CN115444835B - 壳聚糖-磷脂复合纳米铁补铁剂及其制备方法 - Google Patents
壳聚糖-磷脂复合纳米铁补铁剂及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种壳聚糖‑磷脂/纳米铁补铁剂及其制备方法,壳聚糖‑磷脂/纳米铁补铁剂成分为壳聚糖/磷脂/氢氧化铁复合纳米微粒,壳聚糖‑磷脂/纳米铁补铁剂的制备方法,包括下列步骤:将分子量为30kDa的壳聚糖溶解于酸性水溶液中,加入三价铁盐(80‑100 mg/g壳聚糖),边搅拌/振荡边将pH调至3.0‑7.0,制得壳聚糖纳米铁溶液;磷脂乳液经0.1‑0.45μm微孔过滤5‑15次后,制得磷脂纳米乳液;向壳聚糖纳米铁溶液中边搅拌/振荡滴加磷脂纳米乳液(0.0125‑0.025mg磷脂/mg壳聚糖),加热处理后,制得壳聚糖‑磷脂/纳米铁溶液,冷冻或喷雾干燥获得粉剂。本发明中壳聚糖‑磷脂/纳米铁补铁剂的促氧化活性低、加工稳定性好、生物利用度极高(是硫酸亚铁的1.5倍以上),具有广阔的应用前景。
Description
技术领域
本发明涉及一种壳聚糖-磷脂/纳米铁补铁剂,特别是涉及一种壳聚糖和磷脂介导的铁氧化物纳米微粒的制备方法及其用途。
背景技术
作为人体的必需微量元素,铁能够参与能量代谢,氧气运送等重要的生理功能。当其在体内的储备耗竭而不能充分供应各组织需要时,人体便处于铁缺乏状态。铁缺乏是目前情况最为严重的一类矿物质营养缺乏症,包括绝对性和功能性铁缺乏,绝对性铁缺乏是铁供给量不足导致的,而功能性铁缺乏是机体对于铁营养素的吸收转运出现障碍导致的。针对以上两种铁缺乏,目前主要的应对策略为:口服铁制剂、营养补充、膳食调理等,这些方式使得大量的铁元素进入体内,然而对约30%的孕妇和20%的学龄儿童无显著效果,并伴有一系列的副作用,如打破肠道菌群平衡,损伤肠粘膜屏障,导致机体出现消化不良、细菌感染等。聚阴离子/阳离子生物大分子可以作为生物模型用于绿色合成具有良好分散性和高生物利用度的矿物质纳米颗粒。同时,从与食品基质反应程度上来说,聚阴离子/阳离子生物大分子比游离金属离子作用力弱,可有效防止非血红素铁的沉淀,是铁的理想载体。其中,阴离子聚合物磷脂在机体细胞活化、基础生理代谢及免疫力增强等方面发挥优势作用,还能有效改善大脑功能,预防动脉硬化。磷脂具有有独特的磷脂双分子层结构,能以磷脂脂质体的形式与铁结合,因此可以有效穿透并克服细胞和组织吸收的生物屏障,实现高效的递送效果。目前阳离子聚合物介导形成的纳米铁递送体系研究较少。作为阳离子多糖的壳聚糖是能够实现铁营养素高效递送的极佳载体。壳聚糖是自然界中广泛存在的碱性氨基多糖,具有多种特殊功能特性,如生物安全性、可降解性、相容性等,在食品方面常用作天然保鲜剂、增稠剂及防腐剂等。同时,壳聚糖具有对粘膜表面的显著生物粘附性以及打开紧密细胞屏障的能力。磷脂和壳聚糖已被广泛用于制备各种基于脂质的药物递送载体。然而,壳聚糖在中性或碱性条件下易发生聚沉,磷脂在酸性条件下易发生聚沉,这使得它们在生产过程中面临稳定性差、应用范围窄等问题。本发明通过一种特殊的工艺,复合壳聚糖和磷脂进行了纳米铁补铁剂的制备,兼具壳聚糖和磷脂递送体系的优点,并克服了二者各自在营养递送中的缺陷,制得一种加工稳定性好、生物利用度高、食品基质兼容性加的壳聚糖-磷脂/纳米铁补铁剂,制作工艺操作简单、成本低、易于推广,制得的产品可在营养强化、营养补充或临床治疗中得到广泛应用。
