CN105797175B - PAAs@MnO(OH)-RGD药物释放载体的制备方法及应用 - Google Patents
PAAs@MnO(OH)-RGD药物释放载体的制备方法及应用 Download PDFInfo
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Abstract
本发明提供了一种PAAs@MnO(OH)‑RGD药物释放载体的制备方法及应用。先在聚丙烯酸钠纳米球表面组装氢氧化氧锰壳层,制得复合纳米球;复合纳米球再通过静电吸附作用将RGD多肽分子吸附到复合纳米球表面,制得药物释放载体。本发明所制得的药物释放载体具有在肿瘤部位pH及还原剂双重响应核磁共振成像及药物控制释放特性,同时还具有高药物负载率及生物可降解等优点,可实现对肿瘤或炎症组织的核磁成像、药物递释、靶向一体化的治疗。
Description
技术领域
本发明属于纳米材料制备领域,具体涉及一种PAAs@MnO(OH)-RGD药物释放载体及应用。
背景技术
肿瘤是一种常见病、多发病,其中恶性肿瘤是目前危害人类健康最严重的一类疾病。根据我国最新的疾病数据显示,在最新发布的《2015中国肿瘤登记年报》中,每一分钟,全国就有6人被诊断为恶性肿瘤,有5人死于癌症。因此,随着肿瘤的发病率和死亡率不断增加,警示我们迫切需要新型的、更有效的诊断治疗方法。近年来,随着纳米材料的出现,集多功能化于一体的纳米材料为肿瘤的诊断与治疗一体化提供了新的解决途径。这种多功能纳米载体是在单一的具有空隙的纳米材料上同时修饰上多种具有特定功能的生物分子或功能性纳米颗粒,比如同时集成像、靶向、载药和光动力治疗等功能于一体,实现多种目标功能的一体化治疗,降低单一治疗的毒副作用,从而达到更优化的诊断治疗效果。至今为止已经有很多无机功能纳米材料作为药物载体被广泛报道,比如介孔二氧化硅、氧化石墨烯、硒化物以及过渡金属等。但上述无机纳米载体存在药物负载率低,在体内无法降解等缺陷,这极大影响了此类材料在临床中的实际应用。因此,开发新型的高药物负载率、可降解型、多功能化纳米材料用于不同组织的肿瘤诊断仍是十分必要的。
锰基核磁成像造影剂是一类T1-加权MRI成像造影剂,且锰离子是人体中一种必需的元素,生物相容性好。但是Mn不易形成配合物,且变价较多,因此基于锰的氧化物发展的造影剂r1值较小(一般是0.5 mM-1·S-1)。最近的研究结果表明,如果把Mn的氧化物做成纳米颗粒时,其MRI性能会得到提高。所以,发展基于Mn的氧化物或氢氧化物纳米颗粒制备可降解型多功能药物载体,同时能提高Mn基造影剂的造影性能,对推动其临床应用具有非常明显的意义。
RGD肽是一类含有精氨酸2甘氨酸2天冬氨酸(Arg2Gly2Asp)序列的短肽,广泛存在与生物体内,是整合素(Integrin)与其配体蛋白相互作用的识别位点。对肿瘤细胞亲和力较强,更容易通过主动靶向作用使药物载体进入癌细胞。
发明内容
本发明的目的在于针对现有技术的不足,提供一种PAAs@MnO(OH)-RGD药物释放载体的制备方法及应用。这种药物释放载体是由聚丙烯酸钠/氢氧化氧锰核壳型复合纳米球构建,并通过静电吸附RGD靶分子而制成;集靶向、MRI成像、pH及还原剂双重响应刺激功能于一体,同时还具有高药物负载率、生物相亲性好、可生物降解等优点。
为实现上述目的,本发明采用如下技术方案:
一种PAAs@MnO(OH)-RGD药物释放载体,其特征在于:先在聚丙烯酸钠纳米球表面组装氢氧化氧锰壳层,制得复合纳米球;复合纳米球再通过静电吸附作用将RGD多肽分子吸附到复合纳米球表面,制得药物释放载体。PAAs、MnO(OH)、RGD的质量比为3.3:5.6:1。
一种PAAs@MnO(OH)-RGD药物释放载体的制备方法,包括以下步骤:
(1)PAAs纳米球的异丙醇溶液的制备:根据参考文献Chem. Commun., 2014, 50,1000—1002,制备聚丙烯酸钠(PAAs)球;称量10 mg 直线型聚丙烯酸钠(Mw=5100),加入1ml 去离子水,室温低速搅拌(200rpm),使其溶解分散均匀;然后在搅拌条件下,逐滴滴加19ml异丙醇溶液,溶液逐渐变为乳白色,滴加完后继续搅拌1 h,得到20 ml PAAs纳米球溶液,室温保存备用;
(2)PAAs@MnO(OH)复合纳米球的制备:取上述步骤(1)中得到的PAAs纳米球制备液10 ml,200 rpm搅拌,然后加入19 mg MnCl2·4H2O,继续搅拌1 h,使锰离子尽量吸附在PAAs纳米球表面,离心;将沉淀重新分散到10 ml甲醇中,室温继续200rpm搅拌,加入浓度为0.2M的NaOH溶液,使锰离子快速共沉淀变为MnO(OH),室温搅拌反应2 h,离心甲醇洗2次,即得到PAAs@MnO(OH)复合纳米球;
所述的聚丙烯酸钠/氢氧化氧锰纳米材料的直径为80 nm,MnO(OH)颗粒的粒径大小为2~3 nm,且MnO(OH)壳层厚度及颗粒大小可根据MRI成像条件的需要,调节MnCl2及NaOH溶液的浓度而相应制得;
(3)通过静电吸附作用将RGD多肽分子吸附到PAAs@MnO(OH)复合纳米球表面,RGD分子的吸附率为60.8%。
所述的PAAs@MnO(OH)-RGD药物释放载体,在酸性和还原剂的双重响应刺激条件下,PAAs@MnO(OH)-RGD结构逐渐解离,释放所负载的抗癌药物及Mn2+(T1-加权MRI成像造影剂)。
所述的还原剂包括谷胱甘肽、二硫苏糖醇、维生素C、细胞色素C中的一种或多种。
所述的酸性为pH≤6;所述的抗癌药物是为阿霉素、柔红霉素、紫杉醇中的一种或多种。
实际应用效果:
1)将一定量PAAs@MnO(OH)-RGD复合纳米球溶液与抗癌药物混合12 h后,离心清洗获得PAAs@MnO(OH)-抗癌药物-RGD纳米球,抗癌药物的吸附率达到91.1%。细胞毒理实验结果表明PAAs@MnO(OH)-抗癌药物-RGD纳米球的浓度仅为5.5 μg/ml时,癌细胞抑制率可达到76.58%;
2)所述的PAAs@MnO(OH)-RGD复合纳米球能够在酸性和还原剂的响应刺激条件下,发生结构解离从而释放所负载的药物及二价锰离子。体外释放实验结果显示在pH=5.0及还原剂DTT=2 mM的双重刺激下,DOX的释放量在48 h后达到90%,说明复合纳米球具有良好的双重刺激响应。体外核磁成像实验结果表明,在DTT=5 mM,pH=7.4缓冲液中复合纳米球造影剂的r1值为3.13 mM-1·S-1;在pH=5.0的缓冲液中,复合纳米球造影剂的r1值最高可达到4.09 mM-1·S-1,说明聚丙烯酸钠/氢氧化氧锰复合纳米球可实现针对pH及还原剂双重刺激响应触发的T1加权MRI成像。
与其他药物释放体系相比,本发明的显著优点在于:
(1)本发明PAAs@MnO(OH)-RGD复合纳米球制备过程简单,条件温和可控,易于规模化;
(2)性能优异:药物负载率高,达到91.1%,可有效降低治疗过程中药物载体的使用量,减少因药物载体而引起的副作用;并且该药物载体生物相容性好、易于在细胞内降解,是可降解型药物载体;
