CN116854951A - 由聚甲硫乙基丙烯酸酯的聚合物制备得到的纳米粒、制备方法及其应用 - Google Patents
由聚甲硫乙基丙烯酸酯的聚合物制备得到的纳米粒、制备方法及其应用 Download PDFInfo
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Abstract
本发明公开一种由聚甲硫乙基丙烯酸酯的聚合物制备得到的纳米粒、制备方法及其应用，纳米粒由基于聚甲硫乙基丙烯酸酯的聚合物通过自组装形成。通过调控制备工艺，可得到不同粒度的纳米粒。制备得到的纳米粒具有活性氧响应性，聚合物中的甲硫基团可在活性氧条件下转变为甲砜基团，使得原本疏水的聚合物变得亲水，在纳米粒水解的同时快速清除活性氧，从而抵抗氧化应激给生物体带来的损伤，在广谱抗炎方面有较好的应用前景。
Description
技术领域
本发明属于功能纳米粒技术领域，具体涉及一种由聚甲硫乙基丙烯酸酯的聚合物制备得到的纳米粒、制备方法及其应用。
背景技术
活性氧(ROS)在细胞信号通路中发挥着重要作用，而ROS的过度生成可能会破坏细胞的平衡，损害细胞成分，包括膜脂质、蛋白质和DNA，从而引起氧化应激和一系列的疾病。炎症是免疫系统对损伤和感染的自然反应，可导致炎症物质，如细胞因子、自由基、激素和其他小分子的释放，从而利于保护人体免受影响。然而，有流行病学和临床证据表明，过度炎症是有害的，如肺炎、关节炎、糖尿病、神经退行性疾病和心血管疾病。现在已经有证据阐明，异常的ROS生成是炎症发病机制的关键媒介之一。在内质网中氧化蛋白折叠的过程中，二硫键的形成需要使用分子氧作为终端电子受体，从而导致ROS的产生。此外，大量消耗还原性谷胱甘肽也会引发额外的氧化应激压力。这些ROS有利于钙离子释放到细胞膜和线粒体，导致ROS的第二次产生。这些都可以引发氧化应激的连续循环升高，最终达到毒性阈值，从而导致各种炎症相关的病理异常。不受控制的ROS和持续的氧化应激产生将导致细胞和组织损伤，从而进一步启动炎症周期，因此对不良氧化应激的抑制在各类疾病中均占有重要的地位。
具有纳米尺寸的多功能颗粒已被证实可在炎症等水肿部位聚集，因发生炎症而产生肿胀血管内皮可以为纳米粒提供天然的富集途径。因此，纳米药物载体被认为是炎症治疗的实用工具。然而，目前的研究中尚无针对广谱炎症抗氧化治疗的有效方案。因此，开发结构相对简单、易于实现的纳米粒，用于广谱炎症的抗氧化治疗有着非常重要的临床意义。
发明内容
针对现有技术中的上述不足，本发明提供一种由聚甲硫乙基丙烯酸酯的聚合物制备得到的纳米粒、制备方法及其应用，该纳米粒由聚甲硫乙基丙烯酸酯的聚合物通过自组装形成，在活性氧条件下发生水解，同时快速清除活性氧，从而抵抗氧化应激给生物体带来的损伤，在广谱抗炎方面有较好的应用前景。
为实现上述目的，本发明解决其技术问题所采用的技术方案是：
一方面，一种由聚甲硫乙基丙烯酸酯的聚合物制备得到的纳米粒，所述纳米粒由基于聚甲硫乙基丙烯酸酯的聚合物通过自组装形成，所述聚甲硫乙基丙烯酸酯的聚合物的化学结构式为：
其中，该聚合物的聚合度为20-60。
另一方面，一种由聚甲硫乙基丙烯酸酯的聚合物制备得到的纳米粒的制备方法，其特征在于，该方法包括如下步骤：
