CN113018455A - 一种透明质酸修饰的负载疏水药物的纳米载体及其制备方法和应用 - Google Patents
一种透明质酸修饰的负载疏水药物的纳米载体及其制备方法和应用 Download PDFInfo
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Abstract
本发明提供了一种透明质酸修饰的负载疏水药物的纳米载体及其制备方法和应用,该方法基于腺嘌呤和金属离子的配位自组装特性构建药物负载率高、生物相容性好的纳米载体。其次,通过静电吸附作用将透明质酸修饰在纳米载体的表面形成复合纳米载体,赋予载药体系优异的分散性、稳定性和癌细胞靶向性,提高肿瘤细胞对负载药物的摄取。本发明所述方法制备不仅过程温和,材料均为生物可降解,且来源广泛,可负载药物的种类宽泛,对药物分子在治疗领域中的发展和应用具有重要意义。
Description
技术领域
本发明属于生物材料技术领域,特别涉及一种透明质酸修饰的负载疏水药物的纳米载体及其制备方法和应用。
背景技术
腺嘌呤(Adenine)是从生物质中获得的核碱基之一,其H键结合能力和分子结构的刚性使其成分理想的构建生物框架的分子。Zn2+和Adenine配位自组装可构建3D多孔骨架,该多孔骨架通过Zn2+与Adenine的N1、N3、N7和N9配位,组成由共享顶点延伸的多面体框架,具有稳定特性和独特的吸附功能,可以用于储存敏感药物分子。
但实际上,Zn2+和Adenine配位自组装形成的多孔骨架分散性差,难以在药物运输中进行实际的应用。
因此,如何增加Zn2+和Adenine配位自组装构造的分散性,使其应用于药物运输中,是目前需要解决的一个问题。
发明内容
针对现有技术中存在的问题,本发明的目的在于提供一种透明质酸修饰的负载疏水药物的纳米载体及其制备方法和应用,利用透明质酸的修饰增加载药体系的分散度,并减少纳米颗粒在正常组织处的蓄积,实现癌细胞靶向给药。
本发明的目的是通过以下技术方案实现的:
一种透明质酸修饰的负载疏水药物的纳米载体的制备方法,包括以下步骤:
步骤1,Zn-Adenine纳米颗粒的制备:将Zn2+和Adenine(腺嘌呤)的水溶液、疏水药物的乙醇溶液在缓冲溶液中,通过一锅法制备得到负载药物的Zn-Adenine纳米颗粒,记为Drug@(Zn-Adenine);
步骤2,透明质酸的修饰:将步骤1制备得到的Drug@(Zn-Adenine)纳米颗粒离心收集,而后和透明质酸分别溶解在去离子水中,在搅拌过程中通过静电吸附作用形成均一的溶液;
步骤3,纯化处理:将步骤2中所得溶液离心处理,并用去离子水洗涤底部沉淀,从而得到透明质酸修饰的Drug@(Zn-Adenine)纳米颗粒,记为Drug@(Zn-Adenine)@HA,即所述透明质酸修饰的基于Zn2+和Adenine配位自组装的纳米药物载体。
进一步的,所述疏水药物包括光甘草定、喜树碱、紫杉醇。
进一步的,步骤1中Zn2+来源于含锌离子的试剂,优选为六水合硝酸锌。
进一步的,步骤1中所述缓冲液为HEPES缓冲溶液;优选的,所述HEPES缓冲溶液的体积分数为62.5%,浓度为50mM,pH为7.4。
进一步的,步骤1中Zn2+和Adenine的质量比为(5~15):1;所述疏水药物和Adenine的质量比为(1~5):1。
进一步的,步骤2中所述透明质酸的分子量MW<150 KDa,优选的,所述透明质酸的分子量MW=100 KDa。
进一步的,步骤2中所述透明质酸与Drug@(Zn-Adenine)纳米颗粒两者之和的质量浓度为15%~25%。
进一步的,步骤2中产生静电吸附的搅拌条件为600~1000 rpm/min,3~5小时。
进一步的,步骤2中静电吸附作用的搅拌条件为600~1000rpm/min,3~5小时;优选的,搅拌条件为800rpm/min,4小时。
本发明的另一方面:
一种透明质酸修饰的负载疏水药物的纳米载体,所述纳米载体由上述制备方法制备得到。
所述纳米载体的应用,其中,所述纳米载体科应用于制备药物。
本发明相比现有技术的有益效果为:
1、本发明所述透明质酸修饰的负载疏水药物的纳米载体的制备方法,利用了配位自组装技术,首次成功制备了锌离子和腺嘌呤金属-生物分子框架,并作为药物载体负载疏水药物;
2、本发明采用静电吸附作用,利用透明质酸修饰负载疏水药物的纳米载体,使得到的溶液分散性高,从而大大提高所负载药物的稳定性;同时当所述纳米载体负载的药物具有癌细胞靶向性时,还能够提高肿瘤组织的药物摄取量,进一步提高抗癌作用;
3、本发明所述透明质酸修饰的负载疏水药物的纳米载体的制备方法,制备条件温和,全程无高温,减少了药物在制备过程中的损失,提高了药物包埋率和载药率;
4、本发明所述透明质酸修饰的负载疏水药物的纳米载体的制备方法中,使用的材料均为生物可降解材料,生物相容性理想。
附图说明
下面结合附图和实施例对本发明作进一步说明:
图1为本发明实施的一种透明质酸修饰的负载疏水药物的纳米载体的制备流程图;
图2为Cur@(Zn-Adenine)(图2A)和透明质酸修饰的纳米载药颗粒(图2B)Cur@(Zn-Adenine)@HA的透射电镜图;
图3为Cur的标准曲线;
图4为纳米载体负载姜黄素和游离姜黄素的pH稳定性图;
图5为空白载体Zn-Adenine、(Zn-Adenine)@HA对A549细胞作用72 h后的细胞存活率折线图;
图6为负载姜黄素的载体Cur@(Zn-Adenine)、Cur@(Zn-Adenine)@HA和游离姜黄素对A549细胞作用72 h后的细胞存活率柱状图。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合附图及实施例,对本发明进行进一步的详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定发明。
实施例中所用原料均为常规原料,市购产品。其中,腺嘌呤(Adenine,M=135.13):百灵威化学技术有限公司;透明质酸(HA,MW=100KD):华熙福瑞达生物医药有限公司;姜黄素(Cur,M=368.39):韶远化学技术(上海)有限公司。
A549细胞为人非小细胞肺癌细胞,为肿瘤细胞,为普通市购产品。
CCK-8全称为2-(2-甲氧基-4-硝基苯基)-3-(4-硝基苯基)-5-(2,4-二磺酸苯)-2H-四唑单钠盐,购自美国Sigma-Aldrich公司。
实施例1
本实施例提供了一种透明质酸修饰的负载姜黄素的纳米载体,如图1所示其制备方法为:
各溶液的配置:分别配置姜黄素(Cur, Curcumin)乙醇溶液(2 mg / mL Cur)、HEPES缓冲溶液、Zn(NO3)2·6H2O水溶液(50 mM)、Adenine水溶液(10 mM)、HA水溶液(1 mg /mL);
其中所述HEPES缓冲溶液:由4-羟乙基哌嗪乙磺酸配制的缓冲溶液,体积浓度为62.5%,浓度为50mM,pH为7.4。
步骤1,Cur@(Zn-Adenine)纳米颗粒的制备:将4 mL Adenine水溶液、4 mL Cur乙醇溶液、4 mL Zn(NO3)2·6H2O水溶液按顺序加入20 mL HEPES缓冲液中,将混合物在黑暗中强力搅拌(800 rpm/min)2 h;将混合物离心收集,用去离子水洗涤底部沉淀物三次得到负载药物的纳米颗粒,记为Cur@(Zn-Adenine),收集用于下一步反应或冷冻干燥备用。
步骤2,透明质酸的修饰:将步骤1收集的Cur@(Zn-Adenine)分散在5 mL去离子水中,然后倒入装有20 mL HA溶液的小烧杯中,避光处理,剧烈搅拌4 h,搅拌条件为800rpm/min,在搅拌过程中通过静电吸附作用形成均一的溶液。
步骤3,纯化处理:将步骤2中所得溶液离心30min去除未连接的HA,并用去离子水洗涤底部沉淀物3次以得到透明质酸修饰的纳米颗粒,记为Cur@(Zn-Adenine)@HA。
采用透射电镜(型号:HT7700)观察本实施例制备的纳米载药颗粒Cur@(Zn-Adenine)和透明质酸修饰的纳米载药颗粒Cur@(Zn-Adenine)@HA,结果如图2所示,从图中可以看到HA修饰之后的纳米颗粒分散性显著提高。
