CN115607523A - 用于缓解和/或治疗阿尔兹海默症的组合物及其制备方法、应用 - Google Patents
用于缓解和/或治疗阿尔兹海默症的组合物及其制备方法、应用 Download PDFInfo
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Abstract
本发明公开了一种用于缓解和/或治疗阿尔兹海默症的组合物及其制备方法、应用。该制备方法包括以下步骤:(1)制备黑磷纳米片;(2)制备生物肽功能化的可生物降解共聚物;(3)制备载药纳米复合物:将生物肽功能化的可生物降解共聚物加入黑磷纳米片分散液中进行超声处理,低温梯度离心和洗涤后冻干,得纳米复合物;其中,所述超声处理为先水浴超声再探头超声,或者水浴超声与探头超声交替进行;(4)制备组合物。本发明提及的载药纳米复合物不仅增强了BBB穿透作用的同时达到了抑制Aβ聚集的作用,弥补了因B6稳定性较差可能减轻BBB穿透效应的缺陷,即可以大大提高BBB的穿透性,增强药物的靶向效率,有效地抑制了Aβ的聚集,改善因淀粉样蛋白沉积而导致的认知功能缺陷。
Description
技术领域
本发明涉及生物医用材料技术领域,特别涉及了用于缓解和/或治疗阿尔兹海默症的组合物及其制备方法、应用。
背景技术
阿尔兹海默病是一种进行性发展的神经退行性病变,患者会出现不同程度的记忆障碍和认知缺陷,给家庭及社会造成了极大的经济负担。关于该病的发病机制目前众说纷纭,但主流学说认为该病主要是由神经细胞外沉积的淀粉样斑块造成的,而淀粉样斑块的主要成分已被证实是Aβ。
在目前针对Aβ治疗的众多候选药物中,姜黄素展现出了良好的应用价值,包括靶向Aβ,减少淀粉样蛋白的形成,并且还能改善AD的神经炎症,氧化应激等损伤。姜黄素(Cur)是一种源自植物的多酚化合物,天然存在于姜黄中,姜黄是一种在印度和中国广泛使用的食品和药物。Cur靶向AD的两种组织学标志物,β-淀粉样蛋白(Aβ)和tau。它可以减少Aβ的产生、老年斑的形成和聚集、tau过度磷酸化和神经原纤维缠结的形成。此外,它还调节AD的其他方面,例如神经炎症、氧化应激、降低胆固醇、铜结合、小胶质细胞活性、胰岛素信号通路和乙酰胆碱酯酶抑制。Cur可以通过抑制5x FAD转基因小鼠的BACE1表达、Aβ病理学和突触退化来改善认知能力下降。Cur调节PTEN/Akt/GSK-3β通路,从而抑制tau过度磷酸化。Cur给药通过抑制镉处理大鼠中的乙酰胆碱酯酶基因表达来抑制乙酰胆碱酯酶活性。在AD小鼠模型中,姜黄素可以通过ERK和PKC依赖性途径调节神经生长因子(NGF),营养神经促进神经突生长,从而改善记忆缺陷。有研究称,姜黄素封装的PLGA纳米粒子(Cur-PLGA-NPs),通过经典Wnt/β-catenin途径的激活诱导成人神经增殖和分化,并可能通过增强脑部自我修复机制来提供治疗神经退行性疾病(如AD)的治疗方法。但是,由于姜黄素Cur其水溶性低、体内代谢和消除速度快、生物利用度差,以及通过血脑屏障(BBB)的渗透性差,是其应用的主要障碍。
虽然有大量的活性药物成分(API)可用于预防和治疗AD,但血脑屏障(BBB)的选择性以及严重的外周副作用限制了其适用性。解决这些问题的一个有希望的办法是将抗阿尔茨海默病药物纳入聚合物纳米颗粒(NPs)。聚合物可以通过多种方式增强治疗效果:通过增强药物稳定性和半衰期,通过实现靶向功能,通过提高生物降解性,以及通过使用刺激响应聚合物来实现控制释放。另外,在适用于药物递送目的的不同种类的材料中,生物可降解聚合物纳米颗粒因其安全性、大分子合成方法提供的灵活性、广泛的(共)聚合物组合物以及将其功能化以用于靶向和/或成像目的的可能性而引起了广泛关注。现如今,在AD中,聚合物亦被广泛用作纳米载体,以靶向和控释偶联或包封的药物。聚(丙交酯-乙交酯)(PLGA)和聚乙二醇(PEG)由于其生物相容性和生物降解性而被广泛用于药物递送目的。与单独Cur相比,PLGA和PLGA-PEG纳米颗粒可以通过增加Cur的平均半衰期、减少Cur的代谢和维持Cur的递送,分别将Cur的生物利用度提高15.6倍和55.4倍水悬浮液。另外,靶向存在于脑毛细血管内皮细胞和神经元中的TfR的B6肽在与一些纳米颗粒结合时会在BBB中发挥高渗透性。
但姜黄素的应用存在水溶性较差、易被降解、BBB穿透性差等问题。为了解决这个问题引进了PLGA、PEG等纳米材料。PLGA、PGA已被证明具有良好的生物相容性、生物降解性,已有研究证明姜黄素结合PLGA或PLGA-PEG可以极大地提高姜黄素的生物利用度,降低代谢及稳定传递。为了增强BBB的穿透性,有研究尝试将B6肽加入到含姜黄素的复合材料中,实验数据显示,的确增强了BBB的穿透性。但B6作为一种生物肽,其稳定性在研究中未得到充分的评估。
发明内容
为了弥补已有技术的缺陷,本发明提供了用于缓解和/或治疗阿尔兹海默症的组合物及其制备方法、应用。
本发明所要解决的技术问题通过以下技术方案予以实现:
第一方面,一种用于缓解和/或治疗阿尔兹海默症的组合物的制备方法,其特征在于,其包括以下步骤:
(1)制备黑磷纳米片:采用非接触式探头超声的液态剥离方法,将块体黑磷剥离得到少层黑磷纳米片;
(2)制备生物肽功能化的可生物降解共聚物:将丙烯酸化的可生物降解共聚物和生物肽混合溶解在缓冲盐水中,反应后将溶液离心收集,得生物肽功能化的可生物降解共聚物;
(3)制备载药纳米复合物:将生物肽功能化的可生物降解共聚物加入黑磷纳米片分散液中进行超声处理,低温梯度离心和洗涤后冻干,得纳米复合物;其中,所述超声处理为先水浴超声再探头超声,或者水浴超声与探头超声交替进行;
(4)制备组合物:将姜黄素、姜黄素类似物、姜黄素衍生物或其组合与纳米复合物溶解在有机溶剂中,高速搅拌并滴入去离子水中,待有机溶剂完全蒸发后,过滤且将滤液冻干以获得所述组合物。
在本发明中,所述步骤(1)具体包括:将块体黑磷研磨成粉末,并分散于乙醇溶剂中,进行探头和水浴超声处理,剥离得到少层黑磷纳米片;对超声后的黑磷分散液进行梯度离心处理,得到不同厚度和层数分布的少层BP纳米片溶液。
在本发明中,所述步骤(3)具体包括:将生物肽功能化的可生物降解共聚物加入至黑磷纳米片分散液,置于水浴中进行水浴超声,功率150~450W,控制温度低于30℃,超声时间8~12h;接着进行探头超声,功率150~200W,控制温度低于30℃,超声时间5~8h;超声反应后,进行4℃梯度离心,再分别采用丙酮和去离子水各洗涤3次即得相应水分散液,冻干得到纳米复合物。
在本发明中,所述步骤(3)具体包括:将生物肽功能化的可生物降解共聚物加入至黑磷纳米片分散液,交替进行功率为150~450W的水浴超声与功率为150~200W的探头超声,超声时温度低于30℃,水浴超声总时间为8~12h,探头超声总时间为5~8h;超声反应后,进行4℃梯度离心,再分别采用丙酮和去离子水各洗涤3次即得相应水分散液,冻干得到纳米复合物。
在本发明中,所述生物肽为B6肽。
在本发明中,所述可生物降解共聚物为聚丙交酯-乙交酯-聚乙二醇-聚丙交酯共聚物(PLGA-PEG)、聚丙交酯-乙交酯-聚乙二醇-聚丙交酯-乙交酯嵌段共聚物(PLGA-PEG-PLGA)、聚乙二醇-聚丙交酯-乙交酯-聚乙二醇嵌段共聚物(PEG-PLGA-PEG)、DL-乳酸-聚乙二醇共聚物(PLA-PEG-PLA)、聚ε-己内酯(PEG-PCL)、甲氧基聚乙二醇-聚乳酸两亲性嵌段共聚物(MPEG-PLA)、多聚N-(2-羟丙基)甲基丙烯酰胺(HPMA)、聚乙醇酸(PGA)、聚乙二醇1000维生素E琥珀酸酯(TPGS)、聚天冬氨酸(PAA)的一种或者多种高分子聚合物组成。
在本发明中,在步骤(2)中,所述可生物降解共聚物功能化前进行酯化处理,具体为:将可生物降解共聚充分溶解在二氯甲烷中,溶液反复抽真空并用氮气吹扫,得到可生物降解共聚物溶液;将三乙胺和丙烯酰氯分别溶于二氯甲烷中,在冰浴和避光条件下依次滴入可生物降解共聚物溶液中,其中,可生物降解共聚物、三乙胺和丙烯酰氯的摩尔比为1:8:8;化学反应在室温下持续24h以上;过滤溶液以除去三乙胺盐酸盐晶体并将滤液在十倍体积的冷乙醚中沉淀;将沉淀物在40℃下真空干燥,得到的产物是丙烯酸酯化的可生物降解共聚物。
第二方面,一种用于缓解和/或治疗阿尔兹海默症的组合物,所述组合物包含具有姜黄素、姜黄素类似物、姜黄素衍生物或其组合修饰的载药纳米复合物;所述载药纳米复合物包含生物肽、可生物降解共聚物及黑磷纳米片。
第三方面,一种任一上述制备方法制得的组合物或上述组合物在用于制备缓解和/或治疗阿尔兹海默症的功能性食品或药物中的应用。
第四方面,一种任一上述制备方法制得的组合物或上述组合物在制备抗阿尔茨海默症药物的注射剂、口服剂和植入给药剂中的应用。
本发明具有如下有益效果:
为了能够有效解决上述背景技术提及的技术问题,本发明提供了一种用于缓解和/或治疗阿尔兹海默症的组合物及其制备方法,其中,所述组合物包含具有姜黄素、姜黄素类似物、姜黄素衍生物或其组合修饰的载药纳米复合物;所述载药纳米复合物包含生物肽、可生物降解共聚物及黑磷纳米片。
黑磷(Black phosphorus)是一种非金属层状半导体,并且在磷元素的同素异形体中是最稳定的。BP具有良好的生物安全性、光热转化强,载药量大等优点,并且可将BP装载药物后,通过NIR激光照射来控制药物释放。另外一个可以利用BP的光热效应暂时性地打开BBB,有助于协同开放BBB,极大地提高了进入治疗部位的药量,为药物进入脑内提供窗口,提高药物利用率。
本发明提及的载药纳米复合物不仅增强了BBB穿透作用的同时达到了抑制Aβ聚集的作用,弥补了因B6稳定性较差可能减轻BBB穿透效应的缺陷,即可以大大提高BBB的穿透性,增强药物的靶向效率,有效地抑制了Aβ的聚集,改善因淀粉样蛋白沉积而导致的认知功能缺陷。还可以增加姜黄素的细胞摄取率,并且具有良好的血液相容性,同时该体系能有效抑制Aβ的生成和聚集,并降低Tau蛋白的异常磷酸化,为姜黄素以及新型纳米技术应用于AD治疗的研究提供新思路。本发明提供的策略大大提高了脂溶性药物及大分子药物的适用性,也拓宽了治疗脑部疾病的候选药物范围,对进一步开发治疗脑部疾病的治疗药物具有十分重大的意义。
