CN116251201B - 抗类风湿性关节炎的自组装水凝胶及其制备方法与应用 - Google Patents
抗类风湿性关节炎的自组装水凝胶及其制备方法与应用 Download PDFInfo
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Abstract
本发明提供了一种抗类风湿性关节炎的自组装水凝胶及其制备方法与应用,该水凝胶由镥‑177与单磷酸腺苷自组装形成,通过镥‑177金属离子特性与单磷酸腺苷中磷酸基团、腺嘌呤相互配位作用形成具有三维纳米纤维网络结构的水凝胶,镥‑177与单磷酸腺苷的摩尔比为4:1~1:4。该水凝胶的制备过程无需额外添加交联剂,保障制剂的高生物相容性,该水凝胶注射进入关节腔后,可实现镥‑177在关节腔内均匀分布,同时该水凝胶具有自愈合功能,避免在关节活动过程中凝胶使用疲劳导致结构破坏引起的核素泄露,且通过离子束缚效应进一步降低了放射性核素外泄,避免了非靶器官受到辐射损伤。在应用治疗过程中联合PET技术,高灵敏反映关节炎症变化,实现放射滑膜切除术实时治疗监测。
Description
技术领域
本发明涉及纳米材料和纳米生物医药领域,具体涉及一种抗类风湿性关节炎的自组装水凝胶及其制备方法与应用。
背景技术
类风湿性关节炎(RA)是最广泛、最具破坏性的自身免疫性疾病之一。其主要病理特征在于进行性炎症和持续性滑膜炎,导致关节疼痛,甚至关节功能丧失。目前,其主要治疗方法在于控制关节滑膜炎症,然而,持续性滑膜炎症加剧,将严重影响病人关节活动能力,且一般药物难以恢复关节功能。
放射滑膜切除术(RSV)是一种新兴的核医学手术,其原理是将放射性药物注入关节,使其破坏发炎的滑膜,期望再生的滑膜无病,从而减轻症状。近几年,大量放射性核素如90Y、165Dy、177Lu、153Sm被广泛研究用于RSV。其中,镥-177(177Lu)是一种理想的放射性核素,半衰期为6.7天,其发射的β射线能量适中,射程短,能有效杀伤病变组织,同时避免深层穿透带来的副作用,且其易于获得、成本效益高,使得镥-177(177Lu)成为放射治疗中的热门研究对象。近几年来,由于正电子发射计算机断层显像(PET)技术的发展,PET可在放射滑膜切除术过程中,高灵敏反映关节炎症变化,实现实时治疗监测。因此,放射滑膜切除术联合PET成像成为治疗类风湿性关节炎的又一有效途径。
目前,RSV是针对类风湿性关节炎一种极具潜力的治疗方案,但其一直以来未能在临床中广泛应用,其中一个重要原因就是放射核素给药过程中,极易出现关节腔外泄露,导致非靶器官的辐射损伤。单磷酸腺苷源于生物体,是生物体内的能量传递物质,由腺嘌呤碱基、核糖、磷酸基团构成,具有化学性质稳定、生物相容性好等特点,在生物医学等领域备受青睐。其可用于宏量制备金属纳米结构,在与金属离子的结合上已表现出优质潜力,具有良好的产业化前景。
因此,开发一种单磷酸腺苷载放射性核素镥-177的递药载体,并减少关节腔外泄露,具有重要的临床意义。
发明内容
为解决上述技术问题,本发明提出一种抗类风湿性关节炎的镥-177/单磷酸腺苷自组装水凝胶的制备方法及其应用,其目的是将放射性核素镥-177与生物活性分子单磷酸腺苷自组装形成凝胶,制备过程无需额外添加交联剂,在保障制剂的高生物相容性的同时,对镥-177进行封闭,减少关节腔外泄露,避免非靶器官受到辐射损伤。
为实现上述目的,本发明首先提出一种抗类风湿性关节炎的镥-177/单磷酸腺苷自组装水凝胶,由镥-177与单磷酸腺苷形成,所述镥-177通过金属离子特性在缓冲液条件下与单磷酸腺苷中磷酸基团、腺嘌呤相互配位作用形成三维纳米纤维网络结构水凝胶。
单磷酸腺苷是生物体内的能量传递物质,由腺嘌呤碱基、核糖、磷酸基团构成。
作为优选,所述镥-177为氯化镥[177Lu],是一种β衰变核素,主要释放β射线。
作为优选,所述镥-177与单磷酸腺苷的摩尔比为1:4~4:1。
作为优选,所述缓冲液为柠檬酸盐缓冲液、醋酸盐缓冲液、磷酸盐缓冲液中的一种,所述缓冲液pH为4.0-7.0。
基于一个总的发明构思,本发明还提供了一种镥-177/单磷酸腺苷自组装水凝胶的制备方法,包括以下步骤:
S1、将氯化镥[177Lu]使用双蒸水配制成氯化镥[177Lu]水溶液;
