CN116492312B - 一种含有槲皮素的纳米酶颗粒和制备方法及其应用 - Google Patents
一种含有槲皮素的纳米酶颗粒和制备方法及其应用 Download PDFInfo
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Abstract
本发明公开了一种含有槲皮素的纳米酶颗粒和制备方法及其应用,该纳米酶颗粒为聚乳酸‑共羟基乙酸纳米颗粒中封装有槲皮素(Que)和Pt纳米酶(Ptzyme),并在颗粒表面修饰甘露醇配体以实现脑靶向功能。上述的含有槲皮素的纳米酶颗粒的制备方法,包括以下步骤:步骤1:甘露糖醇靶向的PLGA‑OH的制备;步骤2:采用复乳法合成Ptzyme和Que包封PLGA‑OH的PLGA纳米粒子,得到QPMP。本发明结合有机“中药酶”和无机纳米酶的优势,实现了两种酶活性的协同增强效应,能够有效清除帕金森疾病病灶部位的活性氧,并缓解炎症反应。
Description
技术领域
本发明涉及医药工程领域,尤其是一种含有槲皮素的纳米酶颗粒和制备方法及其应用。
背景技术
帕金森疾病(Parkinson's disease,PD)作为第二普遍的神经退行性疾病,在全球范围内患者接近一千万。目前PD的治疗策略主要包括脑深部电刺激术、运动恢复和药物治疗三个方面。其中,脑深部电刺激术尚存在技术壁垒,也没有具体的运动恢复方案批准应用。因此,药物治疗是目前PD治疗的主要选择。PD的直接病理特征是黑质致密部(Substantia nigra pars compacta,SNpc)中多巴胺能神经元的损失,因此,研究多将PD的治疗靶点集中在多巴胺(Dopamine,DA)的补充上,包括多巴胺的小分子前体药物—左旋多巴(Levodopa,L-dopa)、DA拮抗剂和单胺氧化酶B(Monoamine oxidase B,MAOB)抑制剂等。但是,绝大多数治疗药物都会对胃肠道产生明显的副作用,如恶心、呕吐和食欲不振。此外,胃肠道含有大量的微生物群,口服药物会被肠道微生物分解。血液注射的药物也容易被血液中的酶等降解,从而降低其利用率。例如,L-dopa虽然具有较强的血脑屏障(Blood-brainbarrier,BBB)穿透能力,但是其在体内半衰期短、生物利用度低,而高剂量的用药会导致生物耐药性、运动并发症以及运动障碍等严重的副作用。因此,PD的现有治疗手段面临严峻挑战,迫切需要深入阐明并针对PD的发病机制,研制毒性低、疗效好的PD治疗药物。
发明内容
发明目的:本发明目的是提供一种含有槲皮素的纳米酶颗粒。本发明另一个目的是提供该纳米酶颗粒的制备方法。本发明还有一个目的是提供该含有槲皮素的纳米酶颗粒在制备帕金森疾病药物中的应用。
技术方案:本发明所述的含有槲皮素的纳米酶颗粒,该纳米酶颗粒为聚乳酸-共羟基乙酸纳米颗粒上封装有槲皮素和Pt纳米酶。
本发明还提供了上述的含有槲皮素的纳米酶颗粒的制备方法,包括以下步骤:
步骤1:甘露糖醇靶向的PLGA-OH的制备;
步骤2:采用复乳法合成Pt纳米酶和槲皮素包封PLGA-OH的PLGA纳米粒子,得到QPMP。
优选的,所述步骤1中,包括:
将HOOC-PLGA-OH溶解在甲苯中,通过共沸蒸馏干燥;
干燥得到的样品在冰浴中冷却,并在二氯甲烷中重新收集;
再与甘露糖醇和DMAP混合,然后将混合液滴加至含有EDCI的二氯甲烷溶液之中;;将反应溶液在20~30 ℃氩气气氛下连续搅拌;
将连续搅拌后的反应溶液滴入乙醚中,使其反应;
形成的聚合物通过离心分离并在真空下干燥,得到甘露糖醇靶向的PLGA-OH,即Man-PLGA-OH,其中,HOOC-PLGA-OH、甘露糖醇、DMAP用量摩尔比为(3~9):(8~12):(2~10)。
