CN112574415B - 一种活性氧响应性材料及其制备方法与应用 - Google Patents
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Abstract
本发明的一种活性氧响应性材料及其制备方法与应用属于纳米材料制备技术领域，所述的活性氧响应性材料，结构式如下：
制备方法包括PGED的制备、PGED‑PPS的制备等步骤，所述的活性氧响应性材料可用于制备既能消耗ROS又具备特异性释放药物能力的纳米胶束。本发明制备的纳米胶束具有过氧化氢特异性响应的特点，还可以通过消耗过氧化氢实现和辛伐他汀等协同治疗的效果。
Description
技术领域
本发明属于纳米材料制备技术领域，具体涉及一种具有活性氧(ROS)响应，既能消耗ROS又具备特异性释药能力的纳米胶束的制备与应用。
背景技术
目前，心血管疾病是威胁人类生命安全的最觉见的疾病之一。心血管疾病的主要死亡原因之一是由于其多种严重的并发症，包括：高血压、冠心病、心绞痛、中风、血管病变等。动脉粥样硬化的发病机制尚未完全阐明，但常被认为是一种可引起心血管疾病的慢性炎症性疾病。在正常生理条件下，ROS在细胞生长、增殖和信号通路中发挥重要作用。细胞内氧化和还原性物质之间的氧化还原平衡对于信号通路调节是必要的，但是ROS的过量产生会引起氧化应激，氧化内皮中的低密度脂蛋白(ox LDL)激活免疫反应，从而导致内皮细胞功能障碍，刺激泡沫细胞形成，使白细胞持续迁移到病患部位并且分泌更多的炎性细胞因子，诱导炎症级联反应，加速动脉粥样硬化过程。因此，以炎症和氧化应激为主要方向可以为动脉粥样硬化的治疗提供新的策略。
迄今为止，辛伐他汀(SV)作为最有效的抗血栓药物之一，可以通过减少肝脏中低密度脂蛋白(LDL)的产生和增加其在血液中的流出来改善内皮功能和减少平滑肌细胞增殖，从而减少炎症和氧化应激，以降低心血管疾病的风险。然而，SV是一种亲脂性药物，水溶性低，在水中不稳定并且体内半衰期短，使得治疗效果大打折扣。长期自由给药不仅导致动脉粥样硬化斑块处的药物浓度过低，还会引发一系列副作用如：心肌病、糖尿病和出血性中风等问题。
纳米给药技术是一种解决以上问题的很有前途的方法。纳米颗粒(MC)已经被证明具有被动靶向的优势，其可以通过受损的内皮或由于外膜功能障碍导致的新生血管转运靶向动脉粥样硬化斑块。然而，非特异性纳米粒子在体内循环时往往不可避免地导致药物在非患病处的大量泄漏。为了实现纳米颗粒的靶向释放，必须合理运用动脉粥样硬化部位的特定环境(如高浓度的H2O2)将纳米颗粒设计成特异性响应药物递送系统。
传统的响应型胶束往往只具备特异性释药的能力，功能单一，大大的浪费了纳米系统的多功能性。最近的进展表明，本身就具有抗氧化和抗炎活性的纳米粒子有望成为动脉粥样硬化和其它炎症类疾病更为有效的治疗方法。
发明内容
本发明的目的在于，为解决传统响应性胶束功能单一的局限，提供一种既能响应活性氧又能消耗活性氧的材料PGED-PPS(聚甲基丙烯酸缩水甘油酯-聚硫化丙烯)，同时还提供该材料的制备方法及其在制备抗血栓纳米胶束方面的应用。
本发明的技术方案如下：
一种活性氧响应性材料，结构式如下：
一种活性氧响应性材料的制备方法，具有以下步骤：
1)PGED的制备
