CN114522181A - 氨基酸修饰的介孔聚多巴胺纳米粒子及其制备方法与应用 - Google Patents
氨基酸修饰的介孔聚多巴胺纳米粒子及其制备方法与应用 Download PDFInfo
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Abstract
本发明属于生物医药技术领域，具体涉及一种氨基酸修饰的介孔聚多巴胺纳米粒子及其制备方法与应用。本发明的纳米粒子采用在多巴胺中掺杂碱性氨基酸的方法制备得到。所得纳米粒子的结构为介孔球形结构，能有效增加纳米粒子的比表面积，延长在体内的保留时间；掺杂碱性氨基酸后，其抗氧化能力显著提高，可以有效降低炎症组织内氧化应激水平，减缓炎症进程；除此之外，本发明制备得到的纳米粒子还具有T1‑T2双模磁共振成像的功能，可用于炎症组织的磁共振成像。
Description
技术领域
本发明属于生物医药技术领域。更具体地，涉及一种氨基酸修饰的介孔聚多巴胺纳米粒子及其制备方法与应用。
背景技术
炎症是机体对诸多病原体、化学刺激、身体创伤、受损细胞、烧伤、辐射和冻伤等有害刺激的一种基本免疫应答。然而，炎症的持续发展可能引发多种疾病，如哮喘、炎性肠病、类风湿性关节炎和神经退行性疾病等，这些疾病往往难以治愈，是目前研究的重点和难点。当前炎症的治疗方法主要是药物治疗，包括服用非甾体类抗炎药、皮质类固醇等，通过减少炎症细胞(如巨噬细胞、白细胞等)聚集、抑制炎性因子释放等作用缓解炎症，但小分子药物缺乏靶向性，需长期频繁用药以达到治疗效果，因此具有较大副作用，增加患者负担。
近年来有研究表明，除直接抑制炎性因子释放以外，还可以通过降低炎症细胞内的氧化应激水平减缓炎症进程。在炎症患者体内，抗氧化剂机制(包括超氧化物歧化酶(Superoxide dismutase，SOD)、过氧化氢酶(catalase，CAT)和谷胱甘肽过氧化酶(glutathione peroxidise，GPX))的调节被放松，氧自由基(Reactive oxygen species，ROS)和氮自由基(Reactive nitrogen species，RNS)产生过量，导致氧化应激升高，从而引起DNA、脂质和蛋白质损伤以及产生细胞毒性，对炎症病情发展的多个阶段有促进作用。因此，抑制相关细胞中的ROS和RNS有望成为炎症治疗的有效手段。目前报道的抗氧化剂大多为小分子材料，如褪黑激素和N-乙酰半胱氨酸等，虽然具有抗炎功效，(Lim,H.D.；Kim,Y.S.；Ko,S.H.,Cytoprotective and anti-inflammatory effects of melatonin inhydrogen peroxide-stimulated CHON-001human chondrocyte cell line and rabbitmodel of osteoarthritis via the SIRT1 pathway.J Pineal Res 2012,53(3),225-237.)，但小分子的分子量小，在体内循环的半衰期短、作用时间短、易通过循环排出体内的问题，除此之外，小分子的尺寸达不到EPR效应，因此，还存在靶向性差的问题，导致治疗效果并不理想。
发明内容
本发明要解决的技术问题是克服现有抗炎药物靶向性差，在体内循环的半衰期短、作用时间短、易通过循环排出体内，炎症治疗效果不理想的缺陷和不足，提供一种氨基酸修饰的介孔聚多巴胺纳米粒子的制备方法，该制备方法所得氨基酸修饰的介孔聚多巴胺纳米粒子在人体内保留时间较长，能同时具有治疗炎症与核磁共振成像的功能。
本发明的目的是提供一种氨基酸修饰的介孔聚多巴胺纳米粒子。