优选的,所述步骤2中,将溶解于三氯甲烷的Man-PLGA-OH加入到溶解于甲醇的Pt纳米酶和槲皮素溶液中;
通过超声搅拌使溶剂溶解,然后加入PVA ,将混合物用超声乳化器乳化,制备第一种乳剂;
然后将PVA粉末溶解在双蒸馏水中,PVA水解度为87~90%,将PVA加入第一种乳剂中,均质,得到第二种乳剂;
将制备好的乳液加入异丙醇中,搅拌使有机溶剂挥发。然后离心,洗涤,形成QPMP,其中,Man-PLGA-OH、Ptzyme、Que、PVA用量质量比为(125~250):(10~25):0.1:1。
本发明还提供了上述的含有槲皮素的纳米酶颗粒在制备帕金森疾病药物中的应用。
发明机理:本发明协同有机“中药酶”和无机纳米酶的优势,制备一体化纳米体系,高效清除PD脑病灶部位活性氧(活性氧),缓解炎症反应,促进小胶质细胞从M1到M2期的转变,进而缓解PD的生理学和病理学症状;利用甘露糖醇(Mannitol,Man)对脑的靶向作用,制备的脑靶向纳米体系,实现药物对BBB的高效穿透作用,进而实现药物的脑靶向递送和PD的精准治疗。
有益效果:相对于现有技术,本发明具有如下的技术优点:
本发明将纳米酶和“中药酶”组装到纳米级别的帕金森治疗体系之中,并结合脑靶向的配体,实现帕金森疾病的精准治疗。
本发明结合有机“中药酶”和无机纳米酶的优势,实现了两种酶活性的协同增强效应,能够有效清除帕金森疾病病灶部位的活性氧,并缓解炎症反应。
本发明通过小鼠构建的帕金森疾病模型,证实该纳米体系能够有效缓解PD小鼠的行为学和病理学症状,达到治疗PD的目的。
附图说明
图1为本发明的QPMP合成、电镜表征和元素分析图,其中,图1(A)表示QPMP的合成、图(B-D)表示其电镜表征、图(E)为表示其元素分析;
图2为本发明的QPMP、Ptzyme和槲皮素的CAT和SOD模拟酶活性图,其中,图2(A)表示QPMP、Ptzyme和槲皮素的CAT,图2(B)表示SOD模拟酶活性;
图3为本发明的帕金森模型鼠的构建和QPMP药物治疗示意图;
图4为本发明的水迷宫和开野实验进行帕金森模型鼠的行为学评价图,其中,图4(A)为水迷宫实验行为学评价图,图4(B)为开野实验行为学评价图;
图5为本发明的小鼠黑质和纹状体区域的免疫荧光分析帕金森模型鼠脑区酪氨酸羟化酶(TH)的表达量图;
图6为海马区尼氏染色分析帕金森模型鼠的神经损伤情况图;
图7为脑病灶部位氧化损伤和胶质细胞激活情况图。
具体实施方式
本发明是一种具有抗氧化作用和缓解大脑炎症微环境的有机“中药酶”和无机纳米酶的集成纳米体系。该体系是通过将中药槲皮素(Que)和Pt纳米酶(Ptzyme)封装到聚乳酸-共羟基乙酸(PLGA)纳米颗粒中设计的。将甘露醇(Man)移植到纳米颗粒上合成Que/Ptzyme@Man-PLGA (QPMP),实现甘露醇靶向的脑药物递送和PD协同治疗。进一步的实验研究了纳米体系的脑靶向和神经胶质靶向性能,以及在行为学和病理水平上对PD的治疗作用。此外,还对其清除活性氧和调节小胶质细胞主导的神经炎症微环境的作用机制进行了深入探讨。
如图1所示,甘露糖醇靶向的PLGA-OH的制备方法,制备过程如下:
HOOC-PLGA-OH (0.1 ~0.3 mmol)溶解在3 mL甲苯中,通过共沸蒸馏干燥。干燥得到的样品在冰浴中冷却,并在30 mL二氯甲烷中重新收集。然后与2 mL甘露糖醇(0.4~0.6mmol)溶液(含有0.1~0.5 mmolDMAP)混合,然后将混合液滴加至3~5 mL含有0.6mmol EDCI的二氯甲烷溶液之中。随后,将反应溶液在20~30 ℃氩气气氛下连续搅拌,直至24 h。将反应溶液滴入乙醚中,使其反应。形成的聚合物通过离心分离并在真空下干燥,最终得到甘露糖醇靶向的PLGA-OH。