相较于先前的发明,本发明人发现,与先前的姜黄素纳米粒相比,所合成的组合物具有更高的能带隙、更小的尺寸,更大的比表面积,单位质量上更多边缘活性位点。因此可以携带更多的姜黄素进入体内,提高载药率。
动物实验表明,与单独施用姜黄素的结果相比,本发明组合物能够显著提高转基因小鼠APP/PS1的空间学习和记忆能力。这些结果都证明本发明组合物具有治疗阿尔兹海默病的巨大潜力。更重要的是该工作提供的策略大大提高了脂溶性药物及大分子药物的适用性,也拓宽了治疗脑部疾病的候选药物范围,对进一步开发治疗脑部疾病的治疗药物具有十分重大的意义。
附图说明
图1(A)为PLGA-PEG-B6纳米粒子合成的一般步骤流程。
图1(B)为(a)PLGA-PEG、(b)丙烯酸酯化PLGA-PEG和(c)PLGA-PEG-B6的1H NMR光谱;
图1(C)为(a)PLGA-PEG、(b)丙烯酸酯化PLGA-PEG,和(c)PLGA-PEG-B6的FTIR光谱;
图2(A)为不同浓度的BP-PLGA-PEG-B6@Cur纳米粒子对红细胞溶血的影响示意图;
图2(B)为BP-PLGA-PEG-B6@Cur纳米粒子对凝血的影响,数据表示为平均值±SD(n=3);
图3(A-E)示出了细胞活力和细胞摄取效率,其中(A)用不同浓度(50、100、200和500mg/mL)的Cur、PLGA-PEG-B6@Cur、BP-PLGA-PEG@Cur、BP-PLGA-PEG-B6@Cur孵育24h后CCK-8测定的细胞活力结果,未经处理的细胞作为对照组。数据为平均值±SD,n=3。HT22细胞摄取(B)50-500lg/mL BP-PLGA-PEG-B6@Cur纳米颗粒在37C孵育4h。(C)200lg/mL BP-PLGA-PEG-B6@Cur纳米粒子在37C孵育不同时间。(D)500lg/mL Cur、BP-PLGA-PEG@Cur和BP-PLGA-PEG-B6@Cur纳米颗粒分别在37C孵育6h。(E)HT22细胞中Cur、BP-PLGA-PEG@Cur和BP-PLGA-PEG-B6@Cur纳米粒子吸收(500lg/mL,6h)的流式细胞术。数据为平均值±标准差,与前一组相比没有显着差异(NS)。)。
图4(A-E)示出了BP-PLGA-PEG-B6@Cur纳米粒子减轻了APP/PS1小鼠的学习和记忆障碍。其中,(A)学习试验中每组从第1天到第5天的逃避潜伏期比较。(B)第5天各组逃逸潜伏期比较。BP-PLGA-PEG-B6@Cur纳米粒子(25.113±2.506)比APP/PS1组(37.034±2.497)缩短了寻找平台的时间。(C)在探测试验中60秒内通过平台的数字。BP-PLGA-PEG-B6@Cur纳米粒子(3.250±0.707)比APP/PS1组(0.375±0.518)大大增加了通过平台的数量。(D)在探测试验中在目标象限中花费的时间百分比。BP-PLGA-PEG-B6@Cur纳米粒子(0.294±0.037)在目标象限搜索平台的时间比APP/PS1组(0.165±0.027)多。(E)各组游泳速度比较。游泳速度各组间无显着差异。(n=8,p<.05与WT组相比,#p<.05与前组)。WT:野生型;APP/PS1:生理盐水;Cur:姜黄素;NT:BP-PLGA-PEG@Cur纳米粒子;Tar:BP-PLGA-PEG-B6@Cur纳米粒子。
图5示出了BP-PLGA-PEG-B6@Cur纳米颗粒降低了APP/PS1小鼠的海马Aβ负荷。APP/PS1小鼠在海马区产生大量淀粉样蛋白(红色、白色和黑色箭头)。与APP/PS1对照组相比,Cur和NT适度减少了Ab斑块的形成。最值得注意的是,焦油显着减弱了这种病理学。其中,(A)各组Aβ斑块的银染(红色箭头)、免疫荧光(IF,白色箭头)和免疫组织化学(IHC,黑色箭头)。(B-D)分别通过银染、AβIF和Ab IHC比较各组中Ab斑块的相对密度。用盐水处理的APP/PS1小鼠和WT小鼠作为阳性和阴性对照。
图6示出了BP-PLGA-PEG-B6@Cur纳米颗粒降低了APP/PS1小鼠的海马Aβ产生并降低了tau磷酸化。其中(A)各组的Aβ、p-Tau(Ser396、Ser202和Thr231)、T-Tau、APP、PS1、BACE1和肌动蛋白的蛋白质条带分别。肌动蛋白担任内部控制。(B-H)这五组中Aβ、p-Tau(Ser396、Ser202和Thr231)、APP、PS1和BACE1的蛋白质表达比较。光密度分析数据显示,BP-PLGA-PEG-B6@Cur纳米粒子(Tar)显着降低了Aβ、p-Tau、BACE1、APP和PS1与肌动蛋白/T-tau的条带密度比。p<0.05与WT组相比,#p<0.05与前组相比。
具体实施方式
本发明中所用原料、设备,若无特别说明,均为本领域的常用原料、设备;本发明中所用方法,若无特别说明,均为本领域的常规方法。
如无特殊说明,本说明书中的术语的含义与本领域技术人员一般理解的含义相同,但如有冲突,则以本说明书中的定义为准。
