CN114146188B - 一种修饰型LMSNs纳米药物载体的制备方法 - Google Patents
一种修饰型LMSNs纳米药物载体的制备方法 Download PDFInfo
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Abstract
本发明公开了一种修饰型LMSNs纳米药物载体的制备方法,包括如下步骤:S1、使用模板法制备介孔二氧化硅纳米粒,使用薄膜分散法制备脂质体,混合后水合处理得脂质‑介孔硅复合纳米粒;S2、分别以聚乙二醇琥珀酸酯、去氧胆酸、壳聚糖对脂质‑介孔硅复合纳米粒进行结构修饰,得到纳米系统DCs‑TPGS‑LMSNs;S3、使用荧光剂异硫氰酸荧光素对制得的纳米样品进行标记,以混合搅拌法将CoQ10负载于纳米载体中;计算载CoQ10的纳米制剂的载药率与包封率。本发明探索出一种可重现、成本低、产品质量好的合成方法。
Description
技术领域
本发明涉及药物或食品成分纳米的技术领域,更具体的说是涉及一种修饰型LMSNs纳米药物载体的制备方法。
背景技术
如今纳米技术的快速进步推进了各种纳米材料的产生,新型纳米材料在很多领域得到了广泛的研究与应用,包括生物医学领域,如疾病治疗、诊断、药物递送等。介孔二氧化硅纳米颗粒(MSNs)具有较大的比表面积,并且在合成过程中能够通过控制反应条件控制其尺寸和形状,并且MSNs特殊的表面和内部多孔结构使其具有优异的性能,可以通过调节合成条件来很好地调节这些特性,例如生物成像、生物催化剂、生物传感、组织工程,以及靶向和受控的药物/蛋白质/基因输送系统。脂质体(Liposomes)是直径为纳米级别的球形囊泡,由一个或多个具有水核的生物相容性脂质双层组成,在囊芯内的物质不易通过完整的脂质双层膜,双层包括两个在简单结构上类似于细胞膜屏障的磷脂单分子层,内脂层面向水性核心,外层面向外部水溶液介质,这种独特的结构使Liposomes可同时包裹亲水性和疏水性药物。用天然脂质制备的Liposomes可以作为高度生物相容性和生物可降解性的药物输送系统,从而降低毒性并提高所包裹药物的治疗效率。此外,Liposomes能够保护被包裹的成分不受氧化、光照和水解等外部因素影响,其与生物膜的相似性使细胞更容易吸收。Liposomes已被公认为是提高药物或功能性食品递送效率最有效的新剂型之一。
受模拟细胞膜的负载型脂质双层的启发,脂质双层涂层可以通过在MSNs表面融合而成为一种新的复合纳米粒,即将脂质双层包覆于MSNs纳米颗粒表面得核/壳型脂质-介孔硅复合纳米粒(LMSNs)。这种集成的药物输送系统能够融合MSNs与Liposomes的优点,并表现出优于任何单一成分的特性。LMSNs具有的显著优点包括:MSNs作为骨架核心可以提供稳定外层脂质双层的支撑物,而脂质双层涂层将提高LMSNs的生物相容性和与细胞膜的亲和力,同时Liposomes和MSNs的双重包裹使集成的纳米载体能够以更高的载药量容纳不同的药物分子。因此,LMSNs的性能优于Liposomes或单独使用的MSNs。此外,与其他表面偶联聚合物、生物大分子或无机纳米颗粒的功能化方法相比,脂质双层覆盖相对简单易行。
辅酶Q10(CoQ10)是一种脂溶性分子,含有一个对苯醌环和10个异戊二烯单元,天然存在于许多真核细胞中。CoQ10主要用作细胞内的电子转运体,在线粒体呼吸中以三磷酸腺苷(ATP)的形式产生能量;此外,它还具有很强的抗氧化能力,可以抑制还原形式的脂质过氧化。外用CoQ10在氧化应激、光保护和伤口愈合方面效果显著。因此,CoQ10可作为一种药物或功能性食品,特定人群补充和摄入外源性CoQ10,对于维持心脑血管健康、预防衰老具有重要意义。然而CoQ10的大分子量(863g/mol)和较差的水溶性(0.7ng/mL)导致其生物利用度极低,使其应用受到极大限制。目前已经采取了许多方法来提高CoQ10的溶解度,以促进其被外周组织和血脑屏障摄取,改善其口服吸收效率,这些方法包括使用固体分散系统、聚合物颗粒、纳米乳液和自乳化药物输送系统(DDS)等,以及液体或半固体制剂包括纳米和微载体系统,均有助于延长CoQ10的体内滞留时间和递送效率。但这些制剂在一定程度上仍存在稳定性差、吸收效果不佳等缺点。