发明内容
本发明要解决的技术问题是提供一种新型的壳聚糖-磷脂/纳米铁补铁剂及其制备方法和应用。
具体的说,本发明提供的补铁剂是一种壳聚糖-磷脂/纳米铁补铁剂,成分为壳聚糖和磷脂共同包覆的氢氧化铁纳米微粒。
实现本发明目的采取的技术方案原理如下:
首先,利用壳聚糖介导三价铁盐水解制得壳聚糖纳米铁,再利用反复微孔过滤制得磷脂纳米乳液,将壳聚糖纳米铁溶液与磷脂纳米乳液以特定的比例混合,再进行加热处理后,制得壳聚糖-磷脂/纳米铁补铁剂。
壳聚糖-磷脂复合纳米铁补铁剂的制备方法,具体包括下列步骤:
(1)将壳聚糖溶解于酸性水溶液中,加入三价铁盐固体或者溶液(80-100mg/g壳聚糖),待三价铁盐固体不再溶解或溶液滴加完毕,边搅拌/振荡边将反应体系的pH调至3.0-7.0,制得无色或浅黄色澄清透亮的壳聚糖纳米铁溶液。
(2)采用反复微孔过滤制备磷脂纳米乳液。具体是:
植物或动物磷脂粉末加水混合制备磷脂悬浊液,利用0.1-0.45μm微孔滤膜过滤5-15次后,制得磷脂纳米乳液。
本发明要制备纳米级的补铁剂,而磷脂粉末的颗粒比较大,本发明采用滤膜法(反复微孔过滤)将磷脂粉末制成纳米乳液。本发明采用滤膜法操作更简单,不需要其他复杂的操作。
(3)向壳聚糖纳米铁溶液中边搅拌/振荡滴加磷脂纳米乳液(0.0125-0.025mg磷脂/mg壳聚糖),55℃-120℃加热处理30-300min,制得壳聚糖-磷脂/纳米铁混悬液,水合粒径小于100nm、ζ电位大于24mV。
(4)冷冻干燥或喷雾干燥制得浅黄色、能完全复溶、稳定性良好的壳聚糖-磷脂复合纳米铁固体粉末。
优选的,本发明步骤(1)中壳聚糖脱乙酰度升高和分子量降低均有利于提升其铁负载能力,分子量30kDa、脱乙酰度≥95%的壳聚糖负载三价铁能力可达到90mg Fe/g以上。
进一步的,本发明步骤(1)反应体系的pH不超过7.0。pH值越高,反应体系氢氧根离子浓度越大,当超过7.0后,氢氧根离子对壳聚糖的铁负载能力影响过大。
优选的,本发明步骤(2)中植物或动物磷脂的纯度升高有利于磷脂纳米乳液的形成,粗磷脂经过脱油处理后使用效果更佳;
进一步的,本发明步骤(2)中磷脂与壳聚糖的比例与所形成的壳聚糖-磷脂/纳米铁微粒的粒径相关,二者比例过高或过低均不利于壳聚糖-磷脂/纳米铁微粒的形成;
优选的,本发明步骤(3)中壳聚糖-磷脂纳米铁的加热处理条件是100℃,60min。
本发明的有益效果:
本发明利用壳聚糖和磷脂的聚阴/阳离子大分子特性制备了一种壳聚糖-磷脂/纳米铁补铁剂,具有加工稳定性好、促氧化活性低、生物利用度极高。结果表明,壳聚糖-磷脂/纳米铁补铁剂的生物利用度是硫酸亚铁的1.5倍以上,且显著高于对照组壳聚糖纳米铁和磷脂纳米铁。
其肠道吸收不仅利用了依赖于二价金属离子载体1(DMT-1)的还原解离途径,还涉及了巨胞饮作用和依赖于发动蛋白的内吞作用,是一种较为理想的补铁剂,可在营养强化、营养补充或临床治疗中应用。
因此,本发明的壳聚糖-磷脂/纳米铁可以作为一种高生物利用度的缓释铁制剂,用于口服治疗和食品铁强化。
附图说明
下面结合附图对本发明的具体实施方式和有益效果作进一步详细的说明。