S2、将单磷酸腺苷溶解在缓冲液中;
S3、将S1中氯化镥[177Lu]水溶液加入至S2溶液中,水浴加热反应,混合液离心,倒掉上清液,沉淀物用缓冲液重悬,即得到镥-177/单磷酸腺苷自组装水凝胶。
作为优选,所述步骤S3中水浴加热反应时间为3h,水浴加热温度为20-50℃。
基于一个总的发明构思,本发明还提供了一种镥-177/单磷酸腺苷自组装水凝胶在类风湿性关节炎中的应用。
作为优选,所述应用通过在炎症部位直接注射给药。
本发明通过将氯化镥[177Lu]与单磷酸腺苷在缓冲液条件下混合,利用镥-177金属离子特性与单磷酸腺苷中磷酸基团、腺嘌呤相互配位作用制备自组装水凝胶,制备工艺简单,反应过程简单可控,无需额外添加交联剂。
与现有技术相比,本发明具有以下有益效果:
1、本发明将放射性核素镥-177与生物活性分子单磷酸腺苷自组装形成凝胶,无需额外添加交联剂,保障制剂的高生物相容性。同时可以实现镥-177在关节腔内均匀分布,并且该水凝胶具有自愈合功能,避免在关节活动过程中凝胶使用疲劳导致结构破坏引起的核素泄露,且通过离子束缚效应,进一步降低了放射性核素从关节腔内外泄的可能,避免非靶器官受到辐射损伤,安全性高。当该凝胶在炎症部位注射后,可以实现镥-177在关节腔内均匀分布,镥-177发射β射线抑制炎症细胞活性,破坏发炎的滑膜,达到控制关节滑膜炎症的效果。
2、本发明制备的镥-177/单磷酸腺苷自组装水凝胶可以在治疗过程中,联合使用正电子发射计算机断层显像(PET)技术,高灵敏反映关节炎症变化,实现放射滑膜切除术实时治疗监测。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1为本发明实施例1中用于抗类风湿性关节炎的镥-177/单磷酸腺苷自组装水凝胶实例图,其中图1A为正置图,图1B为倒置图,图1A和图1B中左侧均为镥-177自组装水凝胶,右侧为AMP水溶液;
图2为本发明实验例1中用于抗类风湿性关节炎的镥-177/单磷酸腺苷自组装水凝胶释放考察;
图3为本发明实验例2中用于抗类风湿性关节炎的镥-177/单磷酸腺苷自组装水凝胶自愈合功能考察;
图4为本发明实验例3中用于抗类风湿性关节炎的镥-177/单磷酸腺苷自组装水凝胶血液渗漏率;
图5为本发明实验例3中用于抗类风湿性关节炎的镥-177/单磷酸腺苷自组装水凝胶放射性器官分布。
具体实施方式
为使本发明要解决的技术问题、技术方案和优点更加清楚,下面将结合附图及具体实施例进行详细描述。
以下实施例用于说明本发明,但不用来限制本发明的范围。在不背离本发明精神和实质的情况下,对本发明方法、步骤或条件所作的修改或替换,均属于本发明的范围。
若未特别指明,实施例中所用的技术手段为本领域技术人员所熟知的常规手段;若未特别指明,实施例中所用试剂均为市售。
实施例1
制备镥-177/单磷酸腺苷自组装水凝胶
将氯化镥[177Lu]使用双蒸水配制成200mM氯化镥[177Lu]水溶液;将单磷酸腺苷溶解在pH 6.0的醋酸缓冲液中,单磷酸腺苷浓度为200mM;将1mL氯化镥[177Lu]水溶液加入至2mL单磷酸腺苷的醋酸缓冲液中(pH 6.0),40℃水浴加热,反应3h,混合液离心(10000r/min,10min),倒掉上清液,沉淀物用醋酸缓冲液(pH 6.0)重悬,即得到镥-177/单磷酸腺苷自组装水凝胶,其自组装结构示意图如下式I所示:
对比例1:
单磷酸腺苷水溶液
将单磷酸腺苷溶解在pH 6.0的醋酸缓冲液中,单磷酸腺苷浓度为200mM;将1mL双蒸水溶液加入至2mL单磷酸腺苷的醋酸缓冲液中(pH 6.0),40℃水浴加热,反应3h。
并将实施例1中获得的镥-177/单磷酸腺苷自组装水凝胶实物与对比例1中单磷酸腺苷水溶液进行拍照,如图1所示,图1A为两者正置图,图1B为倒置图,图1A和图1B的左侧均为镥-177自组装水凝胶、右侧为AMP水溶液。结果显示,没有镥177交联,单磷酸腺苷无法形成水凝胶,不具备水凝胶性质。
实验例1
考察镥-177/单磷酸腺苷自组装水凝胶的释放