实施例2——透明质酸修饰的负载姜黄素的纳米载体包埋率和载药率
Cur标准曲线的建立:
准确称取10 mg Cur于10 mL容量瓶中,用乙醇溶解并稀释至刻度线处,配制浓度为1 mg/mL的标准液,然后依次梯度稀释至1、2、3、4、5 μg/mL,用UV检测Cur标准溶液,检测波长为428 nm。以浓度为纵坐标,吸光值为横坐标作线性回归标准曲线,Cur的标准曲线如图3所示,模拟得到的回归方程为y = 0.1568x+ 0.0296 (R2 = 0.9993)。
称取0.5 mg实施例1制备的透明质酸修饰的负载姜黄素的纳米载体于1 mL乙醇,于超声波清洗机中超声1 h至纳米颗粒完全溶解后,加入1 mL乙醇稀释,取上清液于428 nm的波长下进行紫外检测。
透明质酸修饰的负载姜黄素的纳米载体的包埋率和载药率计算公式为:
包埋率(%)=纳米颗粒中Cur的含量/加入的Cur的总量×100%。
载药率(%)=纳米颗粒中Cur的含量/加入的纳米颗粒的总量×100%。
根据公式计算出实施例1制备的透明质酸修饰的负载姜黄素的纳米载体的包埋率为98.9±1.24%,载药率为18.6±0.65%。
实施例3——透明质酸修饰的负载姜黄素的纳米载体的pH稳定性实验
考察pH 5.5和7.4条件下纳米颗粒的稳定性并与游离姜黄素进行比较。
称取1 mg实施例1制备的负载姜黄素的纳米载体Cur@(Zn-Adenine)、透明质酸修饰的负载姜黄素的纳米载体Cur@(Zn-Adenine)@HA和姜黄素加入到10 mL不同pH的PBS缓冲溶液(10 mM)中,分别在0 min和120 min取样100 μL样品,加入900 μL乙醇使其完全溶解,通过高效液相色谱(HPLC,LC-20A)检测姜黄素含量。将姜黄素初始时间时的含量设定为100%。
HPLC条件:C18反相色谱柱;流动相为:0.1%磷酸盐-乙腈(50:50);检测波长:430nm;流速:1.0 mL/min;柱温为25 ℃,进样量为20 μL。
纳米载体负载姜黄素和游离姜黄素的pH稳定性如图4所示。在pH为5.5和7.4 PBS溶液中反应120 min后,Cur的含量均小于40%,Cur@(Zn-Adenine)在两种溶液中的损失量均小于10%,Cur@(Zn-Adenine)@HA在pH=5.5溶液中含量损失约25.3%。(Zn-Adenine)@HA提高姜黄素稳定性的效果略差一点,可能是因为HA的修饰使纳米载体呈现水溶液的分散状态,增加了纳米载体与外界环境的接触,从而使其稳定性减弱。
实施例4——透明质酸修饰的负载姜黄素的纳米载体的体外毒性实验
使用CCK-8试剂盒分别评估游离姜黄素、纳米载体负载姜黄素和透明质酸修饰纳米载体负载的姜黄素对A549细胞的毒性。
培养基配方:DMEM培养基含10%胎牛血清 (FBS)、1%双抗(100 U/mL链霉素和100U/mL青霉素)。
培养箱条件:37 ℃,5% CO2。
将A549细胞培养至对数生长期后,用0.25%的胰酶溶液消化并离心收集。调配细胞浓度(4000个/mL),每孔加入100 μL细胞悬液,在96孔板中培养12 h。去除培养基,每孔加入100 μL用DMEM稀释的由DMSO预溶解的药物,培养72 h。其中,Zn-Adenine、(Zn-Adenine)@HA溶液的浓度为0, 20, 40, 60, 80, 100 μg/mL;Cur@(Zn-Adenine)、Cur@(Zn-Adenine)@HA和游离Cur中,Cur有效药物浓度为1-10 μg/mL。CCK-8用DMEM培养基以1:10的比例稀释,每孔加入10 μL 稀释后的CCK-8溶液并避光培养1 h。用酶标仪在450 nm波长下检测每个孔的吸光度。
细胞存活率的计算公式如下:
细胞存活率(%)=(实验组的吸光值/对照组的吸光值)⨯100%。