图1壳聚糖-磷脂/纳米铁制备过程的表征。(a),(b)是不同制备方式下磷脂纳米乳液的粒径分布图;(c)是不同浓度的磷脂制备的壳聚糖-磷脂/纳米铁的粒径分布图;(d)是壳聚糖和磷脂介导的氢氧化铁复合纳米微粒的粒径分布图;(e)是100℃加热60min后纳米铁的粒径分布图;(f)是100℃加热60min后纳米铁的拍照图和透射电镜图。
图2壳聚糖-磷脂/纳米铁的稳定性。(a)、(b)分别是在-20℃和-80℃冻融后复融的外观图和粒径分布;(c)、(d)分别是调节pH后的纳米铁的外观图和粒径分布图;(e)、(f)是醇沉后复溶的溶液外观和粒径分布图;(g)、(h)分别是冷冻和喷雾干燥后壳聚糖-磷脂/纳米铁及其复溶后的对比照片和粒径分布图,不同字母组差异有统计学意义(P<0.05)。
图3是大鼠单次灌胃壳聚糖-磷脂/纳米铁后血清铁的代谢动力学变化。(a)水溶液体系;(b)牛奶体系。
图4是壳聚糖-磷脂/纳米铁在Caco-2细胞模型中的铁吸收。采用了Caco-2单层分化细胞,细胞外液pH值为5.5,细胞铁的摄入会让钙黄绿素荧光发生猝灭,利用钙黄绿素荧光的变化相对定量细胞的铁摄入。(a)是壳聚糖-磷脂/纳米铁在Caco-2细胞模型中的铁吸收动力学变化;(b)是不同抑制剂对于Caco-2单层分化细胞吸收壳聚糖-磷脂/纳米铁中铁的影响。不同字母组差异有统计学意义(P<0.05)。
图5是壳聚糖-磷脂/纳米铁在体外Caco-2细胞模型中铁的跨膜转运途径。不同字母组差异有统计学意义(P<0.05)。
具体实施方式
实施例1
本实施例提供一种基于壳聚糖和磷脂制备的壳聚糖-磷脂/纳米铁及其制备过程。
具体技术方案步骤如下:
(1)将壳聚糖溶解于酸性水溶液中,加入三价铁盐固体或者溶液(100mg/g壳聚糖),待三价铁盐固体不再溶解或溶液滴加完毕,边搅拌/振荡边将反应体系的pH调至6.0,制得无色或浅黄色澄清透亮的壳聚糖纳米铁溶液;
(2)将丙酮与磷脂(大豆等植物卵磷脂或蛋黄等动物卵磷脂)1.2mL/g混合,装入玻璃烧杯中混匀,室温静置30min后,加入5体积的95%乙醇萃取,收集底部沉淀后,置于氮吹仪下干燥去除甘油三酯,再将脱油磷脂粉末收集。将脱油磷脂粉加水溶解,利用0.1μm膜过滤5次后制备出磷脂纳米乳液;
(3)向壳聚糖纳米铁溶液中边搅拌/振荡滴加磷脂纳米乳液(0.0175mg磷脂/mg壳聚糖),用孔径为0.2μm滤膜过滤后,100℃沸水浴60min,制得壳聚糖-磷脂复合纳米铁(水合粒径小于100nm、ζ电位大于24mV)混悬液;
(4)冷冻干燥或喷雾干燥制得浅黄色壳聚糖-磷脂复合纳米铁固体粉末。
实施例2
实施例1制备的壳聚糖-磷脂复合纳米铁补铁剂的实验结果
本实施例的相关实验是以实施例1中壳聚糖和磷脂复合制备的壳聚糖-磷脂/纳米铁补铁剂为基础进行的。
具体为:
(一)壳聚糖-磷脂/纳米铁制备过程的表征,具体实验过程和实验结论如下:
图1中,图1壳聚糖-磷脂/纳米铁制备过程的表征。(a),(b)是不同制备方式下磷脂纳米乳液的粒径分布图;(c)是磷脂与壳聚糖比例条件下制备的复合纳米微粒的粒径分布图;(d)是壳聚糖和磷脂介导的氢氧化铁复合纳米微粒的粒径分布图;(e)是100℃加热60min后纳米铁的粒径分布图;(f)是100℃加热60min后纳米铁的外观和透射电镜图。
