CN115177736A - 具有软骨靶向和过氧化氢酶活性的氨基化钽纳米颗粒和制备方法及用途 - Google Patents
具有软骨靶向和过氧化氢酶活性的氨基化钽纳米颗粒和制备方法及用途 Download PDFInfo
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Abstract
本发明公开了一种具有软骨靶向和过氧化氢酶活性的氨基化钽纳米颗粒和制备方法及用途,该颗粒的表面修饰有氨基,该氨基化钽纳米颗粒带正电荷。本发明所述氨基化钽纳米颗粒提高了同关节软骨细胞外基质结合能力,能长时间稳定发挥钽纳米颗粒的类过氧化氢酶活性功能,调控骨关节的氧化应激水平,达到有效延缓骨关节炎进程的目的,为治疗骨关节炎提高一种钽金属纳米药物。
Description
技术领域
本发明涉及医药技术领域,特别涉及一种具有软骨靶向和过氧化氢酶活性的氨基化钽纳米颗粒和制备方法及用途。
背景技术
骨关节炎是一种中老年人群中常见以关节软骨渐行性退变为主要表现形式的骨关节系统临床常见病。
随着全社会人口老龄化的加速,全球每年有近3亿人受骨关节炎疼痛的困扰。骨关节炎与外伤、炎症、衰老、代谢等因素有关,但目前其确切发病机制不清。现有的治疗手段主要包括非甾体类抗炎药、透明质酸、糖皮质激,及物理治疗等,但都不能有效实现对骨关节炎的长期有效控制。
氧化应激是指体内氧化与抗氧化作用失衡的一种状态,是导致衰老和基本的重要因素。骨关节炎发生后会有大量的自由基产生,使这个关节处于氧化应激状态,进而导致软骨细胞损伤和基质降解,加速骨关节炎的进程。因此,氧化应激是骨关节炎发生发展的一个关键因素,干预氧化应激能够有效延缓骨关节炎的进程。基于此,既往使用的方法多为关节腔局部注射大分子或小分子抗氧化剂,这些药物存在关节腔停留时间短,抗氧化能力不稳定等缺点,需要反复注射才能有效。增加干扰风险,病人负担及医务成本。
钽具有极高的抗腐蚀性,无论是在冷和热的条件下,对盐酸、浓硝酸及王水都不反应。钽基金属因具有良好的生物相容性被广泛用于临床植入和诊断,如颅骨成形板、骨科植入物,血管夹、血管内支架和放射标志物等。钽纳米颗粒作为钽基金属的另一种结构形态,本发明发现钽纳米颗粒具有类过氧化氢酶活性,能催化过氧化氢(ROS的主要成分)变成H2O和O2,然后对钽纳米颗粒表明进行氨基修饰,让钽纳米颗粒带正电荷,由于软骨细胞外基质为负电荷,正负电荷结合提高钽纳米颗粒在关节腔的停留时间。钽纳米颗粒的类过氧化氢酶活性不易受温度和pH值,具有稳定的催化能力,能持续保持稳定的抗氧化能力。通过长时间有效调控骨关节的氧化应激水平,达到有效延缓骨关节炎进程的目的。此外,钽纳米颗粒具有良好的生物相容性,针对其它氧化应激相关疾病也有作用,具有广泛的应用前景。
发明内容
本发明的目的是提供一种具有软骨靶向和过氧化氢酶活性的氨基化钽纳米颗粒和制备方法及用途,所述氨基化钽纳米颗粒通过钽纳米颗粒表面氨基修饰,提高同关节软骨细胞外基质结合能力,能长时间稳定发挥钽纳米颗粒的类过氧化氢酶活性功能,调控骨关节的氧化应激水平,达到有效延缓骨关节炎进程的目的,为治疗骨关节炎提高一种钽金属纳米药物。
本发明的技术方案是:
氨基化钽纳米颗粒,该颗粒的表面修饰有氨基,该氨基化钽纳米颗粒带正电荷。
所述氨基为3-氨丙基三甲氧基硅烷。
上述氨基钽纳米颗粒的制备方法,包括以下步骤:
(1)称取纯钽纳米颗粒加入无水乙醇后超声分散,混悬液进行低速离心,保留粒径为30-400nm的颗粒,得钽纳米颗粒乙醇分散液;
(2)步骤(1)所得的钽纳米颗粒乙醇分散液中加入3-氨丙基三甲氧基硅烷,加热磁力搅拌,持续搅拌,反应的温度为60-80℃,反应时间为2-4小时,取沉淀,离心、洗涤,干燥,得氨基化钽纳米颗粒。