本发明的另一目的是提供一种氨基酸修饰的介孔聚多巴胺纳米粒子在制备治疗炎症药物中的应用。
本发明的另一目的是提供一种氨基酸修饰的介孔聚多巴胺纳米粒子在制备核磁共振造影剂中的应用。
本发明的上述目的通过以下技术方案实现：
一种氨基酸修饰的介孔聚多巴胺纳米粒子的制备方法，包括如下步骤：
将多巴胺、金属盐溶解于水中避光反应完全得溶液a；将嵌段式聚醚溶解于水、有机溶剂与溶液a的混合溶液中，滴加1,3,5-三甲苯超声至溶液变色，再滴加碱性氨基酸水溶液反应完全，后处理即得。
优选地，所述金属盐为锰盐。
具体的，所述锰盐为硫酸锰、硝酸锰或盐酸锰。
优选地，所述嵌段式聚醚为嵌段式聚醚F-127或嵌段式聚醚F-68。
优选地，所述碱性氨基酸为精氨酸。
优选地，所述多巴胺、金属盐、嵌段式聚醚与碱性氨基酸的质量比为(20～40):1:(100～130):(1～5)。
更优选地，所述多巴胺、金属盐、嵌段式聚醚与碱性氨基酸的质量比为(20～40):1:(100～130):(2～3)。
优选地，所述水、有机溶剂与溶液a的体积比为(10～30):(10～30):1。
更优选地，所述水、有机溶剂与溶液a的体积比为20:20:1。
优选地，所述有机溶剂为乙醇、丙酮或甲醇中的一种或多种。
本发明进一步保护一种氨基酸修饰的介孔聚多巴胺纳米粒子。
优选地，所述氨基酸修饰的介孔聚多巴胺纳米粒子的粒径为110～240nm。
优选地，所述氨基酸修饰的介孔聚多巴胺纳米粒子的比表面积为20～40m2/gnm。
与正常组织相比，当纳米粒子的粒径在200nm左右时，可以通过高通透性和滞留效应(EPR效应)靶向进入炎症组织并长期滞留，有效提高纳米粒子在炎症组织内的保留时间。
本发明进一步保护一种氨基酸修饰的介孔聚多巴胺纳米粒子在制备治疗炎症药物中的应用。
优选地，所述氨基酸修饰的介孔聚多巴胺纳米粒子用于清除自由基。
本发明创造性的在纳米粒子合成过程中掺杂碱性氨基酸，破坏多巴胺中多巴胺低聚物的致密微观结构，形成弱聚集体，使自由基具有较强的可及性，从而增强聚多巴胺纳米粒子的自由基清除性能，达到降低炎症组织内的氧化应激水平。
优选地，所述自由基包括氮自由基、氧自由基。
更优选地，所述氮自由基主要为1.1-二苯基-2-苦肼基(DPPH)自由基，所述氧自由基主要为羟基自由基。
本发明进一步保护一种氨基酸修饰的介孔聚多巴胺纳米粒子在制备核磁共振造影剂中的应用。
Mn2+具有顺磁性，能够缩短周围组织的T1弛豫时间，在T1W1上呈现高信号，而介孔结构所具有的几何约束作用是一种通过调整内球和外球机制以提高弛豫性的有效策略。具体而言，介孔结构可以使造影剂自由旋转，并使周围水分子的扩散受限，从而显著增加造影剂的旋转相关时间(τR)和水分子的扩散相关时间(τD)，进而同时增强T1和T2造影效果。介孔结构缩短了T2弛豫时间、增加水分子在中孔内的扩散速率增强T1弛豫性，使得本发明制备得到的纳米粒子具有T1 T2造影效果。
本发明具有以下有益效果：
本发明的纳米粒子采用在多巴胺中掺杂碱性氨基酸的方法制备得到。所得纳米粒子的结构为介孔球形结构，能有效增加纳米粒子的比表面积，延长在体内的保留时间；掺杂碱性氨基酸后，其抗氧化能力显著提高，可以有效降低炎症组织内氧化应激水平，减缓炎症进程；除此之外，本发明制备得到的纳米粒子还具有T1-T2双模磁共振成像的功能，可用于炎症组织的磁共振成像。
附图说明
图1为本发明实施例1～3制备得到的氨基酸修饰的介孔聚多巴胺纳米粒子的紫外吸收图。
图2为对比例1制备得到的MM与实施例1制备得到的AMM-9的透射电镜图；图2A为对比例1制备得到MM的透射电镜图；图2B为实施例1制备得到AMM-9的透射电镜图。
