CN115212318A - 一种微环境响应型脂质介孔硅核壳纳米递送载体及其制备方法与应用 - Google Patents
一种微环境响应型脂质介孔硅核壳纳米递送载体及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开了一种微环境响应型脂质介孔硅核壳纳米递送载体及其制备方法,包括以下具体:(1)将介孔二氧化硅纳米粒依次进行氨化、羧基化后,制备含有二硫键的介孔硅;(2)将所述含有二硫键的介孔硅和脂质体混合后处理得到脂质体包覆的脂质‑介孔硅复合纳米粒;(3)分别采用TPGS和HA对所述脂质‑介孔硅复合纳米粒进行修饰,即得一种微环境响应型脂质介孔硅核壳纳米递送载体。本发明纳米载体生物相容性高的同时,其靶向递送性能也得到了增强,降低了潜在毒性,提高了抗肿瘤效果。
Description
技术领域
本发明属于药物制剂技术领域,具体涉及一种微环境响应型脂质介孔硅核壳纳米递送载体及其制备方法与应用。
背景技术
目前,癌症仍是人类最致命的杀手之一,且发病率和死亡率不断上升。传统的抗肿瘤药物经静脉注射或口服后,只有少量的药物分子可以通过血液循环到达癌变部位,导致生物利用率低而需频繁给药。这种治疗方式不仅会促使肿瘤细胞产生耐药性,还会因药物分子缺乏特异性识别而被正常组织摄取,产生严重的组织器官毒副作用。纳米药物传递系统凭借其优良特性能够实现有效荷载抗癌药物、靶向传递及响应性释放抗癌药物,已成为抗癌纳米医学研究的前沿领域之一。
介孔二氧化硅(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调节MSNs的尺寸和形状,合成的MSNs由于其表面丰富的活性基团而易于表面功能化修饰。MSNs在适当剂量下具有良好的生物相容性,因为它们具有大量的硅醇基团,通常会分解为无毒的硅酸分子。脂质体(Liposomes)是直径纳米级别球形囊泡,由一个或多个具有水核的脂质双层组成,这种独特的结构使其能同时包裹亲水性和疏水性药物。用天然脂质制备的Liposomes可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果。单一的脂质体或MSNs用作药物载体均存在一些明显缺陷,如聚集沉降、氧化分解、药物过早泄漏等。
同时,肿瘤微环境具有高谷胱甘肽(GSH)含量、低pH等特性,其中含有比正常组织高出约100-1000倍的还原刺激性GSH,高浓度GSH易导致纳米载体中的某些氧化还原敏感性基团如二硫键等断裂,引起载体结构瓦解和药物的快速释放,同时微酸性环境可引起酸敏感性载体结构发生变化,加速药物的释放,这种基于肿瘤微环境的智能响应性释药,可极大提高载药系统的递送性能与定位可控释放,但是目前未见公开相关现有技术。
因此,能够提供一种微环境响应型脂质介孔硅核壳纳米递送载体及其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,本发明提供了一种微环境响应型脂质介孔硅核壳纳米递送载体及其制备方法,本发明首先合成MSNs,加入琥珀酸酐反应后得到羧基化样品即MSNs-COOH,再以半胱氨酸为二硫键供体,在MSNs表面引入二硫键,合成MSNs-SS-NH2,即为氧化还原响应型载体材料;使用薄膜分散法制备Liposomes包覆的MSNs-SS-NH2复合纳米粒,并将维生素E聚乙二醇琥珀酸酯、透明质酸作为功能化修饰剂对纳米粒进行改性修饰,增加其在癌细胞的摄取效率,提高药物的生物利用度。
为了实现上述目的,本发明采用如下技术方案:
一种微环境响应型脂质介孔硅核壳纳米递送载体的制备方法,包括以下具体:
(1)将介孔二氧化硅纳米粒依次进行氨化、羧基化后,制备含有二硫键的介孔硅;
(2)将所述含有二硫键的介孔硅和脂质体混合后处理得到脂质体包埋的脂质-介孔硅复合纳米粒;
(3)分别采用TPGS和HA对所述脂质-介孔硅复合纳米粒进行修饰,即得一种微环境响应型脂质介孔硅核壳纳米递送载体。
鉴于介孔二氧化硅和脂质体的优势与不足,可将其结合组成核/壳型复合纳米载药系统(LMSNs),其用作药物载体的优势:①MSNs的大比表面积和孔容积可极大提高载体对药物的负载率;②复合载药系统中以脂质双分子层作为MSNs的控制阀,为药物泄露增加了一道屏障,双重包封作用可有效减少药物到达靶部位前的损失;③由于MSNs的支撑,提高了脂质双层膜的物理稳定性;该核壳结构可修饰位点更多,能同时负载多种治疗试剂,有助于发挥不同治疗手段的协同作用;