步骤(1)所述纯钽纳米颗粒的乙醇溶液的浓度为10mg/ml。
步骤(1)所述超声为探棒超声,超声条件为200W,5s On,5s Off,时间为15-30分钟。
步骤(1)所述低速离心为1000rpm,时间为5分钟。
步骤(2)所述3-氨丙基三甲氧基硅烷:钽纳米颗粒乙醇分散液的体积比为1:100-200。
步骤(2)所述加热磁力搅拌反应的温度为60-80℃。
步骤(2)所述离心条件为10000-15000rpm,10-20分钟。
氨基化钽纳米颗粒在制备治疗治疗骨关节炎的药物中的用途。
氨基化钽纳米颗粒在制备过氧化氢分解成水合氧气的催化剂中的用途。
钽纳米颗粒作为钽基金属的另一种结构形态,申请人发现钽纳米颗粒具有类过氧化氢酶活性,能催化过氧化氢(ROS的主要成分)变成H2O和O2,然后对钽纳米颗粒表明进行氨基修饰,使钽纳米颗粒带正电荷,由于软骨细胞外基质为负电荷,正负电荷结合提高钽纳米颗粒在关节腔的停留时间。钽纳米颗粒的类过氧化氢酶活性不易受温度和pH值,具有稳定的催化能力,能持续保持稳定的抗氧化能力,通过长时间有效调控骨关节的氧化应激水平,达到有效延缓骨关节炎进程的目的。
此外,钽纳米颗粒具有良好的生物相容性,针对其它氧化应激相关疾病也有作用,具有广泛的应用前景。
附图说明
图1:本发明实施例1中氨基化钽纳米颗粒的制备过程示意图;
图2:本发明实施例1中氨基化钽纳米颗粒的X射线衍射图;
图3:本发明实施例1中氨基化钽纳米颗粒合成过程中的水合粒径变化图;
图4:本发明实施例1中氨基化钽纳米颗粒合成过程中的Zeta电位变化图;
图5:本发明实施例1中氨基化钽纳米颗粒的扫描电子显微镜图;
图6:本发明实施例1中氨基化钽纳米颗粒的X-射线光电子能谱图;
图7:本发明实施例2中不同浓度氨基化钽纳米颗粒的催化过氧化分解能力图;
图8:本发明实施例3中氨基化钽纳米颗粒在不同温度条件下催化过氧化分解能力图;
图9:本发明实施例3中氨基化钽纳米颗粒在不同pH条件下催化过氧化分解能力图;
图10:本发明实施例4中不同浓度氨基化钽纳米颗粒对软骨细胞活性影响图;
图11:本发明实施例5中氨基化钽纳米颗粒对软骨细胞活性氧表达调控的荧光图;
图12:本发明实施例6中氨基化钽纳米颗粒在大鼠关节腔内的停留时间活体成像图;
图13:本发明实施例7中苏木精-伊红染色评估氨基化钽纳米颗粒对大鼠骨关节炎治疗效果图。
具体实施方式
为了清楚说明本发明的目的、技术方案和优点,现参照下列实施例及附图进一步描述本发明。实施例仅用于解释而不以任何方式限制本发明。
实施例中,各原始试剂材料均可商购获得,未标明具体条件的实验方法为所属领域熟知的常规方法和常规条件。特别指出的是,以下实施例仅用于说明本说明,但不对本发明的范围进行限定。
实施例1氨基化钽纳米颗粒的制备(参见图1)
称取100mg纯钽纳米颗粒用10ml的乙醇进行探棒超声处理,超声条件为(200W,5sOn,5s Off),混悬液进行低速离心,离心条件为1000rpm,5分钟,去掉大的颗粒,获得钽纳米颗粒乙醇分散液。调整上层钽纳米颗粒的浓度为1mg/ml,取10ml浓度为1mg/ml的钽纳米颗粒溶液,接着加入3-氨丙基三甲氧基硅烷100μl,加热到70℃磁力搅拌反应3小时。反应完毕后离心,离心条件为12000rpm,10分钟。用乙醇洗涤3次,将沉淀干燥,得褐色的氨基化钽纳米颗粒。
对本实施例所制得的氨基化钽纳米颗粒进行表征测试如下:
1)根据图2的X-射线衍射结果,本发明制备得到的氨基化钽纳米颗粒与钽纳米颗粒的没有显著变化,在衍射角30-80°区间和钽基金属的X-射线衍射标准卡一致,说明制备的材料是钽纳米颗粒。
2)根据图3的粒径变化图结果,氨基化钽纳米颗粒比纯钽纳米颗粒具有更大的水合粒径,从120nm变大到250nm。