本文中“包括”、“包含”、“含”、“含有”、“具有”或其它变体意在涵盖非封闭式包括,这些术语之间不作区分。术语“包含”是指可加入不影响最终结果的其它步骤和成分。术语“包含”还包括术语“由…组成”和“基本上由…组成”。本发明的组合物和方法/工艺包含、由其组成和基本上由本文描述的必要元素和限制项以及本文描述的任一的附加的或任选的成分、组分、步骤或限制项组成。
在说明书和权利要求书中使用的涉及组分量、工艺条件等的所有数值或表述在所有情形中均应理解被“约”修饰。涉及相同组分或性质的所有范围均包括端点,该端点可独立地组合。由于这些范围是连续的,因此它们包括在最小值与最大值之间的每一数值。还应理解的是,本申请引用的任何数值范围预期包括该范围内的所有子范围。
下面结合实施例对本发明进行详细的说明,实施例仅是本发明的优选实施方式,不是对本发明的限定。
实施例1
本实施例提供了一种用于缓解和/或治疗阿尔兹海默症的组合物的制备方法,其中,所述组合物包含具有姜黄素修饰的载药纳米复合物;所述载药纳米复合物包含生物肽B6肽、可生物降解共聚物PLGA-PEG及黑磷纳米片(BP)。
具体地,所述组合物的制备方法包括以下步骤:
(1)制备黑磷纳米片:采用非接触式探头超声的液态剥离方法,将块体黑磷剥离得到少层黑磷纳米片。
具体地:将块体BP研磨成粉末,并分散于乙醇溶剂中;进而对分散液进行探头和水浴超声处理:探头超声(功率180W,控制温度低于30℃,超声6h);水浴超声(功率300W,控制温度低于30℃,超声10h),超声后在电镜下观察粒径均匀,形貌均一即可;对超声后的BP分散液进行梯度离心处理,得到BP纳米片分散液。
(2)制备生物肽功能化的可生物降解共聚物:将丙烯酸化的可生物降解共聚物和生物肽混合溶解在缓冲盐水中,反应后将溶液离心收集,得生物肽功能化的可生物降解共聚物。
(2.1)合成PLGA-PEG共聚物,采用开环法:将PEG 1500(6g)加载到不锈钢反应器中,并在5mmHg真空下在150℃下加热2h以干燥;然后将D,L-丙交酯(D,L-Lactide)(9.0g)和乙交酯(Glycolide)(3.0g)装入反应器并在真空下在150℃下加热30分钟;接着添加2-乙基己酸亚锡(0.04g)作为催化剂并在真空下在160℃继续加热6h;反应完成后,将共聚物溶于4℃冷水中,然后加热至80℃,使未反应物和水溶性杂质沉淀除去。纯化过程进行了3次,纯化的PLGA-PEG共聚物在37℃真空下干燥以获得恒重;
(2.2)合成丙烯酸酯化的PLGA-PEG:将步骤(2.1)制得的PLGA-PEG(1g)充分溶解在二氯甲烷(15mL)中,溶液反复抽真空并用氮气吹扫;将三乙胺和丙烯酰氯分别溶于5mL二氯甲烷中,在冰浴和避光条件下依次滴入PLGA-PEG溶液中,其中,PLGA-PEG、三乙胺和丙烯酰氯的摩尔比为1:8:8;化学反应在室温下持续24h;过滤溶液以除去三乙胺盐酸盐晶体并将滤液在十倍体积的冷乙醚中沉淀。将沉淀物在40℃真空干燥,得到的产物是丙烯酸酯化的PLGA-PEG。
(2.3)生物肽功能化的可生物降解共聚物:将丙烯酸酯化的PLGA-PEG和B6肽以1:1的摩尔比溶解在磷酸盐缓冲盐水中,调节pH值接近7,室温反应24h。然后将溶液用去离子水透析并冻干,通过上述程序,得到生物肽功能化的可生物降解共聚物(即PLGA-PEG-B6)。
(3)制备载药纳米复合物:将生物肽功能化的可生物降解共聚物加入黑磷纳米片分散液中进行超声处理,低温梯度离心和洗涤后冻干,得纳米复合物;其中,所述超声处理为先水浴超声再探头超声,或者水浴超声与探头超声交替进行。
具体地:将PLGA-PEG-B6与BP纳米分散液以1:1(摩尔比)的比例置于水浴超声中超声,功率300W,控制温度低于30℃,反应10h;接着探头超声,功率180W,控制温度低于30℃,反应6h;超声结束后,4℃梯度离心,得BP-PLGA-PEG-B6分散液,分别采用丙酮和去离子水各洗涤3次即得相应水分散液。
(4)制备组合物:将姜黄素(Cur)与纳米复合物溶解在有机溶剂中,高速搅拌并滴入去离子水中,待有机溶剂完全蒸发后,过滤且将滤液冻干以获得所述组合物。
具体地:采用溶剂蒸发法制备,将Cur和BP-PLGA-PEG-B6以2:1(摩尔比)的比例加入到丙酮中,将悬浮液高速搅拌后滴入去离子水中。待丙酮完全蒸发后,过滤悬浮液以消除未加载的Cur,将滤液冻干以获得负载Cur的BP-PLGA-PEG-B6(BP-PLGA-PEG-B6@Cur)纳米颗粒,即组合物。
实施例2
本实施例与实施例1不同之处仅在于:步骤(3)中“将PLGA-PEG-B6与BP纳米分散液以1:1(摩尔比)的比例置于水浴超声中超声,功率300W,控制温度低于30℃,反应10h;接着探头超声,功率180W,控制温度低于30℃,反应6h”修改为“将PLGA-PEG-B6至入BP纳米分散液中,交替进行水浴超声与探头超声,超声时温度低于30℃,水浴超声总时间为8~12h,探头超声总时间为5~8h,期间水浴超声2h后换成探头超声1h,交替更换”。