维生素E聚乙二醇琥珀酸酯(TPGS)是一种维生素E相关的衍生物,它是由维生素E琥珀酸酯羧基以及聚乙二醇酯化而成;TPGS是一种优异的表面活性剂,其与药物聚合成胶束时会提高胃肠道的吸收率,因此可以明显地提高药物利用率;LiuBY等为了克服多药耐药,将化疗药物紫杉醇(PTX)和耐药抑制剂(tariquar,TQR)共负载在维生素E-TPGS基纳米颗粒中,得到TPGS/PTX/TQR纳米载药颗粒,并在耐药肿瘤细胞(MCF-7/ADR)和非耐药细胞(HeLa)中评估了该给药系统对肿瘤细胞抑制和逆转耐药性的效率,经处理后,细胞上清中IL-10浓度降低,显示了明显的抗肿瘤活性;复合载药维生素E-TPGS纳米颗粒还具有协同给药作用,在逆转肿瘤耐药治疗中具有广阔的应用前景。
透明质酸(Hyaluronic acid,HA),又名糖醛酸、玻尿酸,是一种酸性黏多糖;因具有良好的生物相容性、生物可降解性、受体结合性,同时几乎无毒性和免疫原性,HA及其衍生物作为修饰剂已被广泛地应用于药物载体材料中。肿瘤细胞内存在多种HA受体(如CD44蛋白等),HA及其衍生物可以与细胞表面的特异性受体高效识别并结合,因此HA作为纳米载体的修饰剂可有效提高其肿瘤靶向性,更好地实现对化疗药物的精准递送。
本发明采用介孔二氧化硅通过氨基化反应制得MSNs-NH2,然后又通过酰胺反应与琥珀酸酐反应制得MSNs-COOH,以MSNs-COOH为基础加入L-半胱氨酸盐酸盐(为含硫氨基酸,其结构末端含有巯基和氨基),在N2保护条件下发生反应制得MSNs-SS-NH2,此种连接方式制得的二硫键可稳定存在,连接方式简单高效,产率可高达80%-90%。同时由于-SS-NH2的堵孔作用,使该载药系统在进入到肿瘤微环境中低pH、高GSH环境中时与二硫键反应使其断裂,使得孔隙中DOX可快速释放于肿瘤部位,发挥作用,在核壳结构提高药物缓释的基础上实现DOX的集中定位释放。
此外本发明将大豆磷脂、胆固醇和TPGS溶于乙醚,通过薄膜分散法将TPGS连接到脂质体表面,HA水溶液与脂质介孔硅悬液通过物理混合和分子间作用力相连接,TPGS对MDR型细胞中过表达的P-gp有良好的抑制作用,进而抑制了P-gp外排DOX的功能而使DOX积聚于肿瘤细胞内增强抗肿瘤效果,HA可识别肿瘤细胞表面的多种受体,使该载药系统可靶向作用于肿瘤细胞,二者合用可提高载药系统的细胞摄取效率,针对耐药细胞可极大提高药物内化与定位蓄积效果,提升抗肿瘤药效。
优选的,所述介孔二氧化硅纳米粒的粒径为100-160nm,所述介孔二氧化硅纳米粒采用模板法制备。
优选的,所述氨化步骤为向MSNs中加入无水乙醇和3-氨丙基三乙氧基硅烷反应,即得MSNs-NH2。
优选的,所述羧基化步骤为向所述MSNs-NH2中加入丙酮和琥珀酸酐反应制得MSNs-COOH。
优选的,所述含有二硫键的介孔硅的制备方法为:用PBS溶解MSNs-COOH,并加入半胱氨酸盐酸盐(Cys),在氮气保护的条件下合成MSNs-SS-NH2,由于半胱氨酸为含硫氨基酸,在其结构末端含有巯基,可与MSNs-COOH反应合成二硫键。
优选的,所述含有二硫键的介孔硅和所述脂质体的质量比为1:2-3。
优选的,所述脂质-介孔硅复合纳米粒和所述修饰剂的质量比为2-2.7:1,所述TPGS和所述HA的质量比为1:1。
优选的,所述脂质体由大豆磷脂和胆固醇制备得到。
优选的,所述脂质体采用薄膜分散法制备。
上述所述制备方法得到的一种微环境响应型脂质介孔硅核壳纳米递送载体。
优选的,所述载体的粒径为200-300nm。
上述所述制备方法得到的一种微环境响应型脂质介孔硅核壳纳米递送载体或者上述所述一种微环境响应型脂质介孔硅核壳纳米递送载体在制备靶向化疗药物中的应用。
优选的,所述介孔二氧化硅纳米粒和所述药物的质量比为2-3:1。
优选的,所述药物为临床应用广泛的抗肿瘤药物,如干扰转录过程和阻止RNA合成的药物:多柔比星(DOX)、抑制蛋白质合成与功能的药物:紫杉醇(PTX)、直接影响DNA结构和功能的药物:顺铂(DDP)、干扰核酸生物合成的药物:氟尿嘧啶(5-FU)等。
