CN117379365A - 一种载益母草碱纳米复合水凝胶、制备方法及应用 - Google Patents
一种载益母草碱纳米复合水凝胶、制备方法及应用 Download PDFInfo
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Abstract
本发明涉及生物医药技术领域,公开了一种载益母草碱纳米复合水凝胶、制备方法及应用,该水凝胶包括载有抗炎药物益母草碱的叶酸功能化多巴胺纳米药物(FA‑PDA@Leon)和明胶‑聚乙二醇二丙烯酸酯(Gel/PEGDA)水凝胶基质。该水凝胶具有良好的注射性、生物粘合性和抗炎性,能够被注射进关节腔内成胶并紧密附着于软骨组织,从而延长纳米药物在关节腔局部的驻留时间,提高治疗效果。该水凝胶能够通过下调JAK2/STAT3信号通路抑制滑膜炎症,同时能够通过抑制软骨细胞的铁死亡对关节软骨起到保护作用,从而实现对类风湿性关节炎的有效治疗。
Description
技术领域
本发明涉及生物医药技术领域,具体涉及一种载益母草碱纳米复合水凝胶、制备方法及应用。
背景技术
类风湿性关节炎(RA)是一种慢性自身免疫性炎症疾病,主要影响关节软骨和骨骼,导致关节疼痛、肿胀、僵硬和功能障碍。RA的发病原因尚不明确,但与遗传、环境、生活方式等因素有关。目前,RA的治疗主要依赖于药物干预,包括非甾体抗炎药、糖皮质激素、疾病修饰抗风湿药和生物制剂等,但这些药物的疗效有限,且存在耐药性和副作用等问题。因此,寻找新的治疗靶点和策略是RA研究的重要方向。
近年来,越来越多的研究表明,RA的发病机制与滑膜炎症和软骨细胞的铁死亡有关。滑膜炎症是由于机体免疫功能失调,导致大量的免疫细胞,特别是M1型巨噬细胞浸润到滑膜组织,分泌过量的炎症因子和活性氧(ROS),从而引起关节腔内的炎症反应。滑膜炎症不仅直接损伤关节软骨,还通过炎症介质的作用,诱导软骨细胞发生铁死亡,即铁蛋白溶酶体/铁依赖性细胞死亡,这是一种新发现的细胞死亡方式,以脂质过氧化和铁代谢紊乱为特征。铁依赖性细胞死亡的发生,导致软骨细胞的凋亡和软骨基质的降解,进而加速RA的病变进程。
因此,针对滑膜炎症和铁死亡的治疗,有望实现对RA的有效控制。传统中药在疾病治疗中有着悠久的使用历史,由于其多种生物学益处,目前越来越受到人们的关注,有望提供新的治疗靶点。益母草碱作为从益母草中提取的主要活性成分,具有良好的抗炎活性,可抑制炎症相关信号通路的激活,如核因子κB (NF-κB)、丝裂原活化蛋白激酶(MAPK)、JAK2/STAT3通路。有助于减少促炎细胞因子和ROS的表达,为软骨细胞的存活创造合适的环境。然而,目前的药物干预面临着药物的靶向性差、生物利用度低、治疗时间短等挑战,导致药物的疗效不理想。为了克服这些问题,一些新的技术和方法被开发用于RA治疗,例如纳米粒子药物传递系统、CRISPR-Cas9基因组编辑技术等。本发明提出了一种用于治疗RA的注射性生物粘合水凝胶,该水凝胶能够在关节腔内形成并紧密附着于软骨组织,从而释放载有抗炎药物益母草碱的叶酸修饰的多巴胺纳米药物,抑制滑膜炎症和铁依赖性细胞死亡,保护软骨组织,恢复关节功能。
发明内容
针对上述问题,本发明提供一种载益母草碱纳米复合水凝胶、制备方法及应用。
本发明采用下述的技术方案:
一种载益母草碱纳米复合水凝胶的制备方法,包括如下步骤:
步骤1:溶解多巴胺单体并诱导多巴胺DA单体氧化和自聚合,得到聚多巴胺PDA纳米颗粒,在PDA纳米颗粒表面接枝巯基聚乙二醇叶酸SH-PEG-FA,得到FA-PDA纳米载体;