(3)PAAs@MnO(OH)-RGD复合纳米球在肿瘤细胞内易受酸性及还原剂双重刺激响应,结构解离,释放出所负载药物及Mn2+,可实现对肿瘤或炎症组织的MRI成像、药物递释、靶向一体化的治疗功能。
附图说明
图1(A)PAAs@ MnO(OH)复合纳米球的低倍透射电镜图(TEM);
图1(B)PAAs@ MnO(OH)复合纳米球的高倍透射电镜图(TEM):照片中白色箭头所指小黑点为MnO(OH)纳米小颗粒;
图2为PAAs@ MnO(OH) 纳米球的X射线衍射图像(XRD);横坐标为2θ角度,纵坐标为衍射强度;
图3为PAAs@MnO(OH)-DOX复合纳米球针对不同pH和不同DTT浓度刺激响应的药物体外释放曲线图;横坐标为释放时间,纵坐标为释放百分率;
图4为考察PAAs@MnO(OH)复合纳米球的生物相容性测试;横坐标为复合纳米球浓度,纵坐标为细胞生存率;
图5为加入不同组样品培养后所得的细胞存活率柱状图;横坐标为不同组样品,纵坐标为细胞生存率;
图6为PAAs@ MnO(OH)复合纳米球在不同pH条件下的体外核磁共振成像对比图,磁场强度为0.5T;横坐标为Mn2+浓度,纵坐标为每秒分之一;
图7为PAAs@ MnO(OH)复合纳米球在不同DTT浓度条件下的体外核磁共振成像对比图,磁场强度为0.5T;横坐标为Mn2+浓度,纵坐标为每秒分之一。
具体实施方式
下面以具体实施示例对本发明的技术方案做进一步说明,但是不能以此限制本发明的范围。
实施例1
将PAAs@MnO(OH)复合纳米球水溶液进行超声处理0.5 h,然后滴在铜网上,晾干后进行TEM扫描(见图1(A)、图1(B)),结果见图1(A)、图1(B)所示,从图1(A)中可以看出PAAs@MnO(OH)复合纳米材料为纳米球结构,尺寸均一,平均直径约为80 nm;从图1(B)可以知道包裹在PAAs表面的MnO(OH)纳米小颗粒的直径约为2 nm,尺寸均一、分布均匀(箭头所指)。由XRD测试结果可知产物PAAs上包裹的是氢氧化氧锰纳米颗粒(见图2 )。
实施例2
将PAAs@MnO(OH)复合物和阿霉素(DOX)按质量浓度1:1加入PBS(10 mM,pH=7.4)溶液中,室温避光振荡12 h,离心分离,并用PBS(10 mM,pH=7.4)溶液洗涤,收集上清液,根据DOX的标准曲线计算其中所含DOX的量,并进一步计算DOX的负载量为0.911 mg DOX/1mgPAAs@MnO(OH)。将1 mg吸附药物后的PAAs@MnO(OH)复合物分散于3 ml PBS(10 mM,pH=7.4)溶液中,放入透析袋后将透析袋加入47 ml PBS溶液中透析48 h,每隔1 h,2 h,4 h,6 h,8h,10 h,12 h,14 h,16 h,24 h,36 h,48 h取3 ml溶液测荧光,原溶液再补入3 ml PBS溶液,测试的结果如图3所示:曲线1为常温,pH=7.4;曲线2为常温,pH=7.4,2 mM DTT;曲线3为常温,pH=5;曲线4为常温,pH=5,2 mM DTT;从图3中可以看出在pH=5,2 mM DTT条件下所释放出的DOX荧光强度相应的点最高,说明在此条件下更有利于DOX的释放,可用于肿瘤细胞的药物治疗。
实施例3