(1)将甲硫乙基丙烯酸酯、4-氰基戊酸二硫代苯甲酸和偶氮二异丁腈以摩尔比(80～2400)：(4～40)：(1～10)的比例溶于四氢呋喃，在70℃的氩气保护下进行充分反应，所得溶液在离子水中透析，然后冷冻干燥，得到聚甲硫乙基丙烯酸酯；
具体的操作为：将甲硫乙基丙烯酸酯、4-氰基戊酸二硫代苯甲酸和偶氮二异丁腈溶于四氢呋喃，加入Schlenk烧瓶中。经过三个循环的冷冻-泵送-解冻程序后，在70℃的氩气保护下进行反应，反应时间为24小时。所得溶液在离子水中(MCWO＝2000)透析24小时，然后冷冻干燥得到聚甲硫乙基丙烯酸酯。
(2)将所述聚甲硫乙基丙烯酸酯溶于二甲基亚砜，搅拌得聚甲硫乙基丙烯酸酯的二甲基亚砜溶液，将聚甲硫乙基丙烯酸酯的二甲基亚砜溶液加入生理盐水或超纯水中搅拌，最后透析除去有机溶剂，制得纳米粒。
优选地，所述聚甲硫乙基丙烯酸酯的二甲基亚砜溶液与生理盐水或超纯水的体积比为(1～2):(1～40)，搅拌时间为1～4小时。
一种由聚甲硫乙基丙烯酸酯的聚合物制备得到的纳米粒在抗氧化应激上的应用。
通过调控制备工艺，可得到不同粒度的纳米粒。制备得到的纳米粒具有活性氧响应性，聚合物中的甲硫基团可在活性氧条件下转变为甲砜基团，使得原本疏水的聚合物变得亲水，同时快速清除活性氧，达到广谱抗炎的目的。
本发明的有益效果如下：
(1)本发明通过可逆加成-断裂链转移聚合制备聚甲硫乙基丙烯酸酯聚合物，反应可控性良好，合成的聚合物分子量均一性好，易于大量制备。并由此制备的纳米粒的工艺简单，可大量制备。制备的纳米粒均一且稳定，且可通过改变制备参数可控地调整纳米粒的粒度大小。
(2)本发明制备的抗氧化纳米粒可通过甲硫基团在活性氧条件下向甲砜基团的快速转化，高效清除活性氧，实现抗氧化应激。
(3)本发明制备的抗氧化纳米粒可通过抗氧化这一机制，实现对肺炎、关节炎进行广谱抗炎治疗，有效抑制各病的发展与恶化。
附图说明
图1为聚甲硫乙基丙烯酸酯的核磁共振氢谱图谱。
图2为聚甲硫乙基丙烯酸酯的凝胶渗透色谱图谱。
图3为在PBS中以及活性氧条件下纳米粒的粒径变化图。
图4为纳米粒的体外细胞内活性氧清除结果图。
图5为纳米粒对肺炎治疗的结果图。
图6为纳米粒对关节炎治疗的结果图。
具体实施方式
下面对本发明的具体实施方式进行描述，以便于本技术领域的技术人员理解本发明，但应该清楚，本发明不限于具体实施方式的范围，对本技术领域的普通技术人员来讲，只要各种变化在所附的权利要求限定和确定的本发明的精神和范围内，这些变化是显而易见的，一切利用本发明构思的发明创造均在保护之列。
实施例1
将甲硫乙基丙烯酸酯(3.5g)、4-氰基戊酸二硫代苯甲酸(0.1g)和偶氮二异丁腈(25mg)溶于四氢呋喃，加入Schlenk烧瓶中。经过三个循环的冷冻-泵送-解冻程序后，在70℃的氩气保护下进行反应，反应时间为24小时。所得溶液在离子水中(MCWO＝2000)透析24小时，然后冷冻干燥得到聚甲硫乙基丙烯酸酯。上述制得的大分子聚合物前药的核磁共振氢谱图谱见图1，由其出峰位置以及积分比例可知聚合物成功合成。该聚合物凝胶渗透色谱图见图2，可知该聚合物分子量分布集中，均一性好。所得聚合物的分子量见表1。
然后将上述所得的聚甲硫乙基丙烯酸酯(10mg)溶于1mL二甲基亚砜，搅拌得溶液，将溶液加入3mL生理盐水或超纯水中搅拌2小时，最后透析除去有机溶剂(MCWO＝2000)，制得纳米粒。纳米粒粒径见表2。
实施例2