步骤2:利用步骤1所述FA-PDA纳米载体负载益母草碱Leon,得到FA-PDA@Leon;
步骤3:将步骤2所述FA-PDA@Leon包封至凝胶基质中得到凝胶@FA-PDA@Leon水凝胶。
进一步的,所述步骤2中,所述FA-PDA纳米载体:Leon质量比为20:1。
进一步的,所述步骤1中,DA单体氧化和自聚合的条件为在25℃,pH 8.5的Tris溶液中,搅拌反应12小时。
进一步的,所述步骤3中,凝胶@FA-PDA@Leon水凝胶的具体制备方法如下:溶解明胶与FA-PDA@Leon混合,得到溶液A,在溶液A中加入聚乙二醇二丙烯酸酯PEGDA溶液,并加入NaOH溶液调节pH值,得到凝胶@FA-PDA@Leon水凝胶。
进一步的,所述明胶:FA-PDA@Leon质量比为640:1。
进一步的,所述pH值范围为6-7。
本发明的另一方面提供一种载益母草碱纳米复合水凝胶。
本发明的另一方面提供载益母草碱纳米复合水凝胶在类风湿性关节炎药物制备中的应用。
本发明的有益效果是:
(1)水凝胶能够作为纳米药物的局部库,防止其在关节腔内的快速扩散和清除,从而提高药物的生物利用度和治疗效率。
(2)水凝胶能够在关节腔内形成并紧密地粘附于关节组织,从而延长纳米药物的治疗时间。
(3)水凝胶能够响应关节液的刺激而逐渐降解,从而释放纳米药物。
(4)水凝胶能够与纳米药物协同发挥抗炎和抗氧化的作用,从而抑制M1型巨噬细胞的炎症反应,保护软骨细胞免受铁死亡的损伤,维持关节软骨的结构完整性,加速关节功能的恢复。
附图说明
为了更清楚地说明本发明实施例的技术方案,下面将对实施例的附图作简单地介绍,显而易见地,下面描述中的附图仅仅涉及本发明的一些实施例,而非对本发明的限制。
图1为本发明评价水凝胶的性能示意图,其中图(A)为丁达尔效应图,图(B)为FA-PDA@Leon纳米扫描电镜图,图(C)为纳米颗粒跟踪分析(NTA)图,图(D)为FA-PDA@Leon包封率图,图(E)为FA-PDA纳米颗粒孵育Raw264.7细胞的罗丹明荧光,图(F)为流式细胞分析图,图(G)为western blotting (WB)分析图,图(H)为FA-PDA@Leon抑制巨噬细胞分泌的炎症介质一氧化氮(NO)的释放图,图(I)为FA-PDA@Leon对巨噬细胞促炎细胞因子蛋白表达的抑制作用图,图(J)为实时定量聚合酶链反应(qRT-PCR)分析图;
图2为本发明评价水凝胶的抗炎活性,模拟RA中的炎症环境示意图,其中图(A)为原子力显微镜(AFM)相分析图,图(B)为转管实验图;图(C)为流变学分析图,图(D)水凝胶前驱体凝胶过程分析图,图(E)为原位形成的凝胶/FA-PDA@Leon水凝胶对生物组织粘附性分析图,图(F)为原位形成的凝胶/FA-PDA@Leon水凝胶与生物组织的粘附强度试验量化图,图(G)为荧光成像系统跟踪罗丹明标记的FA-PDA@Leon纳米药物的分布和保留图;
图3为本发明评价水凝胶的体内治疗效果示意图,其中图(A)为治疗14天后,对大鼠进行结扎进行生物学评价图,图(B)为关节炎指数和踝关节直径图,图(C)为治疗14天后的后爪照片图,图(D)和图(E)为近红外成像系统检测RA大鼠局部发热图,图(F)为超声成像系统观察滑膜炎症的进展图,图(G)为定量分析显示Gel/FA-PDA@Leon水凝胶组关节腔尺寸图,图(H)为用苏木精-伊红(HE)染色分析组织学水平上滑膜炎症的抑制作用图,图(I)为通过CD68和iNOS的免疫荧光双染色确定活化的巨噬细胞在滑膜组织中的位置图,图(J)为免疫组化染色图;