LMSNs作为药物与食品营养成分的新型载体,在提高生物利用率和靶向性,以及在胃肠道的消化过程中对包埋物的保护、缓释等方面都具有明显优势。使用薄膜分散法制备Liposomes以及LMSNs,作为CoQ10的高效递送载体,能有效地增强CoQ10的稳定性,防止其被氧化降解,并以D-α-生育酚聚乙二醇1000琥珀酸酯(TPGS)、去氧胆酸(Doca)、壳聚糖(CS)作为修饰剂,以进一步提高复合载体的理化特性和生物相容性。其中:(1)CS是一种存在于自然界的多糖,具有很高的生物安全性,其阳离子聚电解质结构使自身具有粘附性,CS包衣Liposomes能有效提高药物的生物利用度。(2)TPGS可通过共价连接在磷脂表面,为Liposomes提供空间障碍和立体稳定性,还能增加Liposomes在肠道中的滞留时间,增加其与小肠绒毛的接触面积,显著延长体内循环时间,从而改善Liposomes的载体性能。(3)钠离子依赖的尖端胆汁酸转运体(ASBT)是一种回肠中钠离子依赖性转运体,在胆汁酸被肠道细胞吸收的过程中起主导作用,Doca作为肠道细胞胆汁酸转运蛋白的识别配体,能够被ASBT识别,增加了胆汁酸转运途径被肠道摄取。薄膜分散法制备的Liposomes属于动力学稳定体系,具有较高的稳定性,应用薄膜分散法制备具有长循环功能的脂质-介孔硅复合纳米粒LMSNs,可充分发挥两种载体的优势,实现双重缓释并减轻潜在的毒性,从而降低服用剂量与频率,同时提高顺应性与吸收效果,具有显著的开发与应用价值。
因此,提供一种修饰型LMSNs纳米药物载体的制备方法是本领域技术人员亟需解决的问题。
发明内容
有鉴于此,本发明提供了一种修饰型LMSNs纳米药物载体的制备方法。使用薄膜分散法制备Liposomes包覆的MSNs复合纳米粒(LMSNs),以CoQ10为模型化合物,并将CS、TPGS、Doca作为功能化修饰剂对纳米粒进行改性修饰,增加其在肠道的滞留时间以及肠道细胞的摄取效率,提高CoQ10的生物利用度。通过性质表征、负载CoQ10、体外释放、细胞摄取考察等方面的研究,计划探索出一种可重现、成本低、产品质量好的合成方法。材料合成后表征的主要目的是考察相关基团是否修饰成功,修饰后LMSNs性质的变化,并考察其载药量、包封率、体外释放率、细胞摄取等。
为了实现上述目的,本发明采用如下技术方案:
一种修饰型LMSNs纳米药物载体的制备方法,包括如下步骤:
S1、使用模板法制备介孔二氧化硅纳米粒,使用薄膜分散法制备脂质体,混合后水合处理得脂质-介孔硅复合纳米粒,所述脂质-介孔硅复合纳米粒具有脂质体包埋介孔二氧化硅纳米粒的结构;
S2、分别以聚乙二醇琥珀酸酯、去氧胆酸、壳聚糖对脂质-介孔硅复合纳米粒进行结构修饰,得到纳米系统DCs-TPGS-LMSNs;
S3、使用荧光剂异硫氰酸荧光素对制得的纳米样品进行标记,以混合搅拌法将CoQ10负载于纳米载体中;建立测定CoQ10的高效液相色谱法,计算载CoQ10的纳米制剂的载药率与包封率。
优选的,所述步骤S1中的薄膜分散法是称取大豆磷脂于圆底烧瓶,加入胆固醇,加入乙醚作为分散介质,超声混匀后用旋转蒸发仪缓慢蒸发去除乙醚,待缓慢成膜后,关闭旋转蒸发仪,加入超纯水超声水合,即得脂质体。
优选的,所述步骤S1中称取介孔二氧化硅纳米粒于烧杯中,加入超纯水超声混匀成悬液,采用薄膜分散法制备Liposomes薄膜,加入制备好的MSNs悬液,在超声波清洗器中超声水合,即得Liposomes包埋的MSNs悬液,即为脂质-介孔硅复合纳米粒。
优选的,所述步骤S1中介孔二氧化硅纳米粒的粒径为100-160nm。