无水无氧状态下，在圆底烧瓶中加入氯化亚铜和2,2'-联吡啶，络合10分钟后再加入甲基丙烯酸缩水甘油酯(GMA)、N,N-二甲基甲酰胺(DMF)和2-溴代异丁酸乙酯(EBiB)；按摩尔比，氯化亚铜:2,2'-联吡啶:甲基丙烯酸缩水甘油酯:N,N-二甲基甲酰胺:2-溴代异丁酸乙酯＝1:1～5:80～120:50～100:1，全部加入后于50℃下反应3～8h，反应结束后，将反应物溶于氯仿中，过中性氧化铝柱子，收集滤液，旋蒸浓缩液体后于甲醇中沉淀，反复纯化后置于真空烘箱干燥30～50h，得到白色粉状产物PGMA；
在氮气氛围下按摩尔比1:5～10:20～50将上述制得的PGMA、二甲基亚砜(DMSO)和乙二胺(EDA)加入圆底烧瓶，80℃下搅拌3～6h后，用反应液的40～80倍蒸馏水稀释反应液，然后用透析膜(Da＝1000)透析30～50h，最后将透析液冻干24～36h，得到白色固体产物PGED(乙二胺开环型聚甲基丙烯酸缩水甘油酯)；
2)PGED-PPS的制备
将PGED与二甲基亚砜(DMSO)加入圆底烧瓶，冷却至0℃后，加入4-二甲氨基吡啶(DMAP)、吡啶和4-甲苯磺酰氯(TsCl)；按摩尔比，PGED:二甲基亚砜:4-二甲氨基吡啶:吡啶:4-甲苯磺酰氯＝1:30～50:1:30～50:10～30；室温下搅拌10～20h，反应结束后用透析膜(Da＝2000)透析30～50h，透析结束后通过冻干得浅黄色固体PGED-Ts；
将PGED-Ts溶于二甲基亚砜(DMSO)中，然后加入三乙胺(TEA)和硫代乙酸钾；按摩尔比，PGED-Ts:二甲基亚砜:三乙胺:硫代乙酸钾＝1:10～30:1～5:1；室温下反应5～15h，然后用透析袋(Da＝2000)透析30～50h，透析结束后通过冻干得淡黄色固体PGED-硫代乙酸酯；
将PGED-硫代乙酸酯溶解在体积比1:1～5的THF和甲醇混合液中，加入乙醇钠室温下搅拌0.5～1.5h，冷却至0℃后加入硫化丙烯，其中PGED-硫代乙酸酯、甲醇钠和硫化丙烯的摩尔比为1:0.5～1:0.5～10，0.5～1h后恢复室温继续搅拌8～15h，随后用去离子水透析(Da＝2000)30～50h，然后冷冻干燥得到活性氧响应性材料PGED-PPS。
一种活性氧响应性材料的应用，其特征在于，是用于制备既能消耗ROS又具备特异性释放药物能力的纳米胶束，具体步骤为：将PGED-PPS和抗血栓药物完全溶解在N,N-二甲基甲酰胺(DMF)中，混合液在超声处理下滴加到冷的去离子水中，其中PGED-PPS、抗血栓药物、N,N-二甲基甲酰胺和水的质量比为1:1～3:10～30:80～120，滴加完毕后用去离子水透析1～3d，得到既能消耗ROS又具备特异性释放药物能力的抗血栓纳米胶束。
所述的抗血栓药物优选辛伐他汀。
有益效果：
1、本发明将毒副作用较大的辛伐他汀通过用PGED-PPS包覆形成纳米胶束使其具有良好的生物相容性。
2、纳米胶束具有过氧化氢特异性响应的特点。
3、本发明的纳米胶束不仅具有过氧化氢响应的能力，还可以通过消耗过氧化氢实现和辛伐他汀协同治疗的效果。
附图说明
图1是实施例1中过氧化氢响应型聚合物PGED-PPS的核磁图。
图2是实施例1中聚合物PGMA、聚合物PGED-PPS和过氧化氢响应后PGED-PPS的红外光谱图。
图3是实施例3中SV MC的透射电镜图。
图4是实施例4中PGED、MC和SV MC的过氧化氢清除能力图。
图5是实施例5中MC对RAW264.7细胞存活能力的影响图。
图6是实施例5中SV和SV MC对RAW264.7细胞存活能力的影响图。
图7是实施例6中SV、MC和SV MC分别作用RAW264.7细胞1h后细胞内ROS的荧光强度对比图。