与现有技术相比,本发明具有如下有益效果:
(1)本发明采用的MSNs比表面积和孔隙度大,通过表面硅醇基与药物作用,载药量高,在脂质双层膜破裂后,MSNs表面的-NH2基团可有效封堵介孔,避免DOX过早泄漏;-SS-具有良好的氧化还原响应性,能在肿瘤细胞内高浓度GSH的环境中发生断裂,暴露MSNs表面的介孔,高效定位释放DOX;MSNs-SS-NH2还可作为稳定脂质双层的支撑骨架;
(2)本发明脂质膜的包覆可防止药物的过早泄露,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-SS-NH2,可充分发挥两种载体的优势,实现双重缓释且具有较高的生物安全性;
③本发明对LMSNs进行功能化修饰,TPGS能有效抑制耐药癌细胞中P-gp蛋白外排药物的功能,增加药物在细胞内的积累量,因此连接TPGS使LMSNs-SS-NH2能有效克服肿瘤多药耐药,增强杀灭肿瘤细胞的效率;
④本发明采用的HA能特异性地识别肿瘤细胞中过表达的CD44受体,在提高纳米载体生物相容性的同时,增强其靶向递送性能,降低潜在毒性,提高抗肿瘤效果。
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,下面将对实施例或现有技术描述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为本发明实施例1各纳米样品的透射电镜图;
图2为本发明实施例1各纳米样品的红外吸收光谱图;
图3为本发明实施例2各纳米样品负载DOX的红外吸收光谱图;
图4为本发明实施例1各纳米样品的DSC曲线图;
图5为本发明实施例1各纳米样品的XRD曲线图;
图6为本发明实施例1各纳米样品的拉曼光谱图;
图7为本发明实施例2各纳米样品的标记FITC的荧光结果分析图;
图8为本发明实施例1和2各纳米样品和载药纳米样品的比表面积分析及孔径对比图;
图9为本发明实施例2各纳米样品的在不同浓度GSH和pH环境中的体外释放曲线图;
图10为本发明实施例实施例1和2各纳米样品和载药纳米样品对MCF-7和MCF-7/ADR细胞的毒性分析图;
图11为本发明实施例2各标记纳米样品与MCF-7/ADR细胞孵育4h后的荧光图。
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。
实施例1
一种微环境响应型脂质介孔硅核壳纳米递送载体,主要步骤包括:
(1)MSNs合成:
采用模板剂法,具体方法为:称取1g十六烷基三甲基溴化铵(CTAB)于250mL三颈烧瓶中,加入100mL超纯水,放入磁子并安装回流装置,95℃搅拌升温,向其中加入160μL二乙醇胺(DEA)作为催化剂,回流搅拌2h后取8mL硅酸四乙酯(TEOS)逐滴滴加,继续搅拌2h;待溶液降温后,10000rpm离心10min,收集沉淀;用100mL含1g硝酸铵的乙醇溶液超声分散,转入250mL圆底烧瓶中,75℃回流过夜,结束后将溶液分装于离心管中,10000rpm离心10min收集沉淀,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,真空干燥24h,得到纯净的MSNs;
(2)MSNs-SS-NH2合成:
取0.1g MSNs于10ml无水乙醇中,超声使其分散均匀,向其中加入2ml3-氨丙基三乙氧基硅烷(APTES)后,溶液于60℃油浴中回流反应20h,11000rpm离心10min后收集沉淀,真空干燥24h,即得MSNs-NH2;
取100mg MSNs-NH2中加入10ml丙酮,搅拌30min后逐滴加入含有乙二酸酐的丙酮溶液,室温下搅拌24h,11000rpm离心10min后收集沉淀,分别用超纯水和无水乙醇洗涤4次后离心得沉淀,真空干燥24h,即得MSNs-COOH;
向三颈烧瓶中加入磁子,一端连接上带有三通的氮气包,另外两端封闭,三通另一端连接在真空泵上,反复抽取三颈瓶中空气3次,直至瓶中充满氮气,取100mg MSNs-COOH,加入20ml PBS液(pH5.0)后分别加入150mg的1-乙基-(3-二甲基氨基丙基)碳化二亚胺盐酸盐(EDC.HCL)和N-羟基丁二酰亚胺(NHS),溶解,透过胶塞打进充满氮气的三颈瓶中,室温搅拌活化2h后,取20ml丙酮加入1g Cys.HCL并溶解,打进三颈瓶中,在氮气保护下35℃搅拌24h后,11000rpm离心10min收集沉淀并于30℃真空干燥24h,即得MSNs-SS-NH2;