优选的,所述步骤S1中介孔二氧化硅纳米粒的制备方法为:以表面活性剂十六烷基三甲基溴化铵为模板剂,硅酸四乙酯为硅源,在碱性条件下反应,再在含硝酸铵的乙醇溶液中回流,以无水乙醇清洗除去表面活性剂,即得。
优选的,所述步骤S1中脂质体由大豆磷脂、胆固醇制备得到。
优选的,所述步骤S1中介孔二氧化硅纳米材料与大豆磷脂、胆固醇的质量比为1:1-4,LMSNs与修饰剂的质量比为1-3:1。
优选的,所述步骤S1中介孔二氧化硅纳米粒的粒径为200-300nm。
优选的,所述步骤S3中的纳米样品包括介孔二氧化硅纳米粒、脂质体、脂质-介孔硅复合纳米粒、TPGS-LMSNs、DCs-TPGS-LMSNs。
优选的,所述步骤S3中介孔二氧化硅纳米材料与CoQ10的质量比为2:1-8:1。
通过采用上述技术方案,本发明的有益效果如下:
MSNs比表面积和孔隙率大,通过表面硅醇基与药物作用,载药量高,并可作为稳定脂质双层的支撑骨架;
脂质膜的包覆可防止药物的提前泄露,增强对药物的载运效果,薄膜分散法制备的Liposomes属于动力学稳定体系,应用该法制得的复合纳米粒LMSNs,可充分发挥两种载体的优势,实现双重缓释并减轻潜在的毒性;
对LMSNs进行功能化修饰,连接TPGS使LMSNs具有一定的长循环效应,增加其在肠道的滞留时间,提高摄取效率。
采用酰胺反应制备CS衍生物DCs,在提高纳米载体生物相容性的同时,引入肠道细胞独有的胆汁酸转运途径,增加肠道细胞对LMSNs的摄取,进而提高CoQ10的生物利用度。
附图说明
为了更清楚地说明本发明实施例的技术方案,下面对实施例描述中所需附图作简单介绍,下面描述中的附图仅仅是本发明的实施例,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,还可以根据提供的附图获得其他的附图。
图1为不同纳米样品的透射电镜图,A:MSNs,B:LMSNs,C:TPGS-LMSNs,D:DCs-TPGS-LMSNs;
图2为不同纳米样品的红外吸收光谱图,A:LMSNs合成分析,a:MSNs,b:Liposomes,c:LMSNs,d:TPGS-LMSNs,e:DCs-TPGS-LMSNs;B:LMSNs修饰分析,a:Doca,b:TPGS,c:LMSNs,d:TPGS-LMSNs,e:DCs-TPGS-LMSNs;
图3为不同纳米样品负载CoQ10的红外吸收光谱图,a:CoQ10,b:MSNs@CoQ10,c:Liposomes@CoQ10,d:LMSNs@CoQ10,e:TPGS-LMSNs@CoQ10,f:DCs-TPGS-LMSNs@CoQ10;
图4为不同纳米样品的DSC曲线图,a:MSNs,b:Liposomes,c:LMSNs,d:TPGS-LMSNs,e:DCs-TPGS-LMSNs;
图5为不同纳米样品的XRD曲线图,a:MSNs,b:Liposomes,c:LMSNs,d:TPGS-LMSNs,e:DCs-TPGS-LMSNs;
图6为不同纳米样品的拉曼光谱图,a:MSNs,b:Liposomes,c:LMSNs,d:TPGS-LMSNs,e:DCs-TPGS-LMSNs;
图7为不同纳米样品标记FITC的荧光结果分析图,a:DCs-TPGS-LMSNs,b:FITC,c:MSNs-FITC,d:Liposomes-FITC,e:LMSNs-FITC,f:TPGS-LMSNs-FITC,g:DCs-TPGS-LMSNs-FITC;
图8为模拟肠液中各纳米制剂的体外释放曲线图;
图9为不同纳米粒与Caco-2细胞孵育4h荧光图像;
图10为Caco-2细胞摄取不同纳米粒的定量分析(n=3,*p<0.05);
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动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。