在这个过程中,控制水浴超声与探头超声的组合转换非常重要。与探头超声相比,水浴超声可以将大量的黑磷分解成更小的颗粒,但是,单独使用水浴超声可能会导致不均一的纳米片。而将探头超声和水浴超声结合则有利于将BP及复合物进行结合。
下面是制备BP-PLGA-PEG-B6@Cur后的表征及证实其作用的方法。
(1)BP-PLGA-PEG-B6的表征分析
首先使用核磁共振光谱仪测定1H核磁共振(NMR)光谱,使用衰减全反射技术进行傅立叶变换红外(FTIR)分析,并且以500cm-1至4000cm-1的吸光度模式记录光谱。接着用激光粒度分析仪通过动态光散射(DLS)测定粒径分布和表面Zeta电动势。在测量之前,将纳米颗粒溶解在1mL蒸馏水中,使用TEM拍摄纳米颗粒的图像。
(2)纳米颗粒载药量及姜黄素累积释放分析
用紫外分光光度计测定BP-PLGA-PEG-B6@Curcumin纳米颗粒中姜黄素的负载量:首先绘制姜黄素的标准曲线,简而言之,将姜黄素(10mg)溶于DMSO并稀释至不同浓度(1、5、10、12、14、16、18、20、25和30μg/mL),测量425nm处的吸光度值以获得姜黄素的浓度-吸光度标准曲线。随后将BP-PLGA-PEG-B6@Curcumin粉末溶于DMSO中,并在425nm下测量吸光度值。姜黄素的负载量(LC)可用下式计算:
LC(%)=纳米材料中姜黄素的量/纳米材料的总量X100%
BP-PLGA-PEG-B6@Curcumin纳米颗粒中姜黄素的累积释放量测定的方法:用10mL生理盐水稀释BP-PLGA-PEG-B6@Curcumin(10mg),此时溶液浓度为1mg/mL。将该溶液转移至分子量截留为500的透析袋中,随后将透析袋放入10mL的PBS冲液释放介质中(PBS,0.01M,pH=7.4),置于37℃恒温摇床上,在不同的时间点(0、0.25、0.5、1、2、4、6、7、8、10、12、24、48和72h)取样,每次取出3mL的溶液然后向混悬液中补充3mL的PBS。通过紫外分光光度计在425nm处分别测量每次提取的释放液的吸光度值,根据各结果计算姜黄素的累积释放曲线。
结果:根据绘制的Cur标准曲线,Cur在BP-PLGA-PEG-B6@Cur纳米粒子中的负载量为15.6%。研究了胶束中Cur的时间依赖性药物释放曲线,pH值为7.4,相当于人体血液的pH值。如补充图S2所示,BP-PLGA-PEG-B6@Cur纳米颗粒表现出双相释放模式,其特征在于在第一个h内从BP-PLGA-PEG-B6@Cur纳米颗粒中初始释放29.60±0.70%Cur,然后持续在72h内释放至78.01±1.55%。
(3)红细胞渗透脆性及血栓弹力学分析
将红细胞(RBC)悬浮液(50μL,16%的PBS,v/v)加入1mL含有不同浓度纳米颗粒的PBS中,混合物离心5min,孵育一段时间后收集上清液,用酶标仪在540nm处测量释放的血红蛋白的吸光度值。同时以50μL RBC悬浮液加入1mL水中完全溶血作为阳性对照,50μLRBC悬浮液加入到1mL PBS中作为阴性对照。溶血率按照以下公式计算(As、An、Ap分别为样品、阴性和阳性对照的吸光度值):
血栓弹力学实验(thromboelastography,TEG):将新鲜柠檬酸盐全血和不同浓度的纳米颗粒以9:1的体积比混合,然后量取340μL混合物和20μL CaCl2(0.2M)溶液加入TEG杯中,通过血栓弹力图分析仪在37℃记录凝血过程。
溶血是指细胞膜完整性受到破坏,血红蛋白随之释放,反映了生物材料与红细胞膜的相互作用。不同浓度的BP-PLGA-PEG-B6@Cur纳米颗粒对红细胞溶血的影响见图2A。即使浓度达到0.5mg/mL,生理盐水与纳米颗粒溶液的溶血百分比也无显著差异,说明纳米颗粒没有明显的溶血反应。总之,这些结果表明,BP-PLGA-PEG-B6@Cur纳米颗粒的浓度小于0.05mg/mL对全血凝血系统影响不大。
(4)纳米颗粒的细胞毒性分析
采用CCK-8法检测BP-PLGA-PEG-B6@Curcumin纳米颗粒对HT22细胞的毒性评价。本研究分别给予不同浓度(50、100、200和500μg/mL)的样品(BP-PLGA-PEG-B6@Curcumin纳米颗粒、姜黄素、姜黄素装载的纳米颗粒PLGA-PEG-B6@Curcumin和BP-PLGA-PEG@Curcumin),对照组用等体积的培养基处理HT22细胞,空白组仅用培养基(无细胞)处理,各组设5各复孔。干预24h后,将10μL CCK8加入各孔中中,避光孵育2h后用多功能酶标仪在450nm处检测吸光度值,标准化对照组细胞活力为100%,并以此标准计算各组细胞活力。
结果:图3结果证明了在500μg/mL的浓度范围内,所有颗粒都不会影响细胞活力,这是一个相对较高的浓度。可以得出结论,天然Cur、PLGA-PEG@Cur和PLGA-PEG-B6@Cur纳米颗粒具有生物相容性并具有相对较低的毒性特征。
(5)细胞摄取评价