(3)Liposomes与LMSNs-SS-NH2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8mL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,成膜后加入10mL超纯水超声水合,即得Liposomes;
称取100mg的MSNs-SS-NH2于烧杯中,加入10mL超纯水超声混匀成悬液。在制备的Liposomes薄膜中加入制备好的MSNs-SS-NH2悬液,超声水合,即得Liposomes包覆的MSNs-SS-NH2纳米粒(LMSNs-SS-NH2)。
(4)TPGS-LMSNs-SS-NH2的制备:
称取大豆磷脂和胆固醇于圆底烧瓶,加入50mg TPGS,加入8-10mL乙醚超声分散均匀,旋转蒸发去除乙醚并成膜,加入制备好的MSNs-SS-NH2悬液,超声水合,即得TPGS修饰的LMSNs-SS-NH2(TPGS-LMSNs-SS-NH2);
(5)HA-TPGS-LMSNs-SS-NH2的制备:
取50mg HA于20ml超纯水中分散,完全水合后加入1.5倍质量的EDC.HCL和NHS,活化2h后调节pH至8.3,加入100mg制好的TPGS-LMSNs-SS-NH2悬液,常温下搅拌24h,离心除去多余的HA,加入适量超纯水将沉淀重悬后冷冻干燥,即得HA-TPGS-LMSNs-SS-NH2。
实施例2
(1)FITC标记:
制备FITC标记的MSNs-SS-NH2:
准确称取5mg FITC,加入1mL DMSO超声溶解,避光放置;称取100mg MSNs于圆底烧瓶,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,干燥24h后再真空干燥12h,即得FITC标记的MSNs-SS-NH2(MSNs-SS-NH2-FITC);
制备FITC标记的Liposomes:
称取120mg大豆磷脂于圆底烧瓶,加入50mg胆固醇,加入8mL乙醚作为分散介质,超声混匀后蒸发去除乙醚,即得Liposomes膜;称取FITC 5mg,加入1mL DMSO溶解,再加入9mL超纯水,超声混匀后加入Liposomes膜中,超声水合后即得FITC标记的Liposomes溶液(Liposomes-FITC);
用MSNs-SS-NH2-FITC与磷脂薄膜进行水和,同法制备FITC标记的LMSNs-SS-NH2(LMSNs-SS-NH2-FITC)、TPGS-LMSNs-SS-NH2(TPGS-LMSNs-SS-NH2-FITC)、HA-TPGS-LMSNs-SS-NH2(HA-TPGS-LMSNs-SS-NH2-FITC),所有样品制备完成后放于4℃保存备用;
(2)负载DOX:
称取50mg DOX溶于无水乙醇,取100mg MSNs-SS-NH2并加入50mL超纯水超声分散,室温搅拌1h,缓慢加入DOX溶液,避光搅拌24h,11000rpm离心15min,收集沉淀真空干燥2h,即得MSNs-SS-NH2负载的DOX(MSNs-SS-NH2@DOX);
Liposomes负载的DOX悬液的制备:称取120mg大豆磷脂于圆底烧瓶,加入50mg胆固醇,加入8mL乙醚作为分散介质,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DOX水溶液(1mg/mL),超声水和后即得负载DOX的Liposomes悬液(Liposomes@DOX);
以制备好的MSNs-SS-NH2@DOX为原料,同法制备不同功能化修饰型的LMSNs-SS-NH2纳米粒负载的DOX悬液(LMSNs-SS-NH2@DOX、TPGS-LMSNs-SS-NH2@DOX、HA-TPGS-LMSNs-SS-NH2@DOX),制备好的悬液放于4℃,避光保存备用。