图8是实施例7中体内治疗后动脉粥样硬化部位的血管切片的H&E图。
图9是实施例8中SV和SV MC对家兔肝肾功能中的AST、ALT和BUN指标的影响图。
图10是实施例8中SV和SV MC对家兔肝肾功能中的T-BIL、SCr、UA指标的影响图。
图11是实施例8中SV和SV MC对家兔血液中WBC、Lymph#、HCT指标的影响图。
具体实施方式
实施例1：活性氧响应性材料PGED-PPS的合成
将5mL DMF加入到含有0.048g CuCl和0.048g bpy的50mL圆底烧瓶中。然后，在脱气条件下，将12mL GMA和180μL EBiB依次加入上述溶液。在氩气气氛50℃下聚合4h，通过使溶液通过氧化铝除去催化剂，随后用冷甲醇沉淀，产物通过反复重结晶纯化，然后在室温下真空干燥24h，得到6g PGMA。取5g PGMA溶解在20mL DMSO中，然后加入过量的EDA。反应在氮气气氛下于80℃进行4h。用过量的去离子水稀释反应溶液，然后将反应液置于透析膜(MWCO1.0kDa)中用去离子水透析48h以消除过量的EDA。冻干后获得6.6g白色粉末PGED。将1gPGED完全溶解在14mL DMSO中。冷却至0℃后，加入43mg DMAP、1mL吡啶和1g TsCl。将反应物在室温下搅拌12h，反应结束后将反应液置于透析袋(MWCO 2.0kDa)中透析48h。冷冻干燥获得2.04g浅黄色PGED-对甲苯磺酸酯。将2g PGED-对甲苯磺酸酯溶解在10mL DMSO中。再向溶液中加入15mL TEA和3g硫代乙酸钾。反应在室温下进行过夜。然后用透析膜(MWCO 2.0kDa)将溶剂用去离子水透析48h。用冻干机冷冻干燥后，得到1.04g淡黄色固体PGED-硫代乙酸酯。PGED-硫代乙酸酯和硫化丙烯的质量比为1∶1的合成方法如下:将0.5g PGED硫代乙酸酯溶解在THF和甲醇的混合物(v/v，10/10)中。加入64mg CH3ONa，然后将混合物在室温下搅拌1h，冷却至0℃后加入1g硫化丙烯。30min后，移走冷却设备，溶液在室温下搅拌过夜。随后，将混合物用去离子水透析(MWCO 2.0kDa)2d，并冷冻干燥，得到1.57g聚合物PGED-PPS。图1中可看出目标产物各H位置和峰面积均有很好的归属。图2中可看出H2O2响应后S＝O的特征峰的出现，即证明了PGED-PPS的成功合成又证明了H2O2的响应能力。
实施例2：PGED-PPS空白胶束的制备
将PGED-PPS(10mg)完全溶解在3mL DMF中，混合液在超声处理下滴加到8mL冷的去离子水中，然后用去离子水透析(MWCO 3.0kDa)一天，以获得胶束溶液(MC)。
实施例3：SV MC载药纳米胶束的制备
将PGED-PPS(10mg)和辛伐他汀(3mg)完全溶解在3mL DMF中，在超声处理条件下，将上述混合液滴加到8mL冷的去离子水中，然后用去离子水透析(MWCO 3.0kDa)一天，以获得胶束溶液(SV MC)。图3通过透射电镜中纳米粒子的形貌可以看出SV MC的成功制备。
实施例4：活性氧清除能力的测定
以过硫酸盐化学发光法检测PGED、MC和SV MC清除活性氧的能力。分别在37℃含50μM过氧化氢的3mL生理盐水中加入PGED,MC和SV MC(1mg/mL)。在预定的时间间隔，将含有草酸二苯酯和红荧烯的THF加入H2O2溶液中。混合物中H2O2的浓度通过测量过氧化物化学发光反应的发光强度来确定。图4说明MC具有可以与SV协同清除过氧化氢的能力。