将实施例1制备得到的聚甲硫乙基丙烯酸酯(10mg)溶于2mL二甲基亚砜，搅拌得溶液，将溶液加入2mL生理盐水或超纯水中搅拌2小时，最后透析除去有机溶剂(MCWO＝2000)，制得纳米粒。纳米粒粒径见表2。
实施例3
将实施例1制备得到的聚甲硫乙基丙烯酸酯(10mg)溶于3mL二甲基亚砜，搅拌得溶液，将溶液加入1mL生理盐水或超纯水中搅拌2小时，最后透析除去有机溶剂(MCWO＝2000)，制得纳米粒。纳米粒粒径见表2。
实施例4
将实施例1制备得到的聚甲硫乙基丙烯酸酯(10mg)溶于1mL二甲基亚砜，搅拌得溶液，将溶液加入3mL生理盐水或超纯水中搅拌0.5小时，最后透析除去有机溶剂(MCWO＝2000)，制得纳米粒。纳米粒粒径见表2。
实施例5
将实施例1制备得到的聚甲硫乙基丙烯酸酯(10mg)溶于1mL二甲基亚砜，搅拌得溶液，将溶液加入3mL生理盐水或超纯水中搅拌4小时，最后透析除去有机溶剂(MCWO＝2000)，制得纳米粒。纳米粒粒径见表1。
表1实施例1～5的制备工艺条件及制得的纳米粒粒径
| 序号 | 二甲基亚砜体积(mL) | 生理盐水或超纯水体积(mL) | 搅拌时间(h) | 粒径大小(d.nm) |
| 1 | 1 | 3 | 2 | 162.8±10.6 |
| 2 | 2 | 2 | 2 | 264.2±50.7 |
| 3 | 3 | 1 | 2 | 458.6±108.9 |
| 4 | 1 | 3 | 0.5 | 206.4±67.5 |
| 5 | 1 | 3 | 4 | 160.7±15.1 |
实施例6
将甲硫乙基丙烯酸酯(4.6g)、4-氰基戊酸二硫代苯甲酸(0.1g)和偶氮二异丁腈(25mg)溶于四氢呋喃，加入Schlenk烧瓶中。经过三个循环的冷冻-泵送-解冻程序后，在70℃的氩气保护下进行反应，反应时间为24小时。所得溶液在离子水中(MCWO＝2000)透析24小时，然后冷冻干燥得到聚甲硫乙基丙烯酸酯。所得聚合物的分子量见表2。
将上述所得的聚甲硫乙基丙烯酸酯(10mg)溶于1mL二甲基亚砜，搅拌得溶液，将溶液加入3mL生理盐水或超纯水中搅拌2小时，最后透析除去有机溶剂(MCWO＝2000)，制得纳米粒。
实施例7
将甲硫乙基丙烯酸酯(13.8g)、4-氰基戊酸二硫代苯甲酸(0.1g)和偶氮二异丁腈(25mg)溶于四氢呋喃，加入Schlenk烧瓶中。经过三个循环的冷冻-泵送-解冻程序后，在70℃的氩气保护下进行反应，反应时间为24小时。所得溶液在离子水中(MCWO＝2000)透析24小时，然后冷冻干燥得到聚甲硫乙基丙烯酸酯。所得聚合物的分子量见表2。
将上述所得的聚甲硫乙基丙烯酸酯(10mg)溶于1mL二甲基亚砜，搅拌得溶液，将溶液加入3mL生理盐水或超纯水中搅拌2小时，最后透析除去有机溶剂(MCWO＝2000)，制得纳米粒。
实施例8
将甲硫乙基丙烯酸酯(6.9g)、4-氰基戊酸二硫代苯甲酸(0.1g)和偶氮二异丁腈(25mg)溶于四氢呋喃，加入Schlenk烧瓶中。经过三个循环的冷冻-泵送-解冻程序后，在70℃的氩气保护下进行反应，反应时间为24小时。所得溶液在离子水中(MCWO＝2000)透析24小时，然后冷冻干燥得到聚甲硫乙基丙烯酸酯。所得聚合物的分子量见表2。
将上述所得的聚甲硫乙基丙烯酸酯(10mg)溶于1mL二甲基亚砜，搅拌得溶液，将溶液加入3mL生理盐水或超纯水中搅拌2小时，最后透析除去有机溶剂(MCWO＝2000)，制得纳米粒。