磷脂原料(大豆磷脂酰胆碱)是从大豆中提取的副产物,其中含有90%的有效成分:磷脂酰胆碱PC(90%),而剩下的中性脂质(甘油三酯、胆固醇等)可能会影响磷脂乳液的形成。为了让磷脂乳液有更小的粒径尺寸,实现更大的铁负载量,采用原位固相萃取法纯化了磷脂酰胆碱,去除磷脂中的脂质及杂质,为磷脂纳米铁的制备做好原料储备。用超声、冻融、薄膜溶剂、挤压过滤法制备磷脂乳液,DLS测定结果如图1a,b所示,用0.1μm的PVDF滤膜挤压过滤的磷脂乳液粒径显著低于用0.22μm的PES滤膜过滤的磷脂乳液,且随着过膜次数的增加,在过膜5次时粒径趋于稳定,表明已制备出磷脂纳米乳液。
在制备壳聚糖介导的铁氢氧化物纳米微粒的基础上,涡旋滴加不同浓度的磷脂乳液,得到壳聚糖-磷脂铁氢氧化物纳米复合微粒。图1c显示,加入终浓度为0.0005mg/mL的磷脂时,DLS结果表明尚有较多的壳聚糖纳米铁结合的磷脂量过少;加入终浓度为0.01mg/mL的磷脂时,DLS结果表明壳聚糖纳米铁结合的磷脂量过多;添加终浓度为0.007mg/mL的磷脂时,微粒尺寸介于两者之间,表明该磷脂浓度下形成了复合纳米铁,并符合纳米尺度,得到的纳米溶液呈现澄清透亮微黄色,红外线照射时出现明显的光束,表明此时形成的纳米微粒有胶体特性。该复合纳米铁的粒径为122.0±0.113nm,PDI为0.196±0.053,电位为22.0±0.044mV,具有良好的抗聚集稳定性(图1d)。将该胶体溶液置于100℃沸水浴中加热60min,其粒径显著减小(P<0.05),丁达尔现象明显,且光束逐渐变细,清晰且不杂乱,胶体性质稳定。因此,热处理使得磷脂水解后的产物与铁结合后形成了更为微小的纳米铁微粒,即为壳聚糖-磷脂复合纳米铁微粒。
DLS的分析使用激光粒度分析仪(Malvern Nano ZS),633nm He-Ne激光器,在25±0.1℃下,恒定散射角为173°。DLS测定滤膜过滤后滤液中具有散射光信号,也证明了较小的氢氧化铁胶体形成。在壳聚糖和磷脂存在的条件下纳米铁胶体平均水力学粒径为91.0±0.105nm,电位为24.5±0.064mV,粒径显著低于加热前(如图1e)。壳聚糖-磷脂/纳米铁透射电镜(TEM)观测,样品溶液滴加到到碳涂层的铜网上,风干,然后使用JEM-2100Plus设备在200kv下进行检测,观察到其粒径也与DLS结果一致(图1f)。
(二)壳聚糖-磷脂/纳米铁的稳定性研究,具体实验过程和实验结论如下:
结果如图2。(a),(b)分别是在-20℃和-80℃冻融后复融的外观图和粒径分布;(c),(d)分别是调节pH后的纳米铁的外观图和粒径分布图;(e),(f)是醇沉后复溶的溶液外观和粒径分布图;(g),(h)分别是冷冻和喷雾干燥后壳聚糖-磷脂/纳米铁及其复溶后的对比照片和粒径分布图。不同字母组差异有统计学意义(P<0.05)。