本发明使用薄膜分散法制备Liposomes包覆MSNs的复合纳米粒LMSNs,作为CoQ10的递送载体。并将CS、TPGS、Doca作为功能化修饰剂对LMSNs进行改性修饰,增加其在肠道的滞留时间与摄取效率,制备出具有高载药量、缓释性能与良好吸收利用度的新型纳米系统。
实施例1
(1)MSNs制备:采用模板法,具体方法为:先称取1g十六烷基三甲基溴化铵CTAB,放入250mL三颈烧瓶中,加入100mL超纯水,放入磁子并安装回流装置,95℃回流搅拌升温。向其中加入160μL的二乙醇胺(DEA)作为催化剂,回流搅拌1h使充分混合,完成后取8mL硅酸四乙酯(TEOS)逐滴滴加,完成后继续回流搅拌3h使硅源吸附于模板剂上。待溶液降温后,分装在50mL的离心管中,11000rpm离心15min,收集沉淀。
沉淀用100mL含硝酸铵的乙醇溶液(1%,m/m)超声分散,并用玻璃棒搅拌使沉淀尽可能分散,转入250mL圆底烧瓶中,75℃回流过夜以去除反应体系中的模板剂,结束后将溶液分装于离心管中,11000rpm离心15min收集沉淀,将沉淀用无水乙醇清洗三次以去除MSNs孔隙中残留的硝酸铵。每次清洗后均离心,收集沉淀,干燥24h,再真空干燥12h,去除孔隙中的乙醇分子以得到纯净的MSNs。
(2)Liposomes与LMSNs制备:采用薄膜分散法,称取120mg大豆磷脂于圆底烧瓶,加入50mg胆固醇,加入8-10mL乙醚作为分散介质,超声混匀后用旋转蒸发仪缓慢蒸发去除乙醚,待缓慢成膜后,关闭旋转蒸发仪,加入10mL超纯水超声水合5min,即得Liposomes。
称取100mg的MSNs于烧杯中,加入10mL超纯水超声混匀成悬液。采用薄膜分散法制备Liposomes薄膜,加入制备好的MSNs悬液,在超声波清洗器中超声水合5min,即得Liposomes包埋的MSNs悬液(LMSNs)。
(3)TPGS-LMSNs的制备:称取大豆磷脂和胆固醇后于圆底烧瓶,再加入50mg的TPGS,加入8-10mL乙醚超声分散均匀,在旋蒸仪上旋转蒸发去除乙醚并成膜,加入提前制备好的MSNs水溶液,在超声波清洗器中超声水合5min,即得TPGS修饰的LMSNs(TPGS-LMSNs)。
(4)DCs-TPGS-LMSNs的制备:首先利用酰胺反应制备Doca-CS偶合物(DCs),称取1gCS,溶于配置好的盐酸水溶液(1%,v/v)中,室温下搅拌4h,加入50mL甲醇稀释备用。称取Doca 0.3g,EDC﹒HCl 0.2g溶于二甲基亚砜(DMSO)中,室温下搅拌30min,加入0.2g的NHS继续搅拌1h以活化羧基,混合上述CS混合液,继续室温搅拌24h以合成偶合物DCs。反应完成后,向体系中加入过量NaOH溶液(1mol/L)终止反应,并使产物聚集沉淀。11000rpm离心10min收集沉淀,将沉淀分别用水、甲醇、乙醇各清洗5次,干燥24h,再真空干燥12h后即得DCs。
称取100mg DCs溶解于10mL乙酸水溶液(1%,v/v),与TPGS-LMSNs等体积混合,室温搅拌3h后,超声5min即得DCs-TPGS-LMSNs。
实施例2
(1)FITC标记:
首先制备FITC标记的MSNs。准确称取5mg的FITC,加入1mL DMSO超声溶解,避光放置。称取100mg的MSNs于圆底烧瓶中,加入9mL超纯水,搅拌1h后,均匀滴加FITC溶液,避光搅拌24h后离心,收集沉淀。将沉淀干燥24h,再真空干燥12h即得FITC标记的MSNs(MSNs-FITC)。
制备FITC标记的Liposomes。称取大豆磷脂、胆固醇于圆底烧瓶,加入8-10mL乙醚,超声混匀后用旋转蒸发仪蒸发去除乙醚,成膜后关闭旋转蒸发仪。称取FITC 5mg,加入1mLDMSO溶解,再加入9mL超纯水,超声混匀后加入Liposomes膜中,超声水合5min即得FITC标记的Liposomes溶液(Liposomes-FITC)。