3)根据图4的Zeta电位变化图结果出,纯钽纳米颗粒的电位为负电荷-35mV,而经过表面氨基化修饰后,其电位明显升高最终呈正电荷32mV,证明钽纳米颗粒成功被氨基化修饰。
4)根据图5的扫描电镜图结果,纯钽纳米颗粒易团聚,而经过表面氨基化修饰后,氨基化钽纳米颗粒显示出较好的分散性。
5)根据图6的X-射线光电子能谱图结果,N元素,Ta元素和O元素都在氨基化钽纳米颗粒中检测到,说明氨基被成功修饰到了钽纳米颗粒表面。
实施例2氨基化钽纳米颗粒的类过氧化氢酶活性催化过氧化分解能力
将浓度为100μg/ml的氨基化钽纳米颗粒与浓度为1mM的过氧化氢溶液在37℃条件下共孵育1小时,溶液pH值为7.2。然后用过氧化氢检测试剂盒(碧云天公司)检测溶液中过氧化氢含量。如图7所示,实验结果显示随着氨基化钽纳米颗粒浓度升高(10-100μg/ml),过氧化氢的分解能力提高,类过氧化氢酶活性具有浓度依赖性。
实施例3氨基化钽纳米颗粒的类过氧化氢酶活性催化过氧化分解能力具有温度和酸碱稳定性
将浓度为100μg/ml的氨基化钽纳米颗粒与浓度为1mM的过氧化氢溶液在不同温度条件下(25-60℃)共孵育1小时,溶液pH值为7.2。然后用过氧化氢检测试剂盒检测溶液中过氧化氢含量。如图8所示,实验结果显示随着温度的升高,氨基化钽纳米颗粒的过氧化氢分解能力不会减低,还有轻微的升高。说明其类过氧化氢酶活性具有温度稳定性。
将浓度为100μg/ml的氨基化钽纳米颗粒与浓度为1mM的过氧化氢溶液在37℃条件下共孵育1小时,溶液pH值在2-10之间改变。然后用过氧化氢检测试剂盒检测溶液中过氧化氢含量。如图9所示,实验结果显示随着溶液pH值的改变,不管是酸性或是碱性环境,氨基化钽纳米颗粒的过氧化氢分解能力不会受到较大影响。说明其类过氧化氢酶活性具有酸碱稳定性。
实施例4氨基化钽纳米颗粒的生物相容性验证
采用细胞数量检测试剂盒(碧云天公司)检测制备得到的氨基化钽纳米颗粒对间软骨细胞活性的影响。如图10所示,实验结果显示随着氨基化钽纳米颗粒浓度的在0-500μg/mL之间变化,均没有明显的细胞毒性,细胞活性都在95%以上,证明制备的氨基化钽纳米颗粒具有良好的生物相容性。
实施例5氨基化钽纳米颗粒在细胞水平对过氧化氢的催化分解能力验证
正常软骨细胞(从SD大鼠膝关节提取分离)先加含过氧化氢浓度为400μM的细胞培养基;同时加入氨基化钽纳米颗粒让其在培养体系中的浓度为100μg/mL之间,然后共孵育24h。孵育完毕后加入总活性氧探针2',7'-二氯荧光素二乙酸酯(DCFH-DA)(碧云天公司),避光37℃条件下孵育30分钟,用不含血清的DMEM高糖培养基(Gibco公司)洗三次,于荧光显微镜下观察拍照。如图11所示,实验结果显示过氧化氢能导致细胞高活性氧表达,而氨基化钽纳米颗粒可以降低活性氧含量达正常水平。
实施例6氨基化钽纳米颗粒在关节软骨停留时间验证
对氨基化钽纳米颗粒进行荧光CY-5标记,取浓度为1mg/ml的氨基化钽纳米颗粒水溶液10ml,加入Cy5 NHS酯(西安瑞禧公司)10mg,然后避光条件下常温持续搅拌24,反应完毕后离心,用去离子水洗涤三次,离心条件为12000rpm,10分钟,得到CY-5标记的氨基化钽纳米颗粒。然后用生理盐水配制为1mg/ml浓度CY-5标记的氨基化钽纳米颗粒溶液,选取SD大鼠(购买于中国人民解放军陆军军医大学动物中心)膝关节腔内注射100μl,利用小动物活体成像系统(LI-COR公司)在进行近红外荧光实时成像,激发波长为800nm,观察氨基化钽纳米颗粒在膝关节腔内的停留时间。如图12所示,实验结果显示钽纳米颗粒在膝关节腔内的停留时间能长达28天,有利于其在关节腔内持续发挥调控氧化应激的能力,长时间保护关节不受高氧化应激的破坏,从而起到延缓骨性关节炎进程的目的。