采用流式细胞术(FCM)对细胞摄取定量研究。将HT22细胞以2×105个细胞/孔接种于12孔板中,长至融合状态后分化24h。将不同剂量(50、100、200和500μg/mL)的BP-PLGA-PEG-B6@Curcumin纳米颗粒干预HT22细胞不同时长(2、4、6、8和12h)以评价细胞摄取效率。同时评估姜黄素、姜黄素装载的纳米颗粒PLGA-PEG@Curcumin和PLGA-PEG-B6@Curcumin)的细胞摄取效率。由于姜黄素在流式细胞术FITC通道上可自发黄绿色荧光,因此无需使用其他细胞染色技术。未经处理的细胞作为阴性对照。得出结果后分析比较不同组的荧光阳性细胞百分比和荧光强度。
如图3B-E所示,与天然姜黄素相比,BP-PLGA-PEG-B6@Cur纳米颗粒极大地增加了HT22细胞对其的吸收(图3(D,E))。利用率从8.94±1.10~45.72±0.48%(图3(D))。此外,PLGA-PEG-B6@Cur纳米颗粒的细胞摄取是剂量依赖和时间相关的(图3(B,C))。
(6)实验动物及给药方案
本研究使用40只9月龄雄性APP/PS1双转基因小鼠和8只同月龄具有相同遗传背景的C57/BL6雄性小鼠(WT),购自南京大学模式动物研究所,饲养于广州中医药大学SPF动物房,实验过程自由饮食和摄食。将小鼠随机分为WT组(n=8)、Tg对照组(APP/PS1,n=8)、姜黄素(Curcumin,Cur)给药组(APP/PS1,n=8)、BP-PLGA-PEG@Curcumin给药组(APP/PS1,n=8)、PLGA-PEG-B6@Curcumin给药组(APP/PS1,n=8)和PLGA-PEG@Curcumin给药组(APP/PS1,n=8)。相应给予APP/PS1小鼠腹腔注射姜黄素、PLGA-PEG@Curcumin和PLGA-PEG-B6@Curcumin纳米颗粒(3组中姜黄素的有效浓度均为25mg/kg/d)。WT组与Tg组予等体积0.9%无菌生理盐水腹腔注射,分别作为阴性和阳性对照组。上述治疗每周进行1次,共12次。
(7)行为学检测
上述各组(WT、Tg、Curcumin、BP-PLGA-PEG@Curcumin、PLGA-PEG@Curcumin、PLGA-PEG-B6@Curcumin)给药实验结束后,Morris水迷宫检测上述各组小鼠的学习和记忆能力。MWM包括为期5天的定向导航实验和为期1天的空间探索实验。在测试前,将所有小鼠放入池中游泳2分钟,然后引导至平台上保持20秒使之习惯环境。将定向导航实验设置为90秒,分别从4个象限中将小鼠放入池中,当小鼠在设置时间内找到隐藏平台并在平台上停留3秒,计时器将自动停止并记录时间,作为逃避潜伏期,如果小鼠在预定时间内找不到平台,则将引导小鼠停留在平台上20秒,获得的数据平均值为逃逸潜伏期。每天给予动物4次试验。定向导航实验结束后,移走平台,将小鼠放入池中游泳60秒,记录小鼠在目标象限(平台撤离前所在的位置)和通过平台的次数。
在第1天到第5天的定向导航实验中,我们分析了小鼠的逃跑潜伏期,发现随着时间的推移,小鼠找到平台的时间越来越少与APP/PS1组相比,BP-PLGA-PEG-B6@Cur纳米颗粒缩短了逃逸潜伏期(图4(A,B))。与APP/PS1和Cur组相比,预处理BP-PLGA-PEG-B6@Cur纳米颗粒的小鼠跨越平台的次数更多,在目标象限搜索平台的时间也更多(图4(C,D))。各组游泳速度无差异,可以排除身体对认知测试的影响(图4(E))。APP/PS1小鼠是研究阿尔茨海默病的良好模型,空间学习能力恶化。而BP-PLGA-PEG-B6@Cur纳米颗粒能显著改善认知功能APP/PS1小鼠的损伤,这将是潜在的应用于阿尔茨海默病。
(8)取材及脑组织处理
行为学检测结束后,处死各组小鼠(WT、Tg、Curcumin、BP-PLGA-PEG@Curcumin、PLGA-PEG@Curcumin、PLGA-PEG-B6@Curcumin),取材用于后续实验。
用于Bielschowsky银染、免疫组织化学(IHC)和免疫荧光(IF)染色的标本处理:小鼠行为学检测结束后,小鼠称重后,腹腔注射10%水合氯醛(4ml/kg)麻醉小鼠,用生理盐水和4%多聚甲醛先后灌注小鼠,取出大脑置于4%多聚甲醛中后固定过夜,接着用含30%蔗糖的PBS(0.1M)中沉降48h,随后切成厚度为15μm的切片。
用于ELISA(TNF-α、IL-6)、SOD、CAT、MDA、Western Blot等检测的脑组织标本处理:小鼠行为学检测结束后,小鼠称重后,腹腔注射10%水合氯醛(4ml/kg)麻醉小鼠,快速断头取脑,于冰上分离海马组织,迅速置于液氮罐中保存,随后移入-80℃冰箱储存并及时用于后续使用。
(9)Bielschowsky银染、IHC、IF等染色观察Aβ斑块
Bielschowsky银染:将各组小鼠脑组织切片浸入20%硝酸银溶液中并于37℃孵育30min,随后移入4%甲醛溶液中进行还原,接着滴加银氨染液200μl孵育10min,而后用3%甲醛溶液浸泡,流水冲洗5min,梯度酒精脱水,二甲苯进行透明处理,树脂封片,最后镜下观察海马区并摄片。