用MSNs-FITC与磷脂薄膜进行水和,同法制备FITC标记的LMSNs(LMSNs-FITC)、TPGS-LMSNS(TPGS-LMSNs-FITC)、DCs-TPGS-LMSNs(DCs-TPGS-LMSNs-FITC)。所有样品制备完成后放于4℃保存备用。
(2)负载CoQ10:称取50mg CoQ10溶于无水乙醇,称取100mg MSNs并加入50mL超纯水超声分散,室温搅拌1h,缓慢加入CoQ10溶液,室温避光搅拌24h。11000rpm离心15min,收集沉淀干燥24h,再真空干燥12h,即得MSNs负载的CoQ10(MSNs@CoQ10)。
Liposomes负载的CoQ10悬液的制备:称取大豆磷脂、胆固醇于圆底烧瓶,加入8-10mL乙醚,超声混匀后用旋转蒸发仪蒸发去除乙醚。加入10mL提前制备好的CoQ10水溶液(5mg/mL,m/m),超声水和5min即得负载CoQ10的Liposomes悬液(Liposomes@CoQ10)。
以制备好的MSNs@CoQ10为原料,同法制备不同功能化修饰型的LMSNs纳米粒负载的CoQ10悬液(LMSNs@CoQ10、TPGS-LMSNs@CoQ10、DCs-TPGS-LMSNs@CoQ10)。制备好的悬液放于4℃,避光保存备用。
(3)HPLC法测定CoQ10的色谱条件:
色谱柱:C18柱(4.6mm×200mm,5μm),流动相:甲醇-异丙醇(35:65),柱温:30℃,流速:1.0mL/min,检测波长:275nm,进样量:10μL。建立定量测定CoQ10的方法,为体外释放实验中CoQ10含量的测定、包封率和载药量的计算做准备。
其中,药物或保健食品可为疏水性药物或多肽、蛋白质、核酸类生物,大分子多醣或单糖、维生素、谷胱甘肽、二十八醇等。优选的,所述药物或保健食品选自阿霉素(DOX)、紫杉醇、自由基清除剂、低聚糖中任一种。
应用实施例1
应用本发明实施例1中制得的各载体——MSNs、Liposomes、LMSNs、TPGS-LMSNs、DCs-TPGS-LMSNs,以去离子水为分散介质,用激光粒度分析仪测定样品的粒径、多分散系数(PDI)和Zeta电位,结果见表1。由结果可知:MSNs粒径约为149nm,分散性良好,Zeta电势为-14.5mV,负的电势主要来自于表面的硅醇基团。经Liposomes薄膜包埋后的纳米粒粒径略微增大,电势变化较小。经TPGS修饰后,LMSNs的粒径有所减小,说明TPGS的加入对于Liposomes的包埋水合具有很好的促进作用,也提高了LMSNs的分散性,同时引入了正电荷。TPGS的PEG链从Liposomes表面向外延伸,可通过空间位阻形成保护性外层,屏蔽带负电荷的Liposomes表面,表面电荷由负向正转变。加入DCs后,纳米粒的粒径有一定程度的增大,约为228nm,该纳米粒形态较小,具有被细胞摄取的可能。而Zeta电势为66.9mV,可增加纳米粒与细胞接触的可能。
图1是各纳米样品的透射电镜图。如图所示,MSNs颗粒大小均匀,分散性较好,MSNs表面有密集的空腔,这些介孔的存在使负载CoQ10成为可能。经Liposomes包埋后的MSNs能够明显看到在外层包裹的一层薄膜。随着TPGS及DCs的修饰,LMSNs表面的空隙已不可见,且纳米粒的分散性相较于未修饰型LMSNs有了很大提高。Liposomes表面的DCs壳层可增强制剂的吸收,保护其在肠道内不被破坏。
应用实施例2
应用本发明实施例1中提供的各载体——MSNs、Liposomes、LMSNs、TPGS-LMSNs、DCs-TPGS-LMSNs,分别进行红外光谱分析、差示扫描量热(DSC)、X射线衍射(XRD)、拉曼光谱等表征。