图4为本发明评价水凝胶的体内生物安全性示意图,其中图(A)为采用HE染色和血液生化分析评价凝胶/FA-PDA@Leon水凝胶在植入14 d后的毒性图,图(B)为凝胶/FA-PDA@Leon水凝胶组的血液生化指标。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚,下面将结合本发明实施例的附图,对本发明实施例的技术方案进行清楚、完整地描述。显然,所描述的实施例是本发明的一部分实施例,而不是全部的实施例。基于所描述的本发明的实施例,本领域普通技术人员在无需创造性劳动的前提下所获得的所有其他实施例,都属于本发明保护的范围。
下面结合附图和实施例对本发明进一步说明。
一种载益母草碱纳米复合水凝胶的制备方法,包括如下步骤:
步骤1:溶解多巴胺单体并诱导多巴胺DA单体氧化和自聚合,得到聚多巴胺PDA纳米颗粒,在PDA纳米颗粒表面接枝巯基聚乙二醇叶酸SH-PEG-FA,得到FA-PDA纳米载体。
其中,所述DA氧化和自聚合的条件为在25℃,pH 8.5的Tris溶液中,搅拌反应12小时。
步骤2:利用步骤1所述FA-PDA纳米载体负载益母草碱Leon,得到FA-PDA@Leon。
其中,所述FA-PDA纳米载体:Leon质量比为20:1。
步骤3:将步骤2所述FA-PDA@Leon包封至凝胶基质中得到凝胶@FA-PDA@Leon水凝胶。
所述凝胶@FA-PDA@Leon水凝胶的具体制备方法如下:溶解明胶与FA-PDA@Leon混合,得到溶液A,在溶液A中加入聚乙二醇二丙烯酸酯PEGDA溶液,并加入NaOH溶液调节pH值,得到凝胶@FA-PDA@Leon水凝胶。
其中,所述明胶:FA-PDA@Leon按质量为640:1;所述pH值范围为6-7。
本发明使用的基于PDA纳米载体具有以下三个优点。首先,PDA纳米载体表面具有高活性的儿茶酚基团,有利于通过Michael加成反应对叶酸配体进行表面修饰。其次,纳米载体上的邻苯二酚基团可以通过π-π堆叠与疏水性Leon非共价相互作用,从而实现药物在纳米载体上的有效固定。第三,抗氧化儿茶酚群可以保护Leon免受ROS损伤,维持其在炎症环境中的激活。因此,含有丰富儿茶酚基团的基于PDA的纳米载体是Leon递送的理想候选者。
实施例
步骤1:将100mg多巴胺DA溶解在200mLTris缓冲液中(10mm;pH=8.5),在25℃下搅拌,诱导DA氧化和自聚合。反应12 h后,将上清液在离心条件10000 rpm,5 min离心3次,得到FA-PDA纳米载体。
步骤2:将100mg FA-PDA纳米载体悬浮在100 mL去离子水中。然后将5mg益母草碱溶解于10ml DMSO中,加入至上述悬液中。在25℃下反应12 h后,在离心条件10000 rpm, 5min离心3次,得到FA-PDA@Leon。
步骤3:首先制备相分离凝胶基水凝胶(Gel):将PEGDA与明胶混合诱导相分离制备凝胶水凝胶;具体的,将1.6g明胶溶于10 mL 37℃的去离子水中,然后与300 μL PEGDA混合。用20mg NaOH调节pH值,所述pH值范围为6-7,形成明胶水凝胶。
然后将FA-PDA@Leon包封到凝胶基质中制备凝胶/FA-PDA@Leon水凝胶:具体的,将1.6g明胶溶解于10mL去离子水中,在37℃条件下与2.5 mg FA-PDA@Leon混合;最后在上述混合物中加入300 μL PEGDA和20 mg NaOH,形成凝胶/FA-PDA@Leon水凝胶。