图2a是壳聚糖-磷脂/纳米铁胶体溶液放置在-20℃和-80℃下反复冻融2次后的溶液外观图和粒径大小分布。壳聚糖-磷脂/纳米铁微粒的粒径大小随着冷冻温度的降低而增加,随着冻融次数的增加而增加,但从外观上看(图2b),溶液仍能呈现出原有的澄清透亮状态,无明显沉淀产生,因此,壳聚糖-磷脂/纳米铁具有良好的抗冻融稳定性。如图2c所示,依次调节壳聚糖-磷脂/纳米铁胶体溶液的pH为3.0、4.0、5.0、6.0、7.0、8.0,利用精密pH试纸测定CP-FeONPs沉淀时的pH值,发现随着pH的升高,溶液逐渐形成不同程度的聚集性沉淀,图2d的DLS测定结果显示,壳聚糖和磷脂空白溶液在pH 6.5时粒径急剧上升,而壳聚糖-磷脂/纳米铁在pH 7.5时才出现少量沉淀,说明壳聚糖和磷脂介导形成铁氢氧化物纳米微粒后,拓宽了壳聚糖和磷脂的pH稳定范围,壳聚糖-磷脂/纳米铁具有良好的耐酸碱稳定性。向壳聚糖-磷脂/纳米铁胶体溶液中加入5mg/mL 95%的乙醇至溶液终体积的70%,将沉淀出的纳米微粒干燥处理后复溶,图2f的DLS测定结果显示,在醇沉前后,壳聚糖-磷脂/纳米铁的粒径显著增加,但复溶后的溶液外观上仍保持原有的淡黄色澄清状态,无明显颗粒产生,丁达尔效应无明显变化(图2e),因此,壳聚糖-磷脂/纳米铁经醇沉复溶后仍具有良好的稳定性。
壳聚糖-磷脂/纳米铁的促氧化活性,是在亚油酸乳液体系下测定脂质氧化速率来判定的。使用磁力搅拌器将5g亚油酸与1g吐温20在150mL 0.2M磷酸盐缓冲液(pH 7.4)中混合15min,然后使用超声探针在4℃下以5.0s脉冲速率超声10min。以不添加铁的乳化液作为对照,将新制备的铁浓度为20mM的硫酸亚铁或纳米铁的溶液按照体积比1:19加入到亚油酸乳液中,不断搅拌,然后在30℃黑暗中孵育96h。每隔一段时间取0.2mL进行分析。利用硫代巴比妥酸(TBA)法测定脂质过氧化产物,如表1所示,壳聚糖-磷脂/纳米铁在亚油酸乳状液中储存24、48、72和96h后,TBA值显著低于硫酸亚铁(P<0.01)。脂质过氧化导致不良的感官变化和酸败是铁强化食品的主要挑战,与催化活性较强的硫酸亚铁相比,壳聚糖-磷脂/纳米铁在催化食品基质脂质氧化方面具有相对惰性。
表1.促脂质氧化实验的设计和结果
数据均以平均值±标准偏差(n=3)来表示。TBA值=当前实验条件下给定波长下的吸光度。小写字母a-c表示行内不同组之间有显著性差异(P<0.05),大写字母A-E表示列内不同组之间有显著性差异(P<0.05)。
喷雾干燥和冷冻干燥是食品加工中的延长货架期的良好技术。纳米颗粒溶液的干燥可能会造成颗粒的不稳定性增加,导致不可逆的聚集沉淀。图2g为冷冻干燥和喷雾干燥制备的壳聚糖-磷脂/纳米铁粉剂形态和复溶溶液状态。冷冻干燥时,将壳聚糖-磷脂/纳米铁样品在-20℃下预冻24h,然后转移到Scientz-10ND冷冻干燥机(宁波新芝生物技术有限公司),进行梯度干燥:-30℃—-20℃2h,-10℃—0℃10h,5℃—20℃20h。喷雾干燥采用SD-1550实验型喷雾干燥机(上海沃迪智能装备股份有限公司),入口温度为180℃、进料速度为1.3L/h,对壳聚糖-磷脂/纳米铁样品溶液进行喷雾干燥。图2h的DLS分析显示,喷雾和冷冻干燥制备的壳聚糖-磷脂复合纳米铁干粉复溶于水中后能够形成具有明显丁达尔效应的澄清溶液,冻干复溶后的壳聚糖-磷脂/纳米铁粒径未增加,喷干复溶后壳聚糖-磷脂/纳米铁粒径轻微增加,表明在喷雾和冷冻干燥条件下具有壳聚糖-磷脂/纳米铁良好的加工稳定性。因此,冷冻干燥和喷雾干燥技术可以作为壳聚糖-磷脂/纳米铁补铁剂产业化的制备手段。
(三)壳聚糖-磷脂/纳米铁生物利用度的药代动力学评估,具体实验过程和实验结论如下:
具体见图3,(a)水溶液体系中血清铁浓度药代动力学曲线;(b)牛奶体系中血清铁浓度药代动力学曲线。
7周龄的雄性Sprague-Dawley大鼠(200g)-单笼饲养,动物房温度22±2℃,湿度55±15%,12/12h光照周期(早上8点至晚上8点照明),在整个研究期间动物可自由摄食和饮用超纯水。
药代动力学实验如下:
适应1周后,将大鼠随机分为6组(每组6只),禁食过夜。动物单次灌胃含有硫酸亚铁或者壳聚糖-磷脂复合纳米铁的水溶液或全脂牛奶,灌胃剂量为2mg Fe/kg体重。定期从颈动脉取血,室温凝血约30分钟后,4000rpm离心10分钟,取血清。使用微量血清铁含量测定试剂盒测定血清样品中的铁浓度。药代动力学参数使用PKSolver软件计算。各补铁剂组的曲线下面积(AUC)计算方法为血清铁含量曲线下和对照组基线上的面积。铁的相对生物利用度计算公式为AUC(壳聚糖-磷脂/纳米铁)/AUC(硫酸亚铁)。图3a和b表示在水溶液或全脂牛奶中口服FeSO4和壳聚糖-磷脂/纳米铁后血清铁浓度(SIC)的变化。在对照组中,SIC在实验期间几乎保持恒定,其平均值为24.2μM。在铁给药组中,SIC迅速升高到峰值水平,然后逐渐回落到基线水平。向水溶液中加入FeSO4和壳聚糖-磷脂/纳米铁后的较短时间内,SIC的峰值水平显著高于全脂牛奶(P<0.05),表明食物基质释放铁的时间延长,且在全脂牛奶体系中,FeSO4的吸收峰值高于壳聚糖-磷脂/纳米铁的吸收峰值,说明在该体系中,机体对壳聚糖-磷脂/纳米铁的吸收较为温和。表2显示壳聚糖-磷脂/纳米铁在水溶液和全脂牛奶体系中被摄入后血清铁的时间与曲线下面积增值(iAUC)分别为FeSO4的1.57和1.67倍,表明壳聚糖-磷脂/纳米铁具有极高的生物可利用性,且显著高于对照组壳聚糖纳米铁和磷脂纳米铁。因此,壳聚糖-磷脂/纳米铁可以作为一种高生物利用度的缓释铁制剂,用于口服治疗和食品铁强化。
表2.水溶液和全脂牛奶体系单次灌胃硫酸亚铁或壳聚糖-磷脂/纳米铁大鼠的药代动力学参数
数据均以平均值±标准偏差(n=3)来表示。均值的差异性采用LSD进行分析,在没有共同上标字母(a,b和c)的行中表示的P<0.05。
缩略词释义:iAUC,曲线以下和基线以上的面积;Tmax,达到最高血清铁浓度的时间;Cmax,给药后观察到的最大血清铁浓度。铁的相对生物利用度通过iAUC(壳聚糖-磷脂复合纳米铁)/iAUC(硫酸亚铁)计算。
(四)壳聚糖-磷脂/纳米铁在体外Caco-2细胞模型中的铁吸收动力学,具体实验过程和实验结论如下:
具体见图4,采用了Caco-2单层分化细胞,细胞外液pH值为5.5,细胞铁的摄入会让钙黄绿素荧光发生猝灭,利用钙黄绿素荧光的变化相对定量细胞的铁摄入。
人结肠腺癌细胞Caco-2细胞株,购自中国科学院典型培养物保藏委员会细胞库;Caco-2细胞日常培养于高糖DMEM完全培养液(含10%胎牛血清、25mM HEPES、4mM谷氨酰胺和1mM丙酮酸钠),在37℃、5%二氧化碳和恒定湿度的培养箱中培养,每隔2-3d传代一次。将Caco-2细胞用高糖DMEM完全培养液稀释至一定浓度,以5×104个/cm2的密度接种于胶原覆盖的24孔板,每隔2d更换一次培养液;从细胞完全融合(接种后2-3d)开始计时,12d后Caco-2细胞分化完全,即得体外肠道细胞模型。随后更换无血清MEM培养基进行饥饿处理24h。之后加入钙黄绿素在37℃孵育30分钟后,加入970μL含有MES(调节pH值5.5)的Tyrod溶液,及包含1mM Fe或壳聚糖-磷脂复合纳米铁的样品溶液,在Synergy H4荧光酶标仪(Bio-Tek)中37℃孵育30分钟,每3分钟记录一次钙黄绿素荧光(485nm激发,530nm发射)。