图2是各纳米样品的红外吸收光谱图,扫描波数范围为500-4000cm-1,X轴表示透光率(%),Y轴表示波数,单位为cm-1。由图可知,MSNs在800cm-1-1150cm-1处有明显的伸缩振动峰,在3500cm-1处的红外峰是硅醇基的特征光谱。对于Liposomes的红外光谱特征锋,在2930cm-1和2850cm-1处有明显的伸缩振动,来自于长链脂肪酸的C-H伸缩带振动。在Liposomes包埋MSNs形成壳/核结构后,位于1240cm-1处的P=O伸缩带变宽,位于3500cm-1处的硅醇基的特征峰也有一定程度的减弱。随着TPGS以及DCs的添加,在3500cm-1处的硅醇基的特征峰以及在800cm-1~1150cm-1处Si-O-Si的不对称和对称伸缩逐渐减缩。在添加TPGS修饰后的LMSNs谱图中,能够看到在1342cm-1处和1278cm-1处的振动双峰,这是甲基基团的特征峰,表明TPGS的成功修饰。CS表面有含量丰富的氨基,Doca含有羧基基团,位于1700cm-1处的C=O伸缩振动峰来源于Doca含有的羧基基团,在与CS共价偶联之后,属于C=O的红外特征峰消失,在1650cm-1处出现了新的红外特征峰,这来源于酰胺键中的C-N键伸缩振动。
图3是各同纳米样品负载CoQ10的红外吸收光谱图。由图可知,在3000cm-1处有明显的C-H伸缩振动区,在2960cm-1处的-CH3振动峰,在2900cm-1处的-CH2-伸缩振动,在1700cm-1处的伸缩振动区为羰基特征振动区域,在1500cm-1处为泛醌化合物中六元环的伸缩振动区。在MSNs负载CoQ10后,样品在3000cm-1处、2960cm-1处、1700cm-1处、1500cm-1处的特征峰均未出现明显变化,这表明在MSNs上负载有大量的CoQ10。对于不同功能化修饰的LMSNs,均能检测到以上各处CoQ10的特征峰,证明各LMSNs纳米粒子均能负载CoQ10分子。
图4是各纳米样品的DSC曲线图。由图可知,MSNs在70℃左右有一个巨大的峰,这是MSNs向结晶态转变的标志。冻干的Liposomes在112℃左右处有一个吸热峰,对应于从固态到凝胶态的转变,在240.5℃有一个强烈的吸热峰,对应于从凝胶状态到液晶状态的转变。LMSNs在的DSC曲线与Liposomes相比并无太大变化,相变温度稍有降低,表明MSNs上存在脂质双层,由于多孔二氧化硅的支撑和界面相互作用增加了脂质膜的流动性使得相变温度降低。经TPGS和DCs修饰后的纳米粒,在240.5℃处的吸热峰消失,可以认为修饰后LMSNs会熔融溶解为结晶态。这些结果表明脂质双层成功包埋在了MSNs表面,且经过功能化修饰后的LMSNs稳定性有极大的提升。
图5是各纳米样品的XRD曲线图。由图可知,MSNs并没有明显的精细谱峰结构,在22°处有一个大包峰,说明MSNs在正常状态下为无定型态。Liposomes在19°处有一个大包峰,说明冻干的Liposomes也是以无定形态存在。在LMSNs以及修饰后的样品中,在21°处有一个大包峰,也是以无定形态存在。经TPGS修饰后的LMSNs在20°与24°处有明显的谱峰,说明经修饰后的LMSNs由无定型态向有序转变,修饰后的磷脂双分子层稳定性会有一定的提升。
图6是各纳米样品的拉曼光谱图。由图可知,MSNs在1450cm-1处具有一个羟基的特征峰,在2900cm-1处有硅醇基的特征峰。Liposomes的磷脂分子在1450cm-1处也有羟基的特征峰。Liposomes在MSNs作用下715cm-1与1100cm-1左右的峰强度均降低,表明LMSNs中磷脂以其极性头部与MSNs结合包埋,形成稳定的复合体。脂质双层在2800cm-1处的峰强度随着修饰剂的添加也降低,峰形变宽,表明修饰剂与Liposomes紧密结合。
图7是各纳米样品的标记FITC的荧光结果分析图。由图可知,FITC在525nm处有明显的荧光峰,未标记FITC的DCs-TPGS-LMSNs在520nm-550nm范围内,曲线平坦,无明显荧光峰。负载FITC后的MSNs在525nm处有明显的荧光特征峰,同样地,负载FITC的Liposomes、LMSNs及修饰型纳米样品在525nm左右都检测到荧光峰,证实各纳米载体均能成功负载FITC荧光分子。