如图1所示,图1(A)的丁达尔效应可知,所形成的FA-PDA@Leon纳米药物在去离子水中分散良好,扫描电镜图像显示FA-PDA@Leon纳米药物呈球形,直径均匀,约为100 nm,与PDA和FA-PDA纳米颗粒相似(图1B),此纳米尺寸有利于内化到细胞中。纳米颗粒跟踪分析(NTA)表明,PDA纳米颗粒的水动力直径按照FA-PDA和FA-PDA@Leon的顺序略有扩大(图1C),这与FA-PDA@Leon制备过程中的表面修饰和载药过程相对应。通过Leon标定曲线计算,FA-PDA纳米载体的Leon包封率为77.5%,如图1D所示。由上述结果可知已成功制备了FA修饰和Leon负载的FA-PDA@Leon纳米药物。
活化的M1巨噬细胞是引起RA关节炎症的主要致病细胞之一。FA-PDA@Leon纳米药物可靶向进入M1巨噬细胞,在细胞内递送抗炎Leon,有利于提高Leon的治疗效率。为了评估FA-PDA纳米载体对M1巨噬细胞的靶向性和细胞摄取能力,以Raw264.7细胞为代表的巨噬细胞,在静息状态和激活状态下与罗丹明标记的纳米颗粒孵育,然后在荧光显微镜下观察。使用脂多糖(LPS)诱导Raw264.7向促炎M1极化表型激活。如图1(E)所示,FA-PDA纳米颗粒孵育Raw264.7细胞的罗丹明荧光信号明显强于PDA组,这表明叶酸的表面修饰通过叶酸介导的配体受体特异性识别促进了巨噬细胞对FA-PDA纳米颗粒的富集和摄取。此外,FA-PDA纳米颗粒培养的lps刺激Raw264.7细胞的罗丹明荧光信号最强。这是因为在LPS刺激后,Raw264.7细胞表面表达和暴露了更多的叶酸受体,这提供了更多的结合位点,以吸引FA-PDA纳米颗粒内化到M1巨噬细胞中。流式细胞分析进一步表明FA-PDA纳米载体对M1巨噬细胞具有更高的靶向能力和细胞摄取能力(图1F)。
为评估M1巨噬细胞靶向FA-PDA纳米载体是否能提高负载Leon的抗炎治疗效率,将FA-PDA@Leon与lps刺激的Raw264.7细胞共培养2天后进行western blotting (WB)分析。如图1G所示,LPS刺激显著促进促炎细胞因子的蛋白表达,包括诱导型一氧化氮合酶(iNOS)、白细胞介素(IL)-1β、IL-6和肿瘤坏死因子(TNF)-α。相比之下,与Leon或PDA、PDA@Leon或FA-PDA@Leon共培养后,这些细胞因子的表达下调。特别是,FA-PDA@Leon处理的细胞在这些处理组中具有最低的细胞因子蛋白表达水平。FA-PDA@Leon还可以抑制巨噬细胞分泌的炎症介质一氧化氮(NO)的释放(图1H)。酶联免疫吸附试验(ELISA)和免疫荧光双染色进一步显示,与其他治疗组相比,FA-PDA@Leon对巨噬细胞促炎细胞因子蛋白表达的抑制作用更强(图1I)。实时定量聚合酶链反应(qRT-PCR)分析在遗传水平上证实了这一趋势(图1J)。
原子力显微镜(AFM)相像分析(图2A)发现,与相差不大的纯明胶图像相比,明胶-PEGDA图像表现出明显的相分离特征,同时存在孔洞状亮区(富PEGDA结构域)和网格状暗区(富明胶结构域),说明明胶链与PEGDA链相分离并聚集形成网络。这种现象可以解释为PEGDA可以通过排除明胶链周围的溶剂来改变明胶链的水化状态,从而驱动明胶链之间的关联。
由于PEGDA驱动明胶链的分子间相互作用增强,凝胶/FA-PDA@Leon水凝胶在生理温度(37°C)下具有可注射性,这是纳米药物关节内递送的关键性能。通过图2B的转管实验,FA-PDA@Leon、明胶、PEGDA、NaOH混合后出现溶胶-凝胶转变,凝胶/FA-PDA@Leon水凝胶形成。