空白载体Zn-Adenine、(Zn-Adenine)@HA对A549细胞的毒性情况如图5所示,结果表明,Zn-Adenine处理的细胞活力略有所下降,但即使在100 μg/mL的浓度下细胞的存活率仍超过80%。(Zn-Adenine)@HA几乎对细胞活力没有影响。说明纳米载体本身对细胞没有明显的毒副作用,具有良好的生物相容性。负载姜黄素的纳米载体Cur@(Zn-Adenine)、Cur@(Zn-Adenine)@HA和游离Cur对A549细胞的抑制效果如图6所示,随Cur浓度增加,游离Cur、Cur@(Zn-Adenine)和Cur@(Zn-Adenine)@HA表现出的细胞存活率逐渐下降,说明不论是游离Cur还是NPs负载的Cur都对肿瘤细胞具有抑制作用。当Cur浓度为1 μg/mL时,游离Cur表现出的细胞存活率为97.32%,Cur@(Zn-Adenine)的细胞存活率为83.18 %,Cur@(Zn-Adenine)@HA的细胞存活率为76.92%。当Cur浓度为7 μg/mL时,游离Cur仅诱导了30.83%的细胞死亡,Cur@(Zn-Adenine)的细胞死亡率为44.94%,而Cur@(Zn-Adenine)@HA处理的细胞死亡率为79.69%,其抑癌细胞作用比游离Cur提高了约2.58倍。当浓度上升至10 μg/mL时,游离Cur处理后的细胞死亡率为61.21%,Cur@(Zn-Adenine)的细胞死亡率为80.65%,Cur@(Zn-Adenine)@HA处理的细胞死亡率高达84.5%。结果表明,Cur@(Zn-Adenine)可以提高Cur的生物利用度,而经过透明质酸修饰后,Cur@(Zn-Adenine)@HA的抗癌作用显著提高,一方面归因于其稳定性的增加;另一方面,HA的癌细胞靶向性,促进了药物的内吞,实现了药物在细胞内的累积释放。
最后应说明的是,以上仅用以说明本发明的技术方案而非限制,尽管参照较佳布置方案对本发明进行了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的精神和范围。
Claims (10)
1.一种透明质酸修饰的负载疏水药物的纳米载体的制备方法,其特征在于,所述制备方法包括以下步骤:
步骤1,Zn-Adenine纳米颗粒的制备:将Zn2+和Adenine(腺嘌呤)的水溶液、疏水药物的乙醇溶液在缓冲溶液中,通过一锅法制备得到负载药物的Zn-Adenine纳米颗粒,记为Drug@(Zn-Adenine);
步骤2,透明质酸的修饰:将步骤1制备得到的Drug@(Zn-Adenine)纳米颗粒离心收集,而后和透明质酸分别溶解在去离子水中,在搅拌过程中通过静电吸附作用形成均一的溶液;
步骤3,纯化处理:将步骤2中所得溶液离心处理,并用去离子水洗涤底部沉淀,从而得到透明质酸修饰的Drug@(Zn-Adenine)纳米颗粒,记为Drug@(Zn-Adenine)@HA,即所述透明质酸修饰的基于Zn2+和Adenine配位自组装的纳米药物载体。
2.根据权利要求1所述的制备方法,其特征在于,所述疏水药物包括光甘草定、喜树碱、紫杉醇。
3.根据权利要求1所述的制备方法,其特征在于,步骤1中Zn2+来源于含锌离子的试剂。
4.根据权利要求1所述的制备方法,其特征在于,步骤1中所述缓冲液为HEPES缓冲溶液。
5.根据权利要求1~4任一项所述的制备方法,其特征在于,步骤1中Zn2+和Adenine的质量比为(5~15):1;所述疏水药物和Adenine的质量比为(1~5):1。
6.根据权利要求1~4任一项所述的制备方法,其特征在于,步骤2中所述透明质酸的分子量MW<150 KDa。
7.根据权利要求1~4任一项所述的制备方法,其特征在于,步骤2中所述透明质酸与Drug@(Zn-Adenine)纳米颗粒两者之和的质量浓度为15%~25%。
8.根据权利要求1~4任一项所述的制备方法,其特征在于,步骤2中产生静电吸附的搅拌条件为600~1000 rpm/min,3~5小时。
9.一种透明质酸修饰的负载疏水药物的纳米载体,其特征在于,所述纳米载体由权利要求1~8任一项所述制备方法制备得到。
10.如权利要求9所述纳米载体的应用,其特征在于,所述纳米载体在制备药物中的应用。
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