综合以上各项表征结果可知,我们成功制备了复合型LMSNs纳米粒,并且修饰上了TPGS、Doca、CS等功能化成分,最终合成的DCs-TPGS-LMSNs纳米系统具有很好的物理稳定性,呈现均一的球型,分散性较好,具有作为CoQ10优良递送载体的可能。
应用实施例3
应用本发明实施例1、2中提供的负载CoQ10的各纳米样品——MSNs@CoQ10、Liposomes@CoQ10、LMSNs@CoQ10、TPGS-LMSNs@CoQ10、DCs-TPGS-LMSNs@CoQ10(即各纳米制剂),测定载药量与包封率。
取各纳米制剂,离心后量取上清液的体积,HPLC法进样测定,以峰面积代入标准曲线求出上清液中CoQ10含量。根据公式计算各载体对CoQ10的包封率与装载量。计算公式为:
表2为包封率与装载量测定结果。结果表明MSNs由于其表面极大的比表面积,即能够对CoQ10进行很好的包埋,包封率达89.06%。制备的新型纳米载体DCs-TPGS-LMSNs对CoQ10的包封率达到94.5%,高包封率证明其对CoQ10的包埋效果好,载药性能优异。
应用实施例4
应用本发明实施例1、2中提供的负载CoQ10的各纳米样品——MSNs@CoQ10、Liposomes@CoQ10、LMSNs@CoQ10、TPGS-LMSNs@CoQ10、DCs-TPGS-LMSNs@CoQ10(即各纳米制剂),测定体外释放度。
采用膜透析法。由于CoQ10为脂溶性分子,选用PBS-乙醇(1:4)混合溶液作为释放介质,实验在pH=6.8的PBS-乙醇混合液中进行,模拟人体肠道环境。首先同前所述方法制备不同修饰型LMSNs负载CoQ10纳米粒。取1mL纳米制剂,加入4mL释放介质混匀,加入到透析袋中,封好端口,转入具塞三角瓶中,加入50mL释放介质,在37℃下振荡,速度调节至160rpm。分别在1、2、4、6、8、10、12、24、36、48、72、96、120h取样2mL,同时补充新鲜介质。HPLC法检测,计算释放的CoQ10浓度,以时间为横坐标,CoQ10的释放度为纵坐标做图,评估不同载体中CoQ10的体外溶出度。CoQ10的体外释放度计算公式为:
图8为各纳米制剂的体外释放曲线图。结果显示溶液的CoQ10在2h处的释放度已超过10%,而纳米载体负载的CoQ10制剂,释放度均不到5%,表明纳米载体负载CoQ10能起到很好的缓释效果。纳米材料在进入人体后,会逐渐富集形成一个纳米囊,能够在机体内长时间存在。从释放曲线中可知,溶液中的CoQ10在2天后已经基本完全释放(近90%),而载体负载的CoQ10在5d后仍然在缓慢释放出CoQ10分子,负载CoQ10的纳米样品能够在人体停留较长时间,使得CoQ10能够被机体充分吸收,大大提高了其生物利用度。
应用实施例5
应用本发明实施例1、2中提供的负载CoQ10的各纳米样品——MSNs@CoQ10、Liposomes@CoQ10、LMSNs@CoQ10、TPGS-LMSNs@CoQ10、DCs-TPGS-LMSNs@CoQ10(即各纳米制剂),考察细胞摄取效果。
细胞培养:取人结直肠癌上皮Caco-2细胞,培养在含15%胎牛血清(FBS)、1%非必需氨基酸、1%青霉素和链霉素、1%L-谷氨酰胺的MEM培养基中。细胞在37℃、含5%CO2的加湿培养箱中培养,培养液每两天更换一次。
采用荧光定位与流式细胞术分析Caco-2细胞对各纳米制剂的摄取。先用FITC标记纳米样品,将其作用于Caco-2细胞,在荧光显微镜下观察细胞摄取。取对数生长期的细胞,接种在12孔细胞培养板,每孔1.5mL,培养贴壁。长满孔板后,加入新配置的含有FITC标记的各纳米制剂,继续孵育4h,吸去培养液,加入Hoechst33342染色液孵育30min后用PBS清洗两次,然后用4%多聚甲醛固定,在倒置荧光显微镜下观察。