如图1为各纳米载体的透射电镜图,图A是空白未修饰型MSNs,呈现大小均匀的分散球状,尺寸均匀且在100nm以下,并且表面可以清楚地看到有规则排列的孔隙;图B是MSNs-SS-NH2,与MSNs相比,-NH2、-COOH、-S-S-等基团并没有明显改变其形态;图C是Liposomes,呈球型膜状,与MSNs相比,其表面光滑、无孔隙;图D是LMSNs-SS-NH2,可以明显看到MSNs表面被一层膜状物质覆盖;图E是TPGS-LMSNs-SS-NH2,可以观察到MSNs被脂质层包裹,经TPGS修饰后,粒径有所增大;图F是HA-TPGS-LMSNs-SS-NH2,可以看到MSNs被脂质层包裹,经HA修饰后,粒径增大;
表1为实施例1各纳米载体的粒径与Zeta电位测定结果,根据表中数据可知,其中MSNs的电位为负值,主要是其表面的硅醇基所致;由于氨基带正电,经过氨基修饰的MSNs-NH2的Zeta电势为正值;经Liposomes薄膜包埋后的纳米粒粒径略微增大,电势变正,这可能是由于LMSNs-SS-NH2中存在的氨基数量较多;随着修饰剂TPGS、HA修饰后粒径慢慢变大,表明修饰剂已成功连接,HA-TPGS-LMSNs-SS-NH2复合纳米系统构建成功,Zata电势为-30左右;
表1各纳米载体的粒径、Zeta电位测定结果
样品 | 粒径(nm) | PDI | Zata电位(mV) |
MSNs | 158.33±0.54 | 0.13±0.02 | -10.87±0.12 |
MSNs-SS-NH<sub>2</sub> | 173.93±3.61 | 0.31±0.02 | 35.13±0.73 |
Liposomes | 207.60±1.26 | 0.43±0.01 | -28.20±0.51 |
LMSNs-SS-NH<sub>2</sub> | 181.23±5.74 | 0.35±0.04 | 6.25±0.16 |
TPGS-LMSNs-SS-NH<sub>2</sub> | 185.67±3.92 | 0.24±0.01 | -4.60±0.03 |
HA-TPGS-LMSNs-SS-NH<sub>2</sub> | 196.20±2.32 | 0.22±0.01 | -31.07±0.83 |
如图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800-1150cm-1处有明显的伸缩振动峰,3500cm-1处的吸收峰是硅醇基的特征光谱;MSNs-SS-NH2在1720cm-1处有二硫键的特征峰,表明二硫键成功连接在MSNs表面;对于Liposomes,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形成核/壳结构后,位于1240cm-1处的P=O伸缩带变宽,3500cm-1处的硅醇基特征峰也有一定程度的减弱;随着TPGS与HA的添加,在3500cm-1处的特征峰以及800-1150cm-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;HA的吸收峰主要是在3435cm-1和2930cm-1处,-OH和-CH是其主要特征峰;
如图3是实施例2各纳米样品负载DOX的红外吸收光谱图,由图可知,DOX在3000cm-1处有明显的C-H伸缩振动区,2960cm-1处为-CH3振动峰,2900cm-1处为-CH2-伸缩振动,1700cm-1处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DOX后,样品在3000cm-1、2960cm-1、1700cm-1、1500cm-1处的特征峰均未出现明显变化,表明在MSNs上负载有大量的DOX;对于不同功能化修饰的LMSNs,均能检测到以上各处DOX的特征峰,证明各LMSNs纳米粒均能负载DOX分子;
如图4是实施例1各纳米样品的DSC曲线图,由图可知,MSNs在70℃左右有一个大峰,这是MSNs向结晶态转变的标志;MSNs-SS-NH2的曲线与MSNs相比无太大变化;Liposomes在112℃左右有吸热峰,对应从固态到凝胶态的转变,在240.5℃有强烈的吸热峰,对应从凝胶状到液晶态的转变;LMSNs-SS-NH2的曲线与Liposomes相比无太大变化,相变温度稍有降低,表明MSNs上存在脂质双层,由于多孔MSNs的支撑和界面相互作用增加了脂质膜的流动性,使相变温度降低;经TPGS和HA修饰后的纳米粒,在240.5℃处的吸热峰消失,可认为修饰后LMSNs会熔融溶解为结晶态;结果表明脂质双层成功包覆在MSNs表面,且经过功能化修饰后的LMSNs稳定性有极大的提升;