用HepG2细胞作为目标癌细胞来考查PAAs@MnO(OH)纳米材料的细胞生物相容性:将肝癌HepG2细胞接种于96孔板中,加入细胞需要的培养液,然后在细胞培养箱中培养24 h后,取出培养液,加入实施例1制得的PAAs@MnO(OH)纳米材料,其浓度分为5 μg/ml、15 μg/ml、25 μg/ml、50 μg/ml和100 μg/ml的PAAs@MnO(OH)复合物来进行MTT试验,每个浓度平行四组,培养24 h后,然后在酶标仪上于490 nm处读取吸收值,根据空白组和样品组的吸收值计算各组细胞的存活率。从图4结果中可以看出,每组细胞的存活率都在90%以上,说明PAAs@MnO(OH)纳米球的生物相容性良好,没有明显的毒性,甚至是高浓度的PAAs@MnO(OH)纳米材料对细胞也基本无毒。
实施例4
将实施例1制得的PAAs@MnO(OH)纳米材料修饰靶向分子RGD,并吸附DOX用作下面的细胞毒性试验的样品。先将肝癌HepG2细胞接种于96孔板中,培养24h后,然后加入不同组等量浓度的样品,分别为见图5中(1、control,2、PAAs@MnO(OH),3、PAAs@MnO(OH)-DOX 4、PAAs@MnO(OH)-DOX-RGD;PAAs@MnO(OH)浓度均为5.5 μg/ml, DOX浓度均为5 μg/ml)的标号,加入培养基后,分别培养24 h和48 h后,于酶标仪490 nm处读取吸收值,根据空白组和样品组的吸收值计算各组细胞的存活率;从图5结果中可以看出,1组:空白组的细胞为100%的存活率,2组:控制组的细胞在培养24 h和48 h存活率都在90%以上,说明该纳米材料没有明显的毒性;3组:没有修饰靶向分子的PAAs@MnO(OH)-DOX组细胞培养48 h比24 h那一组的细胞凋亡多,说明随着培养时间增加,该纳米材料被细胞内吞的多,释放DOX也越多,进而细胞凋亡的也更多;由3和4组中对比可知:修饰RGD的4组比3组在24h和48h培养的细胞死亡率高,说明RGD起到靶向性的作用,导致HepG2细胞内摄入PAAs@MnO(OH)-DOX-RGD的纳米材复合物更多,DOX释放也更多。
实施例5
聚丙烯酸钠/氢氧化氧锰[PAAs@MnO(OH)]纳米复合球溶液的体外核磁共振成像:
(1)先取1 ml PAAs@MnO(OH)纳米材料加入透析袋中,放入49 ml 2% 硝酸进行解离24 h,使其完全解离,再取一定量按需要稀释测ICP-MS,根据ICP-MS测试结果计算出 1ml PAAs@MnO(OH)溶液中含有Mn2+ 为0.6 mM;
(2)取0.417 ml PAAs@MnO(OH)制备液,分别加入到1 ml pH=5和pH=7.4的溶液中((相当于所含Mn2+ 浓度为0.25 mM)),浸泡24h,离心后,取一定量上清液配成6个不同浓度,取出0.5 ml 去测MRI。从图6a可以看出:在pH=5条件下,随着解离出来锰离子的浓度增加,成像的亮度也逐渐变亮,而在pH=7.4条件下,成像的亮度没有明显变化,说明在pH=7.4缓冲液中锰离子解离的量较少;由图6b可知:在pH=5条件下的T1-弛豫时间的倒数比pH=7.4条件下的T1-弛豫时间的倒数要大,即在pH=5条件下的r1=4.09 mM-1·S-1大于pH=7.4条件下的r1=0.0206 mM-1·S-1,这说明在微酸条件下,MnO(OH)被溶解成Mn2+的量要多,即造影剂增多,进而MRI成像效果增强。
实施例6