流变学分析表明,凝胶/FA-PDA@Leon水凝胶的储存模量(G’)和损失模量(G’)在160 s处相交(图2C),进一步揭示了凝胶化时间。值得注意的是,水凝胶的前驱体在凝胶过程的早期表现出低粘度(100秒时为0.12 Pa·s)(图2D)。
如图2E所示,原位形成的凝胶/FA-PDA@Leon水凝胶即使被水冲洗后也能紧密附着在软骨组织表面,说明原位形成的凝胶/FA-PDA@Leon水凝胶对生物组织具有很强的粘附性,这使得包封的纳米药物能够固定在局部病变部位,并有可能延长其在关节腔中的滞留时间。原位形成的凝胶/FA-PDA@Leon水凝胶与生物组织的粘附强度通过lap-shear试验进行量化。以猪皮为代表的生物组织。如图2F所示,凝胶水凝胶的粘附强度高达69 kPa。这是由于水凝胶前体的低粘度使其能够渗透到微小的间隙中,实现了原位凝胶化后与猪皮肤不规则表面的充分接触。此外,FA-PDA@Leon纳米药物的掺入增强了凝胶/FA-PDA@Leon水凝胶的粘附强度(124±16 kPa),这是由于凝胶/FA-PDA@Leon水凝胶中高活性的儿茶酚基团促进了与生物组织的界面结合。在关节内注射后,使用荧光成像系统跟踪罗丹明标记的FA-PDA@Leon纳米药物的分布和保留,有或没有凝胶水凝胶封装。如图2G所示,凝胶/FA-PDA@Leon水凝胶注射后稳定地驻留在大鼠踝关节内。相比之下,部分FA-PDA@Leon纳米药物和PBS扩散到前足。凝胶/FA-PDA@Leon水凝胶在踝关节腔内的维持时间长达7天,优于FA-PDA@Leon和PBS。体内显像结果表明,水凝胶包封可提高FA-PDA@Leon纳米药物在关节腔内的稳定性和滞留时间。
用CIA大鼠模型评价凝胶/FA-PDA@Leon水凝胶对RA的体内治疗效果。将凝胶/FA-PDA@Leon水凝胶、凝胶/FA-PDA水凝胶、FA-PDA@Leon纳米药物、Leon溶液和PBS溶液(RA)分别注射于RA大鼠初始免疫21和28天后的踝关节内,以正常大鼠注射PBS作为对照。治疗14天后,对大鼠进行结扎进行生物学评价(图3A)。
滑膜炎症引起的关节肿胀和局部发热是RA的病理特征。为了反映治疗期间后爪肿胀的严重程度,每2天记录一次临床评分,包括关节炎指数和踝关节直径(图3B)。临床评分下降表明,各治疗组均能减轻RA大鼠后肢肿胀。特别是,与其他治疗组相比,凝胶/FA-PDA@Leon水凝胶组的临床评分要低得多,这表明凝胶/FA-PDA@Leon水凝胶组的治疗效果更高。治疗14天后的后爪照片如图3C所示,进一步证实Gel/FA-PDA@Leon水凝胶缓解了RA大鼠严重的爪子肿胀。采用近红外成像系统检测RA大鼠局部发热。RA组大鼠的膝关节和后爪由于严重的滑膜炎症表现出33℃的相对高温,而抗炎凝胶/FA-PDA@Leon水凝胶治疗后,温度降至27℃(图3D和E)。