利用Caco-2细胞模型模拟小肠近端pH值5.5的条件。外源铁通常先进入肠道细胞的细胞质中,即先进入细胞弱结合铁池,再用于合成带有铁辅基的功能酶,或者贮存于铁蛋白,或者排出细胞外。因此,利用钙黄绿素是反映细胞弱结合铁池中的铁含量。如图4a所示,细胞对壳聚糖-磷脂/纳米铁的荧光淬灭能力显著高于壳聚糖纳米铁和磷脂纳米铁,说明相比于对照组,壳聚糖-磷脂/纳米铁具有更高的铁营养递送效率。BPDS阻断细胞铁吸收中依赖于DMT-1的还原解离途径后,细胞对壳聚糖-磷脂/纳米铁中铁的吸收并未被BPDS全部阻断,说明除了依赖于二价金属转运体1(DMT1)的还原解离途径以外,可能还存在其他的细胞吸收途径。
含铁纳米颗粒的细胞铁吸收涉及依赖于DMT1或内吞途径。特异性内吞抑制剂能特异性抑制细胞对铁的吸收途径。细胞内吞作用一般可分为受体介导的特异性内吞作用和非特异性巨胞饮作用,前者需要能量消耗。如图4b叠氮钠能够影响细胞对三磷酸腺苷(ATP)的利用,吡嗪类衍生物AMI能通过阻碍钠和氢离子交换来抑制巨胞饮作用,Dynamin能与三磷酸鸟苷(GTP)的活性区域结合并水解,Dyngo 4a能够作用于dynamin的G结构域的变构位点,使得dynamin失去发挥作用的能力。这三种抑制剂对壳聚糖-磷脂复合纳米铁的吸收均有明显的抑制作用,说明细胞对壳聚糖-磷脂/纳米铁中铁的吸收涉及了巨胞饮作用和依赖于发动蛋白的内吞作用,且吸收过程需要三磷酸腺苷(ATP)。而在细胞外液中添加缺钾细胞液、Pitstop 2和氯喹啉后,细胞对壳聚糖-磷脂/纳米铁中铁的吸收均未受到影响。说明非网格蛋白依赖性的内吞吸收途径并未参与该铁吸收过程,且溶酶体在机体利用壳聚糖-磷脂/纳米铁方面并未发挥作用。
综上,钙黄绿素荧光淬灭动力学结果表明,壳聚糖-磷脂/纳米铁的肠上皮吸收途径不仅涉及依赖于二价金属离子转运蛋白(DMT-1)的还原解离途径,还涉及了巨胞饮作用和依赖于发动蛋白的内吞作用,且吸收过程需要三磷酸腺苷(ATP)。
(五)壳聚糖-磷脂/纳米铁在体外Caco-2细胞模型中的跨膜转运途径,具体实验过程和实验结论如下:
具体见图5。壳聚糖-磷脂/纳米铁在体外Caco-2细胞模型中铁的跨膜转运途径。
黄酮醇槲皮素是广泛存在于蔬菜水果中的膳食类黄酮。Caco-2细胞吸收槲皮素后,能显著降低3’UTR的结构活性,从而剂量依赖性地降低了mRNA和FPN蛋白的表达。渥曼青霉素由微生物代谢产生,其能对肌球蛋白轻链激酶起到抑制作用。Schultz等证明了这一观点,并提出渥曼青霉素可以以此作为抑制胞吐作用的特征。图5显示,在相同时间范围内,转至下室的壳聚糖-磷脂/纳米铁的铁浓度显著高于FeSO4组(P<0.05),说明壳聚糖-磷脂/纳米铁中的铁能更高效地被细胞吸收至血液。加入渥曼青霉素和槲皮素后,壳聚糖-磷脂复合纳米铁的跨膜转运效果受到明显抑制作用,说明有部分壳聚糖-磷脂/纳米铁是通过FPN途径和胞吐作用被细胞吸收,被人体利用。如表3所示,相比于对照组壳聚糖纳米铁和磷脂纳米铁,壳聚糖-磷脂/纳米铁经单层细胞吸收至下室的铁浓度最高,表明壳聚糖-磷脂复合纳米铁中铁的跨膜转运效果最好,能高效利用FPN途径和胞吐作用实现机体对铁的吸收。