在本实施例中,HOOC-PLGA-OH浓度为0.2mmol,甘露糖醇浓度为0.5mmol,DMAP浓度为0.3 mmol,二氯甲烷溶液用量为4ml。
在本发明另一实施例中,HOOC-PLGA-OH浓度为0.3 mmol,甘露糖醇浓度为0.6mmol,DMAP浓度为0.5 mmol,二氯甲烷溶液用量为5ml。
在本发明另一实施中,HOOC-PLGA-OH浓度为0.1 mmol,甘露糖醇浓度为0.4mmol,DMAP浓度为0.1 mmol,二氯甲烷溶液用量为3ml。
QPMP的制备,采用复乳法合成Ptzyme和Que包封的PLGA纳米粒子,即QPMP。具体的,包括如下步骤:
将溶解于三氯甲烷(CHCl3) (1~3 mL)的Man-PLGA-OH (25~50 mg)加入到溶解于甲醇(500 μL)的Ptzyme (2~5 mg)和Que (2~5 mg)溶液中。通过超声搅拌使溶剂溶解,然后加入PVA (1 mL, w/v = 2%)。将混合物用超声乳化器乳化3分钟,制备第一乳剂。然后将PVA粉末溶解在双蒸馏水中,PVA水解度为87~90%。将5 mL PVA (w/v = 4%)加入第一种乳剂中,均质2~5 min,得到第二种乳剂。将制备好的乳液加入2%异丙醇(5 mL)中,磁搅拌2 h,使有机溶剂挥发。然后离心(7000~9000 g, 10~15分钟),洗涤3次,形成QPMP, 4℃保存。
在本实施例中,Man-PLGA-OH用量为35 mg,Ptzyme用量为4 mg,Que 用量为4 mg。
在本发明另一实施例中,Man-PLGA-OH用量为25 mg,Ptzyme用量为2 mg,Que 用量为2 mg。
在本发明另一实施例中,Man-PLGA-OH用量为50 mg,Ptzyme用量为5 mg,Que 用量为5 mg。
对合成的QPMP电镜观察和元素分析:
合成后的QPMP纳米粒子通过透射电子显微镜(HT7700,日立,日本))进行观察并进行化学元素(Pt,O,N,C)分析。结果见图1。由图1可见,成功通过上述方法合成了QPMP粒子(含有Pt、O、N和C元素),其具有均一、规整的形貌和纳米级别的粒径,有助于其入胞实现帕金森疾病的治疗。
SOD和CAT模拟酶活性分析:
纳米体系的超氧化物歧化酶(SOD)活性测定:通过分析纳米酶的O2•−消除率来测定纳米酶的SOD样活性。O2•−由黄嘌呤-黄嘌呤氧化酶(X-XOD)体系生成,细胞色素C作为O2•−指示剂。用紫外分光光度计(TuxiT6,北京)在1分钟内测定细胞色素C在550 nm (ΔA1)处的吸光度,测定对照体系(共3 mL:黄嘌呤0.5 mL,细胞色素C 0.5 mL,黄嘌呤氧化酶0.2 mL,PBS缓冲液1.8 mL)的O2•−浓度。当ΔA1调整为0.025时,分别在对照体系中加入纳米体系,记录细胞色素C在550 nm处的吸光度(ΔA2)在1分钟内的增加情况。纳米酶的O2•−去除率计算为(ΔA1-ΔA2)/ΔA1*100%。
纳米体系的过氧化氢酶(CAT)活性测定:使用溶解氧计(InPro 6860i, MettlerToledo, Switzerland) (InPro 6860i, Mettler Toledo, Switzerland)监测0.3% H2O2溶液中O2浓度的增加,测量纳米体系的CAT样活性。反应体系中含有40 μ g纳米酶和0.3% H2O2在PBS缓冲液(pH 7.4)或醋酸酯缓冲液(pH 4.5)中。通过监测H2O2在240 nm处吸光度的下降,测定纳米体系对H2O2的分解。其活性测定结果见图2。
帕金森小鼠模型的构建:
如图3所示,小鼠首先在转棒仪上依次进行5次8、16、24 rpm的匀速练习以及4~44rpm的匀加速练习,选用在转棒仪上行为一致的小鼠用于帕金森模型的构建。小鼠随机分为5组,分别命名为对照组、帕金森模型组(1-甲基-4-苯基-1,2,3,6-四氢吡啶盐酸盐(MPTP)建模)、Ptzyme、槲皮素以及QPMP。除对照组外,其余4组小鼠均通过腹腔注射MPTP(35mg/kg/day)的方式构建帕金森模型,连续注射5天,每隔一天注射一次,连续注射5次。对照组和帕金森模型组小鼠注射相同体积的生理盐水。
行为学评价:
水迷宫实验:首先将实验小鼠分别放置在四个象限,训练它们独立到达目标象限平台的能力。将未找到平台的小鼠引导至平台处,并停留1 min。训练结束后,对小鼠进行空间记忆测试。将训练实验中使用的固定平台从迷宫中移除,小鼠放入平台对面的水中自由游泳4 min,期间记录小鼠运动轨迹。
开野实验:开野实验用于评价实验小鼠在新环境中的自主行为和探索行为。器械(RWD 63041)为50×50×40 cm。将每只小鼠置于指定位置,通过SMART V3.0软件记录小鼠在随后5 min内的活动情况,并记录其在中心区的时间占比、在外围区的时间占比和平均速度。
水迷宫实验和开野实验的结果见图4。
免疫组化分析帕金森模型鼠脑区酪氨酸羟化酶(TH)的表达量:
将C57BL/6小鼠的脑部取出,放置于4%多聚甲醛中进行固定处理。接着,根据第三版小鼠脑图谱(Mouse Brain Atlas:C57BL/6 Coronal)的说明,取小鼠脑部前囟后2.80 mm至3.97 mm之间的部分(脑黑质区域)和纹状体区域依次进行70%、80%、90%、95%、无水酒精的梯度脱水,随后进行透明、浸蜡和石蜡包埋等处理。结束后,进行切片及烘干操作,然后将组织切片脱蜡至水,磷酸盐缓冲液(pH:7.2~7.4)冲洗3次,每次3~5 min,然后在室温下一抗孵育1~2 h,磷酸盐缓冲液冲洗3次后,接着进行二抗的孵育(Alexa Fluor 488标记的鼠抗,15min),磷酸盐缓冲液冲洗3次,干燥后进行封片处理。最后,通过荧光显微镜对组织切片进行观察并拍照。结果见图5。由图2和图5,QPMP脑靶向纳米粒子通过高效清除病灶部位的活性氧,增强了脑黑质和纹状体区域的TH水平。因为TH水平是帕金森疾病重要的病理指标,因此,该纳米粒子能够有效缓解帕金森疾病的病理症状。
海马区尼氏染色分析神经损伤情况:
将C57BL/6小鼠的脑部取出,放置于4%多聚甲醛中进行固定处理。取出海马区域,依次进行70%、80%、90%、95%、无水酒精的梯度脱水,随后进行透明、浸蜡和石蜡包埋等处理。结束后,进行切片及烘干操作,切片经二甲苯脱蜡5~10 min,入新鲜二甲苯再次脱蜡5~10min;然后切片入无水乙醇5 min,新鲜无水乙醇5 min,再经75%乙醇处理5 min,水洗2 min。上述处理好的样品,经尼氏染液(甲苯胺蓝溶液)染色2~5 min。水洗至玻片流水无颜色。甩干切片上多余水分,切片置于65℃烤箱烤干。充分烤干后以中性树胶封片。结果见图6,显示了海马区尼氏染色分析帕金森模型鼠的神经损伤情况。QPMP能够增强帕金森疾病小鼠脑海马CA1区域的神经元数量,从而证明其缓解帕金森小鼠神经损伤的能力。本发明的纳米体系能够有效缓解PD小鼠的行为学和病理学症状,达到治疗PD的目的。
脑黑质区域氧化损伤和胶质细胞激活情况:
使用试剂盒(E004,南京建成生物工程研究所,南京,中国)测定脑黑质区域活性氧水平。将脑组织机械制备成单细胞悬液,500 g离心10分钟收集。每个样品将细胞稀释为1.0×106。加入10 μM DCFH-DA, 37°C孵育60 min。用Infinite F200 Pro 酶标仪(TECAN,Switzerland)在485 nm激发波长下检测细胞荧光,并用荧光强度表达活性氧水平。脑黑质区域组织的脂质过氧化水平通过检测丙二醛(MDA)水平获得。使用试剂盒(A003,南京建成生物工程研究所,南京,中国)进行BCA检测和MDA含量分析。免疫组化分析星形胶质细胞标志物GFAP和小胶质细胞标志物Iba-1,具体实验方法同上,选用的抗体为GFAP(GB12096,索莱宝,中国)和IBA-1(GB13105-1,索莱宝,中国)。结果见图7,图7(A)显示了各实验组活性氧百分比,图7(B)显示了各实验组脂质过氧化百分比,QPMP纳米粒子能够有效清除脑黑质区域活性氧,并降低MDA水平;图7(C)显示了各实验组脑黑质区域图脑黑质区域,QPMP纳米粒子处理后,脑黑质区域星形胶质细胞和小胶质细胞含量显著降低。本发明的纳米体系能够有效缓解帕金森小鼠病灶部位的氧化损伤,并且抑制由胶质细胞介导的神经炎症反应,达到治疗帕金森疾病的目的。
相较于现有PD治疗药物和技术,本发明的特点是整合无机纳米酶(Ptzyme)和有机天然小分子化合物(槲皮素)的治疗优势,通过两种药物的协同作用,实现神经元氧化损伤的缓解和小胶质细胞M1-M2期的抗炎转变,达到标本兼治的效果。其次,本发明利用脑靶向配体Man,帮助药物高效完成血脑屏障穿透和脑部富集,具有较高的生物利用度。并且,本发明的载体PLGA具有理想的生物安全性,因此,本发明具有临床转化和应用前景。
Claims (5)
1.一种含有槲皮素的纳米酶颗粒,其特征在于,该纳米酶颗粒为聚乳酸-共羟基乙酸纳米颗粒上封装有槲皮素和Pt纳米酶,所述聚乳酸-共羟基乙酸为甘露糖醇靶向的PLGA-OH。
2.一种如权利要求1所述的含有槲皮素的纳米酶颗粒的制备方法,其特征在于,包括以下步骤:
步骤1:甘露糖醇靶向的PLGA-OH的制备,即Man-PLGA-OH;
步骤2:采用复乳法合成PLGA-OH包封Pt纳米酶和槲皮素的PLGA纳米粒子,得到含有槲皮素的纳米酶颗粒QPMP。
3.如权利要求2所述的一种含有槲皮素的纳米酶颗粒的制备方法,其特征在于,所述步骤1中,包括:
将HOOC-PLGA-OH溶解在甲苯中,通过共沸蒸馏干燥;
干燥得到的样品在冰浴中冷却,并在二氯甲烷中重新收集;
再与甘露糖醇和DMAP混合,然后将混合液滴加至含有EDCI的二氯甲烷溶液之中;将反应溶液在20~30 ℃氩气气氛下连续搅拌;
将连续搅拌后的反应溶液滴入乙醚中,使其反应;
形成的聚合物通过离心分离并在真空下干燥,得到Man-PLGA-OH,其中,HOOC-PLGA-OH、甘露糖醇、DMAP用量摩尔比为(3~9):(8~12):(2~10)。
4.如权利要求2所述的一种含有槲皮素的纳米酶颗粒的制备方法,其特征在于,所述步骤2中,将溶解于三氯甲烷的Man-PLGA-OH加入到溶解于甲醇的Pt纳米酶和槲皮素溶液中;
通过超声搅拌使溶剂溶解,然后加入PVA ,将混合物用超声乳化器乳化,制备第一种乳剂;
然后将PVA粉末溶解在双蒸馏水中,PVA水解度为87~90%,将PVA加入第一种乳剂中,均质,得到第二种乳剂;
将制备好的乳液加入异丙醇中,搅拌使有机溶剂挥发;然后离心,洗涤,形成含有槲皮素的纳米酶颗粒QPMP,其中,Man-PLGA-OH、Pt纳米酶Ptzyme、槲皮素Que、PVA用量质量比为(125~250):(10~25):0.1:1。
5.如权利要求1所述的含有槲皮素的纳米酶颗粒或者由权利要求2-4任一项所述制备方法得到的含有槲皮素的纳米酶颗粒在制备治疗帕金森疾病药物中的应用。
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