂导致小鼠肾损伤后体重的变化情况
将小鼠随机分为以下八组(n=6每组):对照组(生理盐水);阿魏酸(100mg/kg);顺铂(20mg/kg)+生理盐水;顺铂(20ng/kg)+岩藻多糖;顺铂(20ng/kg)+阿魏酸(50mg/kg);顺铂(20ng/kg)+阿魏酸(100mg/kg);顺铂(20ng/kg)+阿魏酸-岩藻多糖纳米粒(50mg/kg);顺铂(20ng/kg)+阿魏酸-岩藻多糖纳米粒(100mg/kg);得到了给药前和处死前的体重变化情况如图3.
实施例3
肾脏损伤后小鼠血清尿素氮含量变化
尿素是小鼠体内蛋白代谢的最终产物,血中尿素氮来源于肝脏,通过肾脏随尿液排出体外。肾脏功能衰竭、肾炎、泌尿道梗阻可使血液尿素氮含量升高。通过检测小鼠血清尿素氮含量变化情况,进一步显示阿魏酸-岩藻多糖纳米粒的治疗潜力。
Claims (4)
1.一种岩藻多糖自组装载药纳米粒的制备方法,其特征在于,所述的纳米粒是由疏水性药物通过反溶法自组装而成。
2.根据权利要求1所述的岩藻多糖自组装纳米粒子的制备方法,其特征在于:所述疏水性药物为阿魏酸、咖啡酸、高聚原花青素。
3.如权利要求1所述的制备方法,其特征在于,所述的疏水性药物为阿魏酸。
4.一种岩藻多糖自组装载药纳米粒的制备方法,其特征在于,包括下列步骤:
1)将200mg岩藻多糖加入到20ml的去离子水中,超声2min溶解后,以500r/min速度搅拌2h;将20mg的阿魏酸溶解于1ml的无水乙醇中,超声溶解,得到均匀溶液;
2)使用反溶剂沉淀法,在700r/min搅拌速度下,使用注射器将阿魏酸-乙醇溶液逐滴滴入到岩藻多糖-水溶液中;
3)滴加结束后,继续在500r/min下搅拌1h即得岩藻多糖-阿魏酸自组装纳米颗粒;
4)使用溶剂挥发法,在500r/min以下的转速下,继续搅拌2h即可挥干乙醇;
5)220nm微孔滤膜匀化粒径。
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