图3为对比例1制备得到的MM与实施例1制备得到的AMM-9的粒径分布图；图3A为对比例1制备得到MM的粒径分布图；图3B为实施例1制备得到AMM-9的粒径分布图。
图4为实施例1制备得到的AMM-9的扫描电镜元素分布图。
图5为实施例1制备得到的AMM-9的氮气吸附/脱附曲线；图5A为AMM-9的氮气吸脱附等温线；图5B为AMM-9的孔径分布图。
图6为对比例1制备得到的MM与实施例1制备得到的AMM-9的DPPH自由基清除能力图。
图7为对比例1制备得到的MM与实施例1制备得到的AMM-9的羟基自由基清除能力图。
图8为实施例1制备得到的AMM-9在3.0T场强下成像效果以及弛豫速率与AMM-9浓度的关系；图8A为AMM-9的T1和T2 MRI图像；图8B为纵向弛豫率与AMM-9浓度之间的线性拟合图；图8C为横向弛豫率与AMM-9浓度之间的线性拟合图。
图9为实施例1制备得到的AMM-9在7.0T场强下成像效果以及弛豫速率与载体浓度的关系；图9A为T1 MRI图像；图9B为T2 MRI图像；图9C为纵向弛豫率与AMM-9浓度之间的线性拟合图；图9D为横向弛豫率与AMM-9浓度之间的线性拟合图。
具体实施方式
以下结合说明书附图和具体实施例来进一步说明本发明，但实施例并不对本发明做任何形式的限定。除非特别说明，本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
除非特别说明，以下实施例所用试剂和材料均为市购。
实施例1氨基酸修饰的介孔聚多巴胺纳米粒子Arg-Mn-MPDA-9(AMM-9)的制备
将90mg盐酸多巴胺、3mg水合硫酸锰溶解于3mL超纯水中，在180rpm转速下避光搅拌24h，得溶液a；将0.36g嵌段式聚醚F-127(F-127)溶于6mL水、6mL乙醇、0.3mL溶液a的混合溶液中搅拌20min充分溶解，然后边超声边滴加300μL 1,3,5-三甲苯(TMB)，超声4min至溶液呈乳白色后，在180rpm磁力搅拌边搅拌边滴加9mg/mL精氨酸水溶液(1mL)，搅拌6h后分装至离心管离心，将沉淀用乙醇洗涤一次、水洗涤两次后收集得AMM-9。
实施例2氨基酸修饰的介孔聚多巴胺纳米粒子Arg-Mn-MPDA-6(AMM-6)的制备
将90mg盐酸多巴胺、3mg水合硫酸锰溶解于3mL超纯水中，在180rpm转速下避光搅拌24h，得溶液a；将0.36g嵌段式聚醚F-127(F-127)溶于6mL水、6mL乙醇、0.3mL溶液a的混合溶液中搅拌20min充分溶解，然后边超声边滴加300μL 1,3,5-三甲苯(TMB)，超声4min至溶液呈乳白色后，在180rpm磁力搅拌边搅拌边滴加6mg/mL精氨酸水溶液(1mL)，搅拌6h后分装至离心管离心，将沉淀用乙醇洗涤一次、水洗涤两次后收集得AMM-6。
与实施例1的区别在于，本实施例中的精氨酸水溶液浓度为6mg/mL。
实施例3氨基酸修饰的介孔聚多巴胺纳米粒子Arg-Mn-MPDA-12(AMM-12)的制备
将90mg盐酸多巴胺、3mg水合硫酸锰溶解于3mL超纯水中，在180rpm转速下避光搅拌24h，得溶液a；将0.36g嵌段式聚醚F-127(F-127)溶于6mL水、6mL乙醇、0.3mL溶液a的混合溶液中搅拌20min充分溶解，然后边超声边滴加300μL 1,3,5-三甲苯(TMB)，超声4min至溶液呈乳白色后，在180rpm磁力搅拌边搅拌边滴加12mg/mL精氨酸水溶液(1mL)，搅拌6h后分装至离心管离心，将沉淀用乙醇洗涤一次、水洗涤两次后收集得AMM-12。
与实施例1的区别在于，本实施例中的精氨酸水溶液浓度为12mg/mL。对比例1介孔聚多巴胺纳米粒子Mn-MPDA(MM)的制备