取实施例1中镥-177/单磷酸腺苷自组装水凝胶3份(每份3mL),装入透析袋中(截留分子量为10kDa,放入40mL pH为7.4磷酸缓冲液中,放入恒温振荡器(37℃,120r/min)中进行释放研究。在规定的时间点分别取样3mL,每次取样后补加3mL同条件下的新鲜释放介质。样品用NaI(TI)伽马γ能谱仪测定。结果如图2所示,镥-177/单磷酸腺苷自组装水凝胶在磷酸盐缓冲条件下,释放离子较少,说明该自组装水凝胶具有离子束缚效应,可以降低放射性核素从关节腔内外泄。
实验例2
考察镥-177/单磷酸腺苷自组装水凝胶的自愈合功能
取实施例1中镥-177/单磷酸腺苷自组装水凝胶,将水凝胶暴露在1%和300%之间的切换应变中,固定时间间隔为130秒,在此期间测量存储模量G',结果如图3所示。由图3可知,该水凝胶在1%的应变下显示出高的G'值。在300%的应变下,G'突然下降,这是因为施加的外力足以克服水凝胶三维网络中交联有关的相互作用力。应变降低到1%,储存模量在10秒内迅速恢复到初始状态,这表明水凝胶的自我恢复能力很强。这种自愈合功能保障了水凝胶在关节运动中被压碎后会通过自愈功能重新连接起来,从而保护核素不会迅速从水凝胶中渗出,减少了核素从关节腔外泄。
实验例3
考察镥-177/单磷酸腺苷自组装水凝胶的生物分布
将200μL镥-177/单磷酸腺苷自组装水凝胶、不含单磷酸腺苷的镥-177水溶液分别注射至正常雄性兔子(n=3)的一个膝关节中,总放射性相同,为22.2MBq(0.6mCi)。在预定的时间间隔,从耳静脉采集血样(1mL),并测量了每个样本中的放射性。之后静脉注射戊巴比妥处死,解剖组织器官(骨、肝、脾、肾、肌肉、肺、心脏、膀胱和睾丸),称重并测量了每个样本中的放射性。结果如图4、图5所示,表明与镥-177水溶液相比,该镥-177/单磷酸腺苷自组装水凝胶从关节腔内外泄较少,在血液、各组织中检测均低于镥-177水溶液,说明该自组装水凝胶可以大大降低放射性核素从关节腔内外泄,避免非靶器官受到辐射损伤。
以上所述是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明所述原理的前提下,还可以作出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (7)
1.一种抗类风湿性关节炎的自组装水凝胶,其特征在于,包括放射性核素镥-177和单磷酸腺苷,所述镥-177通过金属离子特性在缓冲液条件下与单磷酸腺苷中磷酸基团、腺嘌呤相互配位作用形成三维纳米纤维网络结构水凝胶;所述镥-177与所述单磷酸腺苷的组成摩尔比为4:1~1:4。
2.根据权利要求1所述的镥-177/单磷酸腺苷自组装水凝胶,其特征在于,所述镥-177为氯化镥177Lu。
3.根据权利要求1所述的镥-177/单磷酸腺苷自组装水凝胶,其特征在于,所述缓冲液为柠檬酸盐缓冲液、醋酸盐缓冲液、磷酸盐缓冲液中的一种,所述缓冲液pH为4.0~7.0。
4.一种如权利要求1~3任一项所述抗类风湿性关节炎的自组装水凝胶的制备方法,其特征在于,包括以下步骤:
S1、将氯化镥177Lu使用双蒸水配制成氯化镥177Lu水溶液;
S2、将单磷酸腺苷溶解在缓冲液中;
S3、将S1中氯化镥177Lu水溶液加入至S2溶液中,水浴加热反应,混合液离心,倒掉上清液,沉淀物用缓冲液重悬,即得到镥-177/单磷酸腺苷自组装水凝胶。
5.根据权利要求4所述的制备方法,其特征在于:所述S3中水浴加热时间为3h,水浴加热温度为20~50℃。
6.一种如权利要求1~3任一项所述的抗类风湿性关节炎的自组装水凝胶或者如权利要求4~5任一项所述制备方法制得的抗类风湿性关节炎的自组装水凝胶在制备抗类风湿性关节炎药物中的应用。
7.根据权利要求6所述的应用,其特征在于,所述抗类风湿性关节炎药物为注射给药。
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first case report and image of Lu -177 HA in the elbow joint.《Indian Journal of Nuclear Medicine》.2014,第29卷(第4期),第270-272页. * |
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