取0.417 ml PAAs@MnO(OH)制备液加入到1 ml PBS(10 mM,pH=7.4)配制的不同浓度DTT溶液中,浸泡24 h,离心后,取一定量上清液配成6个不同浓度,取出0.5 ml 去测MRI。从图7a可以看出:在不同浓度的DTT条件下,锰离子解离的程度随着DTT浓度增加而增大,成像的亮度也逐渐变。5 mM DTT样品组亮度比其它两组都亮,说明此条件下,解离的锰离子量较多。由图7b可知:在0 mM DTT、2.5 mM DTT和5 mM DTT三组条件下的r1弛豫效率值依次增大,说明随着DTT浓度的增大,MnO(OH)被溶解成Mn2+的量增加,进而MRI成像效果依次增强。
由图6a和图7a对比可以看出:在pH=5条件下的成像亮度比在5 mM DTT条件下的亮度要亮,说明在微酸性条件下,锰离子解离程度更大,成像亮度也越亮;由图6b和图7b对比可知:在pH=5条件下的r1弛豫效率值要大于在不同浓度DTT条件下的r1,这表明在酸性条件下,MnO(OH)被溶解成Mn2+的量要更多,MRI成像效果比在DTT条件下的要好。
以上所述仅为本发明的较佳实施例,凡依本发明申请专利范围所做的均等变化与修饰,皆应属本发明的涵盖范围。
Claims (8)
1.一种PAAs@MnO(OH)-RGD药物释放载体,其特征在于:先在聚丙烯酸钠纳米球表面组装氢氧化氧锰壳层,制得复合纳米球;复合纳米球再通过静电吸附作用将RGD多肽分子吸附到复合纳米球表面,制得药物释放载体;释放载体中,聚丙烯酸钠纳米球、氢氧化氧锰和RGD多肽分子的质量比为3.3:5.6:1。
2.一种制备如权利要求1所述PAAs@MnO(OH)-RGD药物释放载体的方法,其特征在于:包括如下步骤:
a)聚丙烯酸钠纳米球的异丙醇溶液的制备;
b)PAAs@MnO(OH)复合纳米球的制备:在聚丙烯酸钠纳米球的异丙醇溶液中加入锰盐,搅拌1h后,离心,将沉淀重新分散到甲醇中,室温继续搅拌,加入NaOH溶液,使锰离子快速共沉淀变为MnO(OH),室温反应2h,离心,用甲醇洗涤2次,即得PAAs@MnO(OH)复合纳米球;
c)通过静电吸附作用将RGD靶分子吸附到PAAs@MnO(OH)复合纳米球表面,制得药物释放载体。
3.根据权利要求2所述的制备PAAs@MnO(OH)-RGD药物释放载体的方法,其特征在于:步骤a)具体为:称量10 mg 分子量为5100的直线型聚丙烯酸钠,加入1 ml 去离子水,室温搅拌,使其溶解分散均匀;然后在搅拌条件下,逐滴滴加19 ml异丙醇溶液,溶液逐渐变为乳白色,滴加完后继续搅拌1 h,得到20 ml PAAs纳米球溶液,室温保存备用。
4.根据权利要求2所述的制备PAAs@MnO(OH)-RGD药物释放载体的方法,其特征在于:步骤b)所述的锰盐为氯化锰、醋酸锰、硝酸锰中的一种;所述NaOH溶液的浓度为0.2M。
5.根据权利要求2所述的制备PAAs@MnO(OH)-RGD药物释放载体的方法,其特征在于:步骤b)所制得的PAAs@MnO(OH)复合纳米球的直径为80 nm,MnO(OH)颗粒的粒径大小为2~3nm。
6.根据权利要求1所述的PAAs@MnO(OH)-RGD药物释放载体,其特征在于:在酸性和还原剂的双重响应刺激条件下,PAAs@MnO(OH)-RGD结构逐渐解离,释放所负载的抗癌药物及Mn2 +。
7.根据权利要求6所述的PAAs@MnO(OH)-RGD药物释放载体,其特征在于:所述的还原剂包括谷胱甘肽、二硫苏糖醇、维生素C、细胞色素C中的一种或多种。
8.根据权利要求6所述的PAAs@MnO(OH)-RGD药物释放载体,其特征在于:所述的酸性为pH≤6;所述的抗癌药物是为阿霉素、柔红霉素、紫杉醇中的一种或多种。
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