实施例5：体外细胞毒性的测定
应用MTT法分析评估SV，MC和SV MC对RAW 264.7的细胞毒性。将RAW 264.7接种到96孔板(每孔5000个细胞)中，在5％CO2湿润的气氛中，于37℃下培养24h。将每个样品以0至64μg/mL的浓度添加到孔中，将细胞继续培养24h。随后，使用MTT检测每个板上的细胞活力，并使用酶联免疫吸附测定仪测定每个孔中溶液在492nm处的吸光度。图5和图6说明与SV相比，MC和SV MC均具有较好的生物相容性。
实施例6：细胞内ROS含量的测量
将RAW 264.7细胞铺板于6孔(每孔1.0×105个细胞)中，并在37℃下用LPS(4μg/mL)处理36h。然后，将细胞用PBS洗涤三次后立即添加SV，MC或SV MC。在预定的时间间隔，将细胞洗涤三次并在黑暗中与DCFH-DA(10μM)一起孵育30min。轻轻洗涤细胞以除去游离的DCFH-DA，然后在室温下与Hoechst 33342染色液(1mM)一起孵育10min以复染细胞核，用PBS洗涤并在共聚焦激光扫描显微镜上观察。图7说明MC具有可以与SV协同清除细胞内ROS的能力。
实施例7：体内治疗情况
麻醉新西兰大白兔后用棉绳固定四肢和头部，用外科剪刀和玻璃分针将迷走神经及其周围组织从下颌分离到胸骨上切迹，显露一段左侧颈动脉。注射SV、SV MC或等量生理盐水后，用含30％FeCl3的滤纸处理左侧颈动脉形成血栓。治疗一定时间后，取左侧颈动脉测量血栓的长度和重量。图8说明SV MC具有良好的抗血栓效果。
实施例8：体内生物安全性评估
家兔禁食过夜后，通过静脉注射SV、SV MC或等量的生理盐水。注射3h后采集全血、血浆和血清进行血常规、凝血时间和肝肾功能指标的测定。图9、图10和图11表示不同组间的血液学指标无明显变化，所测标志物均在正常范围内，说明SV MC具有良好的血液相容性和肝肾安全性。
Claims (4)
1.一种活性氧响应性材料，结构式如下：
所述活性氧响应性材料是按以下步骤制备的：
1)PGED的制备
无水无氧状态下，在圆底烧瓶中加入氯化亚铜和2,2'-联吡啶，络合10分钟后再加入甲基丙烯酸缩水甘油酯、N,N-二甲基甲酰胺和2-溴代异丁酸乙酯；按摩尔比，氯化亚铜:2,2'-联吡啶:甲基丙烯酸缩水甘油酯:N,N-二甲基甲酰胺:2-溴代异丁酸乙酯＝1:1～5:80～120:50～100:1，全部加入后于50℃下反应3～8h，反应结束后，将反应物溶于氯仿中，过中性氧化铝柱子，收集滤液，旋蒸浓缩液体后于甲醇中沉淀，反复纯化后置于真空烘箱干燥30～50h，得到白色粉状产物PGMA；
在氮气氛围下按摩尔比1:5～10:20～50将上述制得的PGMA、二甲基亚砜和乙二胺加入圆底烧瓶，80℃下搅拌3～6h后，用反应液的40～80倍蒸馏水稀释反应液，然后用透析膜透析30～50h，最后将透析液冻干24～36h，得到白色固体产物PGED；
2)PGED-PPS的制备
将PGED与二甲基亚砜加入圆底烧瓶，冷却至0℃后，加入4-二甲氨基吡啶、吡啶和4-甲苯磺酰氯；按摩尔比，PGED:二甲基亚砜:4-二甲氨基吡啶:吡啶:4-甲苯磺酰氯＝1:30～50:1:30～50:10～30；室温下搅拌10～20h，反应结束后用透析膜透析30～50h，透析结束后通过冻干得浅黄色固体PGED-Ts；