实施例7氨基化钽纳米颗粒在对骨性关节炎保护能力的验证
选取SD大鼠,分3组,用碘乙酸钠(MIA)关节腔注射进行氧化应激的骨关节造模。按照动物伦理推荐,配制3%的戊巴比妥钠,按照1ml/kg的标准进行麻醉。然后对大鼠右膝关节腔注射10μl浓度为2mg/ml的碘乙酸钠,在2周后,氧化应激的骨关节炎模型造模成功。然后麻醉,膝关节腔内注射浓度为1mg/ml的氨基化钽纳米颗粒100μl,然后造在注射后第4周及10周时各自取材一次。
将小鼠右后肢单独分离,保留完整膝关节,剔除多余肌肉等组织,生理盐水冲洗后置于4%多聚甲醛中固定。膝关节固定24后,将其浸泡在EDTA脱钙液中进行脱钙处理,脱钙2周后进行脱水,石蜡包埋,然后切片进行苏木精-伊红染色,最后于显微镜下观察关节软骨变化。如图13所示,实验结果显示第4周时,碘乙酸钠组软骨破坏明显,其中胫骨平台病变最为严重,软骨已出现糜烂,软骨组织出现崩坏溶解变化。氨基化钽纳米颗粒组胫骨和股骨侧也有不同程度的影响,软骨表面有絮状改变,但组织病变程度相对较轻,氨基化钽纳米颗粒组的病情较碘乙酸钠组有明显改善。到了第10周时,我们可以看到碘乙酸钠组的软骨损伤已非常严重:股骨侧出现大面积软骨塌陷缺损,糖胺聚糖含量也急剧下降。胫骨平台出现软骨样缺损,缺损深入软骨下骨。与第四周相比,氨基化钽纳米颗粒组的病情也出现了一定程度的恶化,但总体上与碘乙酸钠组相比有明显变化,病变程度得到有效延缓。说明氨基化钽纳米颗粒能通过调控关节腔的氧化应激水平达到延缓骨关节炎进程的目的。
以上所述实施例仅为本发明的部分实施例,而并非因此限制本发明的保护范围。对于所属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式的变化或变动,均同理包括在本发明的专利保护范围内。
Claims (10)
1.一种氨基化钽纳米颗粒,其特征在于:该颗粒的表面修饰有氨基,该氨基化钽纳米颗粒带正电荷。
2.根据权利要求1所述的纳米颗粒,其特征在于:所述氨基为3-氨丙基三甲氧基硅烷。
3.权利要求1或2所述氨基钽纳米颗粒的制备方法,其特征在于,包括以下步骤:
(1)称取纯钽纳米颗粒加入无水乙醇后超声分散,混悬液进行低速离心,保留粒径为30-400nm的颗粒,得钽纳米颗粒乙醇分散液;
(2)步骤(1)所得的钽纳米颗粒乙醇分散液中加入3-氨丙基三甲氧基硅烷,加热磁力搅拌,反应的温度为60-80℃,反应时间为2-4小时,取沉淀,离心、洗涤,干燥,得氨基化钽纳米颗粒。
4.根据权利要求3所述的方法,其特征在于:步骤(1)所述纯钽纳米颗粒的乙醇溶液的浓度为10mg/ml。
5.根据权利要求3所述的方法,其特征在于:步骤(1)所述超声为探棒超声,超声条件为200W,5s On,5s Off,时间为15-30分钟。
6.根据权利要求3所述的方法,其特征在于:步骤(1)所述低速离心为1000rpm,时间为5分钟。
7.根据权利要求3所述的方法,其特征在于:步骤(2)所述3-氨丙基三甲氧基硅烷:钽纳米颗粒乙醇分散液的体积比为1:100-200。
8.根据权利要求3所述的方法,其特征在于:步骤(2)所述离心条件为10000-15000rpm,10-20分钟。
9.权利要求1-2任一所述氨基化钽纳米颗粒或采用权利要求3-8任一所述方法制备的氨基化钽纳米颗粒在制备治疗治疗骨关节炎的药物中的用途。
10.权利要求1-2任一所述氨基化钽纳米颗粒或采用权利要求3-8任一所述方法制备的氨基化钽纳米颗粒在制备过氧化氢分解成水合氧气的催化剂中的用途。
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