免疫组织化学(IHC):滴加适量的PBS湿化各组小鼠脑组织切片3min,滤纸吸干,滴加3%TritonX-100进行破膜,室温孵育20min之后滴加3%H2O2溶液孵育15min,PBS漂洗切片10min×3次,随后滴加10%封闭用血清室温封闭1h,加入一抗(Aβ17-24,1:500)后4℃过夜,次日PBS漂洗切片10min×3次,滴加二抗IgG-HRP室温孵育30min,PBS漂洗切片10min×3次,DAB显色液进行显色,根据显色情况用蒸馏水冲洗终止染色,随后进行梯度酒精脱水(50%5min、75%3min、80%3min、95%3min、95%3min、无水酒精2min、无水酒精2min),随后二甲苯I 5min、二甲苯II 3min,中性树胶封片,最后镜下观察海马区并摄片。
如图5所示,与WT小鼠相比,APP/PS1小鼠的大脑Ab斑沉积明显。而Cur和NT组表现出中度的减轻作用,Tar组表现出最明显的减轻作用。这些结果表明,BP-PLGA-PEG-B6@Cur纳米颗粒可能通过靶向Aβ病理治疗AD。
(10)检测海马组织TNF-α、IL-6、MDA的含量及SOD、CAT的活性
酶联免疫吸附法(enzyme linked immunosorbent assay,ELISA)法定量检测海马组织的TNF-α和IL-6。称取各组小鼠待测海马组织的重量,按组织重量(g):体积=1:9的比例加入pH为7.6的稀释液(50mMTris-HCl,150mMNaCl),冰浴条件下制成10%的脑组织匀浆,离心20min(16000g)后吸取上清液待测。根据TNF-α试剂盒和IL-6试剂盒提供的步骤进行后续实验。
结果:APP/PS1小鼠用生理盐水(APP/PS1)、Cur、PLGA-PEG-B6@Curcumin纳米颗粒(NT)、BP-PLGA-PEG-B6@Curcumin纳米颗粒(Tar)处理,然后进行Bielschowsky银染色和Aβ的IF/IHC脑切片。如图所示图5,与WT小鼠相比,APP/PS1小鼠表现出明显的脑Aβ斑块沉积。虽然Cur g和NT组显示出适度的减少作用,但Tar组在这种病理中表现出最显着的减少。这些结果表明,BP-PLGA-PEG-B6@Curcumin纳米粒子可能通过靶向Aβ病理学来有效治疗AD。
(11)Western Blot法检测Aβ斑块相关蛋白、NFTs相关蛋白、炎症相关蛋白、突触相关蛋白及凋亡相关蛋白的表达
各组小鼠(WT、Tg、Curcumin、BP-PLGA-PEG@Curcumin、PLGA-PEG-B6@Curcumin、BP-PLGA-PEG-B6@Curcumin)行为学结束后,腹腔注射10%水合氯醛(4ml/kg)麻醉小鼠,快速断头取脑,于冰上分离海马组织。本研究所用一抗:Aβ(D54D2)、BACE1、APP、PS1、ADAM10、p-Thr231-tau、p-Ser202-Tau、p-Ser396-tau、total-tau(tau 46)、IBA-1、PSD-95、p-GSK3βTyr216、p-GSK3βSer9、GSK3β、cleaved caspase-3、cleaved PARP和Actin等。
结果:APP/PS1小鼠的Aβ蛋白水平和tau的磷酸化水平显着高于WT小鼠。然而,Cur和NT可以以某种方式降低这些表达,而Tar显示出最显着的抑制作用。有趣的是,还可以发现BACE1、APP和PS1的抑制作用,这表明APP/PS1小鼠中的BP-PLGA-PEG-B6@Curcumin纳米颗粒可能会改变APP加工和γ-分泌酶切割。
(12)统计学分析
所有实验数据采用Mean±SD表示,采取SPSS16.0软件进行数据统计分析。定量资料两组独立样本均数比较采用独立样本t检验,多组间数据比较采用单因素方差分析(one-way ANOVA),多组均数两两比较采用LSD-t检验,P<0.05表示有统计学差异。
缩略语和关键术语定义
BP:黑磷,一种黑色有金属光泽的半导体晶体,它的密度为2.70g/cm3,硬度为2。它的晶格是由双原子层组成的,每一个层是由曲折的磷原子链组成的。在这些链中,P-P-P键角为90°磷一磷键距为2.17埃。黑磷在磷的同素异形体中反应活性最弱,它在空气中不会自燃。
PLGA(poly(lactic-co-glycolic acid):聚乳酸-羟基乙酸共聚物
PEG:聚乙二醇
Cur:Curcumin,姜黄素,是一种源自植物的多酚化合物,天然存在于姜黄中,姜黄是一种在印度和中国广泛使用的食品和药物。
TfR:转铁蛋白受体
AD:Alzheimer's disease,阿尔茨海默症,是一种起病隐匿的进行性发展的神经系统退行性疾病。临床上以记忆障碍、失语、失用、失认、视空间技能损害、执行功能障碍以及人格和行为改变等全面性痴呆表现为特征,病因迄今未明。
Aβ(amyloidβ-protein):β-淀粉样蛋白,分子量约4kDa,由β淀粉样前体蛋白(β-amyloid precursor protein,APP)水解而来,由细胞分泌,在细胞基质沉淀聚积后具有很强的神经毒性作用。