将PGED-Ts溶于二甲基亚砜中，然后加入三乙胺和硫代乙酸钾；按摩尔比，PGED-Ts:二甲基亚砜:三乙胺:硫代乙酸钾＝1:10～30:1～5:1；室温下反应5～15h，然后用透析袋透析30～50h，透析结束后通过冻干得淡黄色固体PGED-硫代乙酸酯；
将PGED-硫代乙酸酯溶解在体积比1:1～5的THF和甲醇混合液中，加入乙醇钠室温下搅拌0.5～1.5h，冷却至0℃后加入硫化丙烯，其中PGED-硫代乙酸酯、甲醇钠和硫化丙烯的摩尔比为1:0.5～1:0.5～10，0.5～1h后恢复室温继续搅拌8～15h，随后用去离子水透析30～50h，然后冷冻干燥得到活性氧响应性材料PGED-PPS。
2.一种权利要求1所述的活性氧响应性材料的制备方法，具有以下步骤：
1)PGED的制备
无水无氧状态下，在圆底烧瓶中加入氯化亚铜和2,2'-联吡啶，络合10分钟后再加入甲基丙烯酸缩水甘油酯、N,N-二甲基甲酰胺和2-溴代异丁酸乙酯；按摩尔比，氯化亚铜:2,2'-联吡啶:甲基丙烯酸缩水甘油酯:N,N-二甲基甲酰胺:2-溴代异丁酸乙酯＝1:1～5:80～120:50～100:1，全部加入后于50℃下反应3～8h，反应结束后，将反应物溶于氯仿中，过中性氧化铝柱子，收集滤液，旋蒸浓缩液体后于甲醇中沉淀，反复纯化后置于真空烘箱干燥30～50h，得到白色粉状产物PGMA；
在氮气氛围下按摩尔比1:5～10:20～50将上述制得的PGMA、二甲基亚砜和乙二胺加入圆底烧瓶，80℃下搅拌3～6h后，用反应液的40～80倍蒸馏水稀释反应液，然后用透析膜透析30～50h，最后将透析液冻干24～36h，得到白色固体产物PGED；
2)PGED-PPS的制备
将PGED与二甲基亚砜加入圆底烧瓶，冷却至0℃后，加入4-二甲氨基吡啶、吡啶和4-甲苯磺酰氯；按摩尔比，PGED:二甲基亚砜:4-二甲氨基吡啶:吡啶:4-甲苯磺酰氯＝1:30～50:1:30～50:10～30；室温下搅拌10～20h，反应结束后用透析膜透析30～50h，透析结束后通过冻干得浅黄色固体PGED-Ts；
将PGED-Ts溶于二甲基亚砜中，然后加入三乙胺和硫代乙酸钾；按摩尔比，PGED-Ts:二甲基亚砜:三乙胺:硫代乙酸钾＝1:10～30:1～5:1；室温下反应5～15h，然后用透析袋透析30～50h，透析结束后通过冻干得淡黄色固体PGED-硫代乙酸酯；
将PGED-硫代乙酸酯溶解在体积比1:1～5的THF和甲醇混合液中，加入乙醇钠室温下搅拌0.5～1.5h，冷却至0℃后加入硫化丙烯，其中PGED-硫代乙酸酯、甲醇钠和硫化丙烯的摩尔比为1:0.5～1:0.5～10，0.5～1h后恢复室温继续搅拌8～15h，随后用去离子水透析30～50h，然后冷冻干燥得到活性氧响应性材料PGED-PPS。
3.一种权利要求1所述的活性氧响应性材料的应用，其特征在于，是用于制备既能消耗ROS又具备特异性释放药物能力的纳米胶束，具体步骤为：将PGED-PPS和抗血栓药物完全溶解在N,N-二甲基甲酰胺中，混合液在超声处理下滴加到冷的去离子水中，其中PGED-PPS、抗血栓药物、N,N-二甲基甲酰胺和水的质量比为1:1～3:10～30:80～120，滴加完毕后用去离子水透析1～3d，得到既能消耗ROS又具备特异性释放药物能力的抗血栓纳米胶束。
4.根据权利要求3所述的一种活性氧响应性材料的应用，其特征在于，所述的抗血栓药物是辛伐他汀。
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