表2实施例1、6～8制备得到的聚甲硫乙基丙烯酸酯的工艺条件及分子量
试验例1纳米载体的稳定性和活性氧响应性研究
将实施例1制得的纳米粒置于37℃，用动态光散射仪测定纳米粒在不同浓度过氧化氢溶液中的粒径变化，结果如图3。由图3可知，本实施例制得的纳米粒在无过氧化氢条件下表现出很好的稳定性，而在过氧化氢条件下可迅速解体，表现为粒径变大。
试验例2纳米粒的体外细胞内活性氧清除能力
将实施例1制备得到的纳米粒配成0.1mg/ml和1mg/ml浓度的溶液，将溶液与被脂多糖激活的巨噬细胞共培养12小时，用DCFH-DA活性氧探针测定细胞内活性氧产生水平。
由图4可知，与阳性对照相比，本发明制得的纳米粒能够高效清除生成的活性氧，且呈浓度相关性。
试验例3纳米粒对肺炎的治疗能力
通过吸入脂多糖构建小鼠肺炎模型，构建模型后通过尾静脉注射，给予小鼠0.1mg/ml和1mg/ml浓度的纳米粒溶液处理。24小时后处死小鼠，取肺部组织做H&E切片染色，观察肺部炎症及水肿情况，如图5所示。
由图5可知，相比于阳性对照组，经纳米粒处理后的肺部水肿、炎症细胞浸润和肺泡出血明显减少，且随着更高浓度的纳米粒能更有效地缓解这些组织学损伤。
试验例4纳米粒对关节炎的治疗能力
通过原位注射II型胶原诱导关节炎构建小鼠关节炎模型，并在构建模型2周后，通过尾静脉注射给予小鼠0.1mg/ml和1mg/ml浓度的纳米粒溶液处理。给药2周后对后肢进行拍照，观察关节肿胀程度，如图6所示。
由图6可知，在阳性对照组中观察到了严重的关节肿胀，而纳米粒处理组在治疗周期结束时表现出明显的消肿情况，且纳米粒浓度越高消肿越明显。
本领域普通技术人员可以理解，以上所述仅为发明的优选实例而已，并不用于限制发明，尽管参照前述实例对发明进行了详细的说明，对于本领域的技术人员来说，其依然可以对前述各实例记载的技术方案进行修改，或者对其中部分技术特征进行等同替换。凡在发明的精神和原则之内，所做的修改、等同替换等均应包含在发明的保护范围之内。
Claims (4)
1.一种由聚甲硫乙基丙烯酸酯的聚合物制备得到的纳米粒，其特征在于，所述纳米粒由基于聚甲硫乙基丙烯酸酯的聚合物通过自组装形成，所述聚甲硫乙基丙烯酸酯的聚合物的化学结构式为：
其中，该聚合物的聚合度为20-60。
2.一种如权利要求1所述的由聚甲硫乙基丙烯酸酯的聚合物制备得到的纳米粒的制备方法，其特征在于，该方法包括如下步骤：
(1)将甲硫乙基丙烯酸酯、4-氰基戊酸二硫代苯甲酸和偶氮二异丁腈以摩尔比(80～2400)：(4～40)：(1～10)的比例溶于四氢呋喃，在70℃的氩气保护下进行充分反应，所得溶液在离子水中透析，然后冷冻干燥，得到聚甲硫乙基丙烯酸酯；
(2)将所述聚甲硫乙基丙烯酸酯溶于二甲基亚砜，搅拌得聚甲硫乙基丙烯酸酯的二甲基亚砜溶液，将聚甲硫乙基丙烯酸酯的二甲基亚砜溶液加入生理盐水或超纯水中搅拌，最后透析除去有机溶剂，制得纳米粒。
3.根据权利要求2所述的纳米粒的制备方法，其特征在于，所述聚甲硫乙基丙烯酸酯的二甲基亚砜溶液与生理盐水或超纯水的体积比为(1～2):(1～40)，搅拌时间为1～4小时。
4.一种如权利要求1所述的由聚甲硫乙基丙烯酸酯的聚合物制备得到的纳米粒在抗氧化应激上的应用。
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