本发明表明壳聚糖和磷脂共同介导了铁氧化物纳米颗粒的形成,该复合纳米铁不仅具有更好的微粒稳定性,还在肠上皮细胞铁吸收能力和细胞铁转运效果等方面崭露头角,极具成为优势补铁剂的潜力。
表3 4h内Transwell铁转运装置中FeSO4及纳米铁经细胞转移至下室的铁浓度
数据均以平均值±标准偏差(n=3)来表示。小写字母a-c表示行内不同组之间有显著性差异(P<0.05),大写字母A-E表示列内不同组之间有显著性差异(P<0.05)。
当然,上述说明并非是对本发明的限制,本发明也并不限于上述举例,本技术领域的普通技术人员,在本发明的实质范围内,作出的变化、改型、添加或替换,都应属于本发明的保护范围。
Claims (5)
1.一种壳聚糖-磷脂/纳米铁补铁剂,其特征在于,成分为壳聚糖和磷脂包覆的铁氢氧化物纳米微粒;该壳聚糖-磷脂/纳米铁补铁剂的制备方法是利用壳聚糖介导三价铁盐水解制得壳聚糖纳米铁,再制备磷脂纳米乳液,将壳聚糖纳米铁溶液与磷脂纳米乳液以混合,再进行加热处理后,制得壳聚糖-磷脂/纳米铁补铁剂;
壳聚糖纳米铁溶液中,壳聚糖的质量分数为80-100 mg/g;
磷脂和壳聚糖的重量比为0.0125-0.025mg:1mg;
壳聚糖-磷脂/纳米铁混悬液的水合粒径小于100 nm、ζ电位大于24 mV;
壳聚糖选择分子量30 kDa、脱乙酰度≥95%的壳聚糖。
2.权利要求1所述的壳聚糖-磷脂/纳米铁补铁剂的制备方法,其特征在于,利用壳聚糖介导三价铁盐水解制得壳聚糖纳米铁,再制备磷脂纳米乳液,将壳聚糖纳米铁溶液与磷脂纳米乳液以混合,再进行加热处理后,制得壳聚糖-磷脂/纳米铁补铁剂。
3.根据权利要求2所述的壳聚糖-磷脂/纳米铁补铁剂的制备方法,其特征在于,具体包括下列步骤:
(1)将壳聚糖溶解于酸性水溶液中,加入三价铁盐固体或者溶液,待三价铁盐固体不再溶解或溶液滴加完毕,边搅拌/振荡边将反应体系的pH调至3.0-7.0,制得无色或浅黄色澄清透亮的壳聚糖纳米铁溶液;
壳聚糖纳米铁溶液中,壳聚糖的质量分数为80-100 mg/g;
(2)反复微孔过滤制得磷脂纳米乳液;
(3)向步骤(1)制备的壳聚糖纳米铁溶液中边搅拌/振荡滴加磷脂纳米乳液,55℃-120℃加热处理30-300 min,制得壳聚糖-磷脂/纳米铁混悬液,磷脂和壳聚糖的重量比为0.0125-0.025mg:1mg;
(4)冷冻干燥或喷雾干燥,制得的壳聚糖-磷脂/纳米铁补铁剂固体粉末。
4.根据权利要求3所述的壳聚糖-磷脂/纳米铁补铁剂的制备方法,其特征在于,步骤(2)反复微孔过滤制得磷脂纳米乳液的具体操作是:将植物或动物磷脂粉末加水混合制备磷脂悬浊液,利用0.1-0.45μm微孔滤膜过滤5-15次后,制得磷脂纳米乳液。
5.权利要求1-4任一项所述的壳聚糖-磷脂/纳米铁补铁剂在制备营养强化、营养补充或临床治疗产品中的应用。
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