将90mg盐酸多巴胺、3mg水合硫酸锰溶解于3mL超纯水中，在180rpm转速下避光搅拌24h，得溶液a；将0.36g嵌段式聚醚F-127(F-127)溶于6mL水、6mL乙醇、0.3mL溶液a的混合溶液中搅拌20min充分溶解，然后边超声边滴加300μL 1,3,5-三甲苯(TMB)，超声4min至溶液呈乳白色，在180rpm磁力搅拌下逐滴加入1mL浓度为9mg/mL的三羟甲基氨基甲烷(Tris)水溶液，搅拌6h后分装至离心管离心，将沉淀用乙醇洗涤一次、水洗涤两次后收集得掺杂锰的介孔聚多巴胺纳米粒子MM。
与实施例1的区别在于，将实施例1中浓度为9mg/mL的精氨酸水溶液替换成9mg/mL的Tris水溶液。
实施例4紫外分光光度计表征
将实施例制备得到的AMM-9、AMM-12、AMM-6用紫外分光光度计进行检测其吸光度。如图1所示，从紫外吸光度值可知，AMM-9精氨酸的相对掺杂量最多。
实施例5透射电子显微镜表征
将对比例1制备得到的MM与实施例1制备得到的AMM-9配制成50μg/mL的样品溶液，充分超声分散后，取10μL滴于碳支持膜铜网的正面，置于干燥器中室温条件下自然风干后于120KV电压条件下，使用透射电子显微镜(FEI，Tecnai G2 Spirit)观察MM、AMM-9的微观形态。
如图2所示，制得的MM(图2A)、AMM-9(图2B)均为球形，粒径均一，MM的透射电镜粒径为218.5nm，AMM-9的透射电镜粒径为225.6nm，呈现均匀分布的介孔结构，且精氨酸的掺杂对介孔球状结构没有明显的影响。
实施例6动态光散射表征
将对比例1制备得到的MM与实施例1制备得到的AMM-9在超纯水中重悬，稀释至50μg/mL后超声均匀，利用动态光散射法检测纳米粒子样品的水合粒径。
如图3所示，MM(图3A)和AMM-9(图3B)纳米粒子粒径分布范围较窄，表明粒径比较均一。MM的水合粒径约为224.7nm，AMM-9的水合粒径约为233.3nm，透射电镜与动态光散射法测量结果基本相同。
实施例7扫描电镜元素分布表征
将实施例1制备得到的AMM-9配制成50μg/mL的乙醇溶液，取少量滴于铝箔上，晾干后置于G500高分辨场发射扫描电镜(Gemini 500，Zeiss/Bruker)下观察粒子形貌，以及元素的分布。如图4所示，可以直观地观察到AMM-9纳米粒子为粒径均匀的圆球形，通过SEM中附带的EDS分析得到AMM-9纳米粒子的元素映射图，可以观察到C、O、N、Mn各元素的均匀分布，表明Mn元素和精氨酸(含N)均匀的掺杂在了介孔聚多巴胺纳米粒子(AMM)纳米粒子的内部。
实施例8氮气/吸脱附表征
将实施例1制备得到的AMM-9真空干燥，获得100mg AMM-9样品，用仪器测定氮气吸附/脱附曲线。如图5所示，利用BJH法计算出AMM-9纳米粒子的比表面积为30.8m2/g(图5A)，孔径大小约为6.3nm(图5B)。
实施例9DPPH自由基清除实验
DPPH在有机溶剂中是一种稳定的氮自由基，当存在自由基清除剂时，DPPH的单电子被捕获，使其颜色变浅，最大吸收波长处的吸光度降低，因此选择它来评估自由基清除能力。将2mL DPPH/乙醇溶液(0.1mM)分别与20μL AMM-9溶液(1mg/mL)与MM溶液(1mg/mL)混合，测量20分钟内517nm处的吸光度，评估清除活性。如图6所示，在同等条件下，添加精氨酸的AMM-9组DPPH的清除率明显高于MM组，证明精氨酸的掺杂能够促进自由基的清除，提高清自由基除率。
实施例10羟基自由基清除实验