如图5是实施例1各纳米样品的XRD曲线图,由图可知,MSNs和MSNs-SS-NH2在22°处有大包峰,表明MSNs在正常状态下为无定型态;Liposomes在19°处有大包峰,表明冻干的Liposomes也是以无定形态存在;在LMSNs-SS-NH2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-SS-NH2在20°与24°处有明显的谱峰,表明经修饰后的LMSNs-SS-NH2由无定型态向有序转变,修饰后的磷脂双分子层稳定性有一定的提升;
如图6是实施例1各纳米样品的拉曼光谱图,由图可知,MSNs在1450cm-1处有羟基的特征峰,在2900cm-1处有硅醇基的特征峰;MSNs-SS-NH2在500cm-1处有明显的伸缩振动峰,即二硫键的特征峰,表明二硫键的存在;Liposomes的磷脂分子在1450cm-1处也有羟基的特征峰,而Liposomes在MSNs-SS-NH2作用下715cm-1与1100cm-1处的峰强度均降低,表明LMSNs-SS-NH2中磷脂以其极性头部与MSNs-SS-NH2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而降低,峰形变宽,表明修饰剂与Liposomes紧密结合;
如图7是实施例2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,负载FITC后的MSNs在525nm处也有荧光特征峰,同样地,负载FITC的MSNs-SS-NH2、Liposomes、LMSNs-SS-NH2及修饰型纳米样品都检测到荧光峰,证实各纳米载体均成功标记了FITC;
如图8是实施例1各纳米载体的比表面积及孔径分析,A图为各纳米载体的比表面积图,由图可知,MSNs的比表面积为511.6,m2/g,随着二硫键、脂质包覆及各种修饰剂的连接,比表面积逐渐下降至极低水平;B图为各载体孔径变化,由图可知MSNs的孔径为2.58nm,MSNs-SS-NH2孔径为2.38nm,这是由于连接二硫键后使孔径略变小;脂质包覆及连接修饰剂后,孔径几乎检测不到,表明脂质双层已成功包覆于MSNs-SS-NH2表面;
综合以上表征结果可知,本发明成功制备了复合型LMSNs-SS-NH2纳米粒,并且修饰上了TPGS、HA等功能化成分,最终制得的HA-TPGS-LMSNs-SS-NH2纳米系统具有良好的物理稳定性,分散性较好,具有作为抗肿瘤药物优良递送载体的可能。
应用例1
对本发明实施例2中提供的负载DOX的各纳米样品:MSNs@DOX、MSNs-SS-NH2@DOX、Liposomes@DOX、LMSNs-SS-NH2@DOX、TPGS-LMSNs-SS-NH2@DOX、HA-TPGS-LMSNs-SS-NH2@DOX(即各纳米制剂),测定载药量与包封率;
取各纳米制剂,离心后量取上清液体积,HPLC法进样测定,其中柱温:30℃,流速:1.0mL/min,检测波长:480nm,进样量:10μL,流动相为甲醇:NaH2PO3(0.01M)=60:40,标准曲线方程为y=10994x-10353,R2=0.9997;
以峰面积代入标准曲线求出上清液中DOX含量,根据公式计算包封率与载药量,计算公式为:
包封率与载药量测定结果见表2,结果表明MSNs由于其较大的比表面积,即能够对DOX进行很好的包埋,包封率达82.79,%,连接上二硫键后由于孔径有所缩小,包封率略有下降,约为81.76%,新型载体HA-TPGS-LMSNs-SS-NH2对DOX的包封率达到90.87%,高包封率证明其对DOX的负载效果好,载药性能优异。
表2应用例1不同纳米制剂的包封率和装载量测定结果
制剂 | 包封率(%) | 载药量(μg/mg) |
MSNs@DOX | 82.79 | 356.74 |
MSNs-SS-NH<sub>2</sub>@DOX | 81.67 | 342.83 |
Liposomes@DOX | 85.03 | 358.64 |