同法培养细胞,加入纳米制剂孵育后,吸去培养液,收集细胞沉淀并用PBS清洗2次,加入1mL PBS重悬细胞,用流式细胞仪上机检测。
图9为各纳米制剂与Caco-2细胞孵育4h荧光图像,图10为Caco-2细胞摄取各纳米制剂的定量分析结果。由图可知,游离FITC在相同浓度条件下,仅有少量能够进入细胞内部,被流式细胞仪检测到荧光信号。而经MSNs负载后,FITC的荧光信号有一定程度的增强,说明Caco-2细胞能够有效摄取MSNs纳米粒。经Liposomes包埋后的纳米载体LMSNs,荧光强度比MSNs与Liposomes均有提升,说明核壳结构的LMSNs具有更强的递送能力。对于DCs-TPGS-LMSNs组,其细胞内的荧光强度进一步增强,培养4h后,荧光强度约为同等条件下游离FITC的3倍,这说明修饰型的载体材料更易被细胞摄取。这可能是载体材料在正常的内吞作用途径下又通过胆汁酸转运途径增加了摄取量。同时,游离FITC在4h与12h的细胞摄取量差异并不明显,而细胞对纳米制剂的摄取有一定的时间依赖性,尤其是DCs-TPGS-LMSNs组,其12h的荧光强度是4h时的1.6倍,是游离FITC在12h时摄取量的4倍。以上结果证实以DCs-TPGS-LMSNs作递送载体能极大增加肠道细胞对CoQ10的摄取量,从而提高其生物利用度。
综上,本发明构建了一种核/壳结构的纳米复合物LMSNs,以CS、TPGS、Doca作为修饰剂对LMSNs进行功能化修饰,并用作CoQ10的递送载体。该制备方法简单,所得的DCs-TPGS-LMSNs样品粒径分布均匀、理化性质稳定,对CoQ10的包封率、装载量高,能缓慢缓释CoQ10,可增加Caco-2细胞对CoQ10的摄取,提高其CoQ10的生物利用度。因此,DCs-TPGS-LMSNs是一种高效的药物或功能性食品递送系统。
表1不同纳米样品的粒径、Zeta电势
表2不同纳米制剂的包封率和装载量
本说明书中各个实施例采用递进的方式描述,每个实施例重点说明的都是与其他实施例的不同之处,各个实施例之间相同相似部分互相参见即可。对于实施例公开的装置而言,由于其与实施例公开的方法相对应,所以描述的比较简单,相关之处参见方法部分说明即可。
对所公开的实施例的上述说明,使本领域专业技术人员能够实现或使用本发明。对这些实施例的多种修改对本领域的专业技术人员来说将是显而易见的,本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下,在其它实施例中实现。因此,本发明将不会被限制于本文所示的这些实施例,而是要符合与本文所公开的原理和新颖特点相一致的最宽的范围。
Claims (3)
1.一种修饰型LMSNs纳米药物载体的制备方法,其特征在于,包括如下步骤:
S1、使用模板法制备介孔二氧化硅纳米粒,使用薄膜分散法制备脂质体,混合后水合处理得脂质-介孔硅复合纳米粒,所述脂质-介孔硅复合纳米粒具有脂质体包埋介孔二氧化硅纳米粒的结构;
S2、分别以聚乙二醇琥珀酸酯、去氧胆酸、壳聚糖对脂质-介孔硅复合纳米粒进行结构修饰,得到纳米系统DCs-TPGS-LMSNs;
所述步骤S1中,脂质体由大豆磷脂、胆固醇制备得到,介孔二氧化硅纳米材料与大豆磷脂、胆固醇的质量比为1:1-4;LMSNs与修饰剂的质量比为1-3:1。
2.根据权利要求1所述的一种修饰型LMSNs纳米药物载体的制备方法,其特征在于,所述步骤S1中介孔二氧化硅纳米粒的粒径为100-160nm。
3.根据权利要求1所述的一种修饰型LMSNs纳米药物载体的制备方法,其特征在于,所述步骤S1中介孔二氧化硅纳米粒的制备方法为:以表面活性剂十六烷基三甲基溴化铵为模板剂,硅酸四乙酯为硅源,在碱性条件下反应,再在含硝酸铵的乙醇溶液中回流,以无水乙醇清洗除去表面活性剂,即得。
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