水杨酸可以与芬顿反应产生的·OH反应生成2,3-二羟基苯甲酸，在510nm处有特殊的吸光度，因此水杨酸法可以用于检测·OH的含量，评估纳米粒子的·OH清除能力。在离心管中加入适量去离子水、15mM水杨酸/乙醇溶液、15mM FeCl2、20mM H2O2和100μg/mL AMM-9或MM，置于37℃水浴中反应30分钟后，以不含H2O2的溶液为背景，检测溶液在510nm处的吸光度。如图7所示，在同等条件下，添加精氨酸的AMM-9组羟基自由基清除率明显高于MM组，进一步证明精氨酸的掺杂能够促进自由基的清除，显著提高自由基清除率。
实施例11磁共振成像(MRI)
将实施例1制备得到的AMM-9配制成不同浓度的溶液(Mn摩尔浓度为0，0.03，0.06，0.09，0.12，0.15，0.18，0.21，0.24mM)，在3.0T核磁共振成像仪下进行扫描，图8A中的T1和T2磁共振图像显示，随着Mn浓度的升高，T1加权信号逐渐降低、T2加权信号逐渐升高，即造影效果逐渐增强。图8B和8C中线性拟合结果显示，AMM-9在3.0T场强下纵向弛豫速率(r1)和横向弛豫率(r2)分别为59.93mM-1S-1和61.59mM-1S-1，说明AMM-9可作为T1-T2双模造影剂用于磁共振成像。
将实施例1制备得到的AMM-9配制成不同浓度的溶液(Mn摩尔浓度为0，0.36，0.40，0.44，0.48，0.52，0.54，0.60mM)，在7.0T核磁共振成像仪下进行扫描。图9A和图9B中T1和T2的磁共振图像显示，随着Mn浓度的升高，T1图像逐渐变亮；T2图像逐渐变暗，造影效果显著。图9C和图9D中线性拟合结果显示，AMM-9在7.0T场强下纵向弛豫速率(r1)和横向弛豫率(r2)分别为5.643mM-1S-1和56.96mM-1S-1。7T磁场的r1值明显小于3T磁场的r1值，这是由于在超高场(7T)下T2效应较强，可能会干扰T1造影剂的弛豫过程，从而显著降低T1信号。以上结果说明AMM-9可作为T1-T2双模造影剂用于超高场磁共振成像。
综合实施例1-11可见，本发明制备得到的AMM粒径均一，呈现均匀分布的介孔球形结构，比表面积大；精氨酸的掺杂量高，使其具有良好的自由基清除能力，可以有效降低炎症组织内氧化应激水平，减缓炎症进程；还可同时作为T1和T2的造影剂用于炎症组织的磁共振成像。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。
Claims (10)
1.一种氨基酸修饰的介孔聚多巴胺纳米粒子的制备方法，其特征在于，包括如下步骤：
将多巴胺、金属盐溶解于水中避光反应完全得溶液a；将嵌段式聚醚溶解于水、有机溶剂与溶液a的混合溶液中，滴加1,3,5-三甲苯超声至溶液变色，再滴加碱性氨基酸水溶液反应完全，后处理即得。
2.根据权利要求1所述制备方法，其特征在于，所述金属盐为锰盐。
3.根据权利要求1所述制备方法，其特征在于，所述嵌段式聚醚为嵌段式聚醚F-127或嵌段式聚醚F-68。
4.根据权利要求1所述制备方法，其特征在于，所述碱性氨基酸为精氨酸。
5.根据权利要求1所述制备方法，其特征在于，所述多巴胺、金属盐、嵌段式聚醚与碱性氨基酸的质量比为(20～40):1:(100～130):(1～5)。
6.根据权利要求1所述制备方法，其特征在于，所述水、有机溶剂与溶液a的体积比为(10～30):(10～30):1。
7.权利要求1～6任一所述制备方法制备得到的氨基酸修饰的介孔聚多巴胺纳米粒子。
8.权利要求7所述氨基酸修饰的介孔聚多巴胺纳米粒子在制备治疗炎症药物中的应用。
9.根据权利要求8所述应用，其特征在于，所述氨基酸修饰的介孔聚多巴胺纳米粒子用于清除自由基。
10.权利要求7所述氨基酸修饰的介孔聚多巴胺纳米粒子在制备核磁共振造影剂中的应用。
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