LMSNs-SS-NH<sub>2</sub>@DOX | 87.98 | 380.09 |
TPGS-LMSNs-SS-NH<sub>2</sub>@DOX | 89.01 | 388.48 |
HA-TPGS-LMSNs-SS-NH<sub>2</sub>@DOX | 90.87 | 396.79 |
应用例2
对本发明实施例1和2中提供的负载DOX的纳米样品:MSNs-SS-NH2@DOX、HA-TPGS-LMSNs-SS-NH2@DOX,采用膜透析法,分别在pH7.4和5.0及不同GSH浓度条件下测定体外释放度,由于DOX为脂溶性分子,选用PBS-乙醇(1:4)混合溶液作为释放介质;
分别取1mL实施例2制备的MSNs-SS-NH2@DOX和HA-TPGS-LMSNs-SS-NH2@DOX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100rpm,分别在1、2、4、6、8、10、12、24、36、48、72、96h取样2mL,同时补充新鲜介质;通过HPLC法检测,计算释放的DOX浓度,以时间为横坐标,DOX的释放度为纵坐标做图,评估不同载体中DOX的体外溶出度,结果见图9,体外释放度计算公式为:
如图9各载药样品在不同浓度GSH和pH环境中的体外释放曲线图:A、B:为MSNs-SS-NH2@DOX在pH7.4(A)和pH5.0(B)条件下的体外释放曲线图,结果显示DOX的释放与GSH浓度成正比,在10mM GSH中DOX的释放度最高,也实了MSNs-SS-NH2纳米载体的构建成功,其具有良好的氧化还原响应性释药特性;C、D为各载药样品分别在pH7.4和pH5.0条件下的体外释放图;E、F为各载药样品分别在pH7.4(10mM GSH)和pH5.0(10mM GSH)条件下的体外释放图,由图C、D可知,各制剂在pH5.0条件下的释放度均高于pH7.4,由图D、F可知,在相同pH条件下,含二硫键的各载药样品在10mM GSH条件下的释放度明显高于不含GSH条件下的释放度,因此具有良好的pH和还原响应释药性能。
应用例3
将实施例1和2中的各纳米样品:MSNs、Liposomes、MSNs-SS-NH2、LMSNs-SS-NH2、TPGS-LMSNs-SS-NH2、HA-TPGS-LMSNs-SS-NH2及负载DOX的各纳米样品:MSNs@DOX、MSNs-SS-NH2@DOX、Liposomes@DOX、LMSNs-SS-NH2@DOX、TPGS-LMSNs-SS-NH2@DOX、HA-TPGS-LMSNs-SS-NH2@DOX,考察其细胞毒性;
细胞培养:取MCF-7和MCF-7/ADR细胞,MCF-7细胞培养在含10%胎牛血清(FBS)的RPMI 1640培养基中,MCF-7/ADR细胞培养在含10%胎牛血清(FBS)、100μg.ml-1DOX的RPMI1640培养基中,细胞在37℃、含5%CO2的培养箱中培养,培养液每两天更换一次;
将MCF-7和MCF-7/ADR细胞接种在96孔板中,密度为5×103个/孔,贴壁后分别加入质量浓度为10、20、50、100、200μg·mL-1的各纳米载体和DOX终浓度为2.5、5、10、15、20μg·mL-1的DOX溶液与各纳米制剂,分别培养24h和48h后取出培养液,每孔加入10μLMTT溶剂(5mg/mL)和90μL完整MEM培养液,37℃继续孵育4h,去除上清液,每孔加入100μL二甲基亚砜溶解甲儹晶体,将96孔平板在圆周摇床100rpm下摇动10min以完全溶解甲瓒晶体,最后在490nm波长处用酶标仪测定OD值,计算活细胞相对含量;
如图10所示,纯材料的细胞毒性均较低,作用24和48h后两种细胞的存活率均高于80%,证明构建的纳米载体具有良好的生物相容性和低毒性,是一种安全有效的载体;对于载药样品,随着修饰度的不断提升,两种细胞的存活率不断下降,经DOX、MSNs@DOX、MSNs-SS-NH2@DOX、Liposomes@DOX、LMSNs-SS-NH2@DOX组处理的MCF-7细胞的存活率要低于MCF-7/ADR细胞,也证明了MCF-7/ADR细胞的耐药性;经TPGS-LMSNs-SS-NH2@DOX、HA-TPGS-LMSNs-SS-NH2@DOX组处理后两种细胞的存活率基本持平,处理48h后存活率均约为40%和24%左右,这是由于TPGS能有效抑制P-gp而具有抗耐药性,HA可靶向于肿瘤细胞表面的CD44受体而特异性发挥杀灭肿瘤作用;结果证实了本发明构建的纳米载药系统可有效逆转肿瘤多药耐药。