P-Tau:磷酸化Tau蛋白
BBB:血脑屏障,指脑毛细血管壁与神经胶质细胞形成的血浆与脑细胞之间的屏障和由脉络丛形成的血浆和脑脊液之间的屏障,这些屏障能够阻止某些物质(多半是有害的)由血液进入脑组织。
NMR:核磁共振
FTIR:傅立叶变换红外
DLS:动态光散射
TEM:透射电子显微镜
RBC:红细胞
TEG(thromboelastograph):血栓弹力学实验
FCM:流式细胞术
IHC:免疫组织化学
IF:免疫荧光染色
ELISA:酶联免疫吸附测定
TNF-α:肿瘤坏死因子
IL-6:白细胞介素-6
SOD:超氧化物歧化酶
CAT:过氧化氢酶
Western Blot:蛋白质印迹法(免疫印迹试验)
以上所述实施例仅表达了本发明的实施方式,其描述较为具体和详细,但并不能因此而理解为对本发明专利范围的限制,但凡采用等同替换或等效变换的形式所获得的技术方案,均应落在本发明的保护范围之内。
Claims (10)
1.一种用于缓解和/或治疗阿尔兹海默症的组合物的制备方法,其特征在于,其包括以下步骤:
(1)制备黑磷纳米片:采用非接触式探头超声的液态剥离方法,将块体黑磷剥离得到少层黑磷纳米片;
(2)制备生物肽功能化的可生物降解共聚物:将丙烯酸化的可生物降解共聚物和生物肽混合溶解在缓冲盐水中,反应后将溶液离心收集,得生物肽功能化的可生物降解共聚物;
(3)制备载药纳米复合物:将生物肽功能化的可生物降解共聚物加入黑磷纳米片分散液中进行超声处理,低温梯度离心和洗涤后冻干,得纳米复合物;其中,所述超声处理为先水浴超声再探头超声,或者水浴超声与探头超声交替进行;
(4)制备组合物:将姜黄素、姜黄素类似物、姜黄素衍生物或其组合与纳米复合物溶解在有机溶剂中,高速搅拌并滴入去离子水中,待有机溶剂完全蒸发后,过滤且将滤液冻干以获得所述组合物。
2.根据权利要求1所述组合物的制备方法,其特征在于,所述步骤(1)具体包括:将块体黑磷研磨成粉末,并分散于乙醇溶剂中,进行探头和水浴超声处理,剥离得到少层黑磷纳米片;对超声后的黑磷分散液进行梯度离心处理,得到不同厚度和层数分布的少层BP纳米片溶液。
3.根据权利要求1所述组合物的制备方法,其特征在于,所述步骤(3)具体包括:将生物肽功能化的可生物降解共聚物加入至黑磷纳米片分散液,置于水浴中进行水浴超声,功率150~450W,控制温度低于30℃,超声时间8~12h;接着进行探头超声,功率150~200W,控制温度低于30℃,超声时间5~8h;超声反应后,进行4℃梯度离心,再分别采用丙酮和去离子水各洗涤3次即得相应水分散液,冻干得到纳米复合物。
4.根据权利要求1所述组合物的制备方法,其特征在于,所述步骤(3)具体包括:将生物肽功能化的可生物降解共聚物加入至黑磷纳米片分散液,交替进行功率为150~450W的水浴超声与功率为150~200W的探头超声,超声时温度低于30℃,水浴超声总时间为8~12h,探头超声总时间为5~8h;超声反应后,进行4℃梯度离心,再分别采用丙酮和去离子水各洗涤3次即得相应水分散液,冻干得到纳米复合物。
5.根据权利要求1所述组合物的制备方法,其特征在于,所述生物肽为B6肽。
6.根据权利要求1所述组合物的制备方法,其特征在于,所述可生物降解共聚物为聚丙交酯-乙交酯-聚乙二醇-聚丙交酯共聚物、聚丙交酯-乙交酯-聚乙二醇-聚丙交酯-乙交酯嵌段共聚物、聚乙二醇-聚丙交酯-乙交酯-聚乙二醇嵌段共聚物、DL-乳酸-聚乙二醇共聚物、聚ε-己内酯、甲氧基聚乙二醇-聚乳酸两亲性嵌段共聚物、多聚N-(2-羟丙基)甲基丙烯酰胺、聚乙醇酸、聚乙二醇1000维生素E琥珀酸酯、聚天冬氨酸的一种或者多种高分子聚合物组成。
7.根据权利要求1所述组合物的制备方法,其特征在于,在步骤(2)中,所述可生物降解共聚物功能化前进行酯化处理,具体为:将可生物降解共聚充分溶解在二氯甲烷中,溶液反复抽真空并用氮气吹扫,得到可生物降解共聚物溶液;将三乙胺和丙烯酰氯分别溶于二氯甲烷中,在冰浴和避光条件下依次滴入可生物降解共聚物溶液中,其中,可生物降解共聚物、三乙胺和丙烯酰氯的摩尔比为1:8:8;化学反应在室温下持续24h以上;过滤溶液以除去三乙胺盐酸盐晶体并将滤液在十倍体积的冷乙醚中沉淀;将沉淀物在40℃下真空干燥,得到的产物是丙烯酸酯化的可生物降解共聚物。
8.一种用于缓解和/或治疗阿尔兹海默症的组合物,其特征在于,所述组合物包含具有姜黄素、姜黄素类似物、姜黄素衍生物或其组合修饰的载药纳米复合物;所述载药纳米复合物包含生物肽、可生物降解共聚物及黑磷纳米片。
9.一种如权利要求1-7任一项所述制备方法制得的组合物或如权利要求8所述组合物在用于制备缓解和/或治疗阿尔兹海默症的功能性食品或药物中的应用。
10.一种如权利要求1-7任一项所述制备方法制得的组合物或如权利要求8所述组合物在制备抗阿尔茨海默症药物的注射剂、口服剂和植入给药剂中的应用。
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