使用超声成像系统观察滑膜炎症的进展,如图3F所示,RA大鼠未检查的滑膜炎症导致关节腔增大。凝胶/FA-PDA@Leon水凝胶组由于具有抗炎作用,关节腔大小恢复到正常水平。定量分析显示Gel/FA-PDA@Leon水凝胶组关节腔尺寸明显小于其他治疗组(图3G),说明Gel/FA-PDA@Leon水凝胶有效抑制滑膜增生。采用苏木精-伊红(HE)染色进一步分析组织学水平上滑膜炎症的抑制作用(图3H)。与RA及其他治疗组比较,凝胶/FA-PDA@Leon水凝胶组切片可见最小的滑膜增生及炎症细胞浸润。通过CD68和iNOS的免疫荧光双染色来确定活化的巨噬细胞在滑膜组织中的位置(图3I)。RA组切片中存在大量CD68+和iNOS+细胞,提示滑膜组织中巨噬细胞浸润活化。相比之下,凝胶/FA-PDA@Leon水凝胶组M1巨噬细胞的数量可以忽略不计。免疫组化染色显示,凝胶/FA-PDA@Leon水凝胶处理后,RA大鼠滑膜组织中pJAK2的表达水平显著降低(图3J),表明水凝胶在体内对JAK2/STAT3信号通路有较强的抑制作用。
采用HE染色和血液生化分析评价凝胶/FA-PDA@Leon水凝胶在植入14 d后的毒性。如图4A所示,与正常组相比,凝胶/FA-PDA@Leon水凝胶组的主要脏器(心、肝、脾、肺、肾)未见病理改变。此外,凝胶/FA-PDA@Leon水凝胶组的血液生化指标,包括谷丙转氨酶(ALT)、天冬氨酸转氨酶(AST)、血尿素氮(BUN)和肌酐(CREA),与正常组几乎相当(图4B),表明水凝胶对肝肾功能的影响可以忽略不计。结果表明,该凝胶/FA-PDA@Leon水凝胶具有良好的体内生物安全性。
以上所述,仅是本发明的较佳实施例而已,并非对本发明作任何形式上的限制,虽然本发明已以较佳实施例揭露如上,然而并非用以限定本发明,任何熟悉本专业的技术人员,在不脱离本发明技术方案范围内,当可利用上述揭示的技术内容作出些许更动或修饰为等同变化的等效实施例,但凡是未脱离本发明技术方案的内容,依据本发明的技术实质对以上实施例所做的任何简单修改、等同变化与修饰,均仍属于本发明技术方案的范围内。
Claims (8)
1.一种载益母草碱纳米复合水凝胶的制备方法,其特征在于,包括如下步骤:
步骤1:溶解多巴胺单体并诱导多巴胺DA单体氧化和自聚合,得到聚多巴胺PDA纳米颗粒,在PDA纳米颗粒表面接枝巯基聚乙二醇叶酸SH-PEG-FA,得到FA-PDA纳米载体;
步骤2:利用步骤1所述FA-PDA纳米载体负载益母草碱Leon,得到FA-PDA@Leon;
步骤3:将步骤2所述FA-PDA@Leon包封至凝胶基质中得到凝胶@FA-PDA@Leon水凝胶。
2.根据权利要求1所述一种载益母草碱纳米复合水凝胶的制备方法,其特征在于,所述步骤2中,所述FA-PDA纳米载体:Leon质量比为20:1。
3.根据权利要求1所述一种载益母草碱纳米复合水凝胶的制备方法,其特征在于,所述步骤1中,DA单体氧化和自聚合的条件为在25℃,pH 8.5的Tris溶液中,搅拌反应12小时。
4.根据权利要求1所述一种载益母草碱纳米复合水凝胶的制备方法,其特征在于,所述步骤3中,凝胶@FA-PDA@Leon水凝胶的具体制备方法如下:溶解明胶与FA-PDA@Leon混合,得到溶液A,在溶液A中加入聚乙二醇二丙烯酸酯PEGDA溶液,并加入NaOH溶液调节pH值,得到凝胶@FA-PDA@Leon水凝胶。
5.根据权利要求4所述一种载益母草碱纳米复合水凝胶的制备方法,其特征在于,所述明胶:FA-PDA@Leon质量比为640:1。
6.根据权利要求4所述一种载益母草碱纳米复合水凝胶的制备方法,其特征在于,所述pH值范围为6-7。
7.采用如权利要求1-6任一所述制备方法得到一种载益母草碱纳米复合水凝胶。
8.权利要求7所述的载益母草碱纳米复合水凝胶的应用,其特征在于,在类风湿性关节炎药物制备中的应用。
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