应用例4
采用荧光定位法分析MCF-7/ADR细胞对实施例2FITC标记各纳米样品的摄取,将其作用于MCF-7/ADR细胞;
取对数生长期的细胞,接种在6孔细胞板,每孔2mL,培养贴壁,长满孔板后,加入FITC标记的各样品,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,倒置荧光显微镜下观察;
如图11为各纳米制剂与MCF-7/ADR细胞孵育4h后的荧光图像,由图可知,游离FITC仅有少量能够进入细胞内部;而经MSNs-SS-NH2负载后,FITC的荧光信号明显增强,说明MSNs-SS-NH2纳米粒能够被细胞有效摄取;LMSNs-SS-NH2组的荧光强度比MSNs-SS-NH2与Liposomes组均有提升,说明核壳结构的复合纳米粒具有更强的递送能力;对于TPGS-LMSNs-SS-NH2与HA-TPGS-LMSNs-SS-NH2组,其胞内荧光强度进一步增强,表明修饰型载体更易被细胞摄取;结果证实以HA-TPGS-LMSNs-SS-NH2用作递送载体能极大增加MCF-7/ADR细胞对DOX的摄取量,从而提高其生物利用度与药效作用。
综上,本发明构建了一种具有二硫键的核/壳结构复合纳米载体LMSNs-SS-NH2,以TPGS、HA对其进行功能化修饰,用作DOX的递送载体;该制备方法简单,所得的HA-TPGS-LMSNs-SS-NH2样品粒径分布均匀、理化性质稳定,对DOX的包封率、载药量高,能在模拟肿瘤微环境中响应性释药,同时可增加MCF-7/ADR细胞对DOX的摄取,提高生物利用度。因此,HA-TPGS-LMSNs-SS-NH2是一种高效的药物递送系统并能有效逆转肿瘤多药耐药。
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 (10)
1.一种微环境响应型脂质介孔硅核壳纳米递送载体的制备方法,其特征在于,包括以下具体:
(1)将介孔二氧化硅纳米粒依次进行氨化、羧基化后,制备含有二硫键的介孔硅;
(2)将所述含有二硫键的介孔硅和脂质体混合后处理得到脂质体包覆的脂质-介孔硅复合纳米粒;
(3)分别采用TPGS和HA对所述脂质-介孔硅复合纳米粒进行修饰,即得一种微环境响应型脂质介孔硅核壳纳米递送载体。
2.根据权利要求1所述的一种微环境响应型脂质介孔硅核壳纳米递送载体的制备方法,其特征在于,所述介孔二氧化硅纳米粒的粒径为100-160nm,所述介孔二氧化硅纳米粒采用模板法制备。
3.根据权利要求2所述的一种微环境响应型脂质介孔硅核壳纳米递送载体的制备方法,其特征在于,所述含有二硫键的介孔硅和所述脂质体的质量比为1:2-3。
4.根据权利要求2所述的一种微环境响应型脂质介孔硅核壳纳米递送载体的制备方法,其特征在于,所述脂质-介孔硅复合纳米粒和所述两种修饰剂的质量比为2-2.7:1,所述TPGS和所述HA的质量比为1:1。
5.根据权利要求2所述的一种微环境响应型脂质介孔硅核壳纳米递送载体的制备方法,其特征在于,所述脂质体由大豆磷脂和胆固醇采用薄膜分散法制备。
6.如权利要求1-5任一项所述制备方法得到的一种微环境响应型脂质介孔硅核壳纳米递送载体。
7.根据权利要求6所述的一种微环境响应型脂质介孔硅核壳纳米递送载体,其特征在于,所述载体的粒径为200-300nm。
8.如权利要求1-5任一项所述制备方法得到的一种微环境响应型脂质介孔硅核壳纳米递送载体或者如权利要求6或7所述一种微环境响应型脂质介孔硅核壳纳米递送载体在制备靶向化疗药物中的应用。
9.根据权利要求8所述的应用,其特征在于,所述介孔二氧化硅纳米粒和所述药物的质量比为2-3:1。
10.根据权利要求8所述的应用,其特征在于,所述药物为干扰转录过程和阻止RNA合成的药物、抑制蛋白质合成与功能的药物、直接影响DNA结构和功能的药物和干扰核酸生物合成的药物中的任意一种。
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