CN117138055B - 一种双载体的阿霉素载药纳米材料及其制备方法 - Google Patents
一种双载体的阿霉素载药纳米材料及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种双载体的阿霉素载药纳米材料及其制备方法,按以下步骤进行制备:S1:称取二硬脂酰磷脂酰乙醇胺‑聚乙二醇和叶酸完全溶解于四氢呋喃中并在室温下搅拌5min,然后以5s/d的速度滴加高纯水,滴加完成后继续搅拌至四氢呋喃完全挥发;S2:将ZIF‑8溶于乙醇中,再与步骤S1得到的混合溶液混合均匀,加入纯水,搅拌6h后收集得到的颗粒;S3:将步骤S2收集的颗粒离心纯化15min,加入阿霉素,置于避光小烧瓶中,室温搅拌24小时,透析后冻干,即得双载体的阿霉素载药纳米材料。该制备方法工艺简单,且制得的双载体的阿霉素载药纳米材料粒径小、稳定性强、分散度好,其与药物结合效果好,在细胞实验中抑制细胞效果眀显。
Description
技术领域
本发明涉及纳米复合材料技术领域,特别涉及一种双载体的阿霉素载药纳米材料及其制备方法。
背景技术
阿霉素(Doxorubicin)或盐酸阿霉素(Doxorubicin hydrochloride,DOX)是一种抗肿瘤抗生素,化学式为C27H29NO11。阿霉素可抑制RNA和DNA的合成,对RNA的抑制作用最强,抗瘤谱较广,对多种肿瘤均有作用,属周期非特异性药物,对各种生长周期的肿瘤细胞都有杀灭作用,它被认为是目前蒽环类抗癌药物中最好的药物。DOX除具有较强的抗肿瘤作用外,还具有严重的副作用,除胃肠道反应和脱发外,可以发生骨髓抑制、心肌毒性反应,严重者可以发生充血性心力衰竭。
聚乙二醇(PEG)因为其无毒、无免疫原性和耐蛋白质的特性,广泛应用于生物医学领域。PEG可使聚合物胶束具有“隐形”特性,避免其被网状内皮***(RES)识别和清除,从而延长生物循环时间。
沸石咪唑骨架8(ZIF-8)是由Zn2+和2-甲基咪唑(2-MIM)配位形成的多孔复合材料。由于其孔隙率高、低pH条件下降解和良好的生物相容性等优点,被广泛用作药物载体。聚乙二醇(PEG)可用作矿化剂来合成ZIF-8NPs,其在水溶液中具有更高的稳定性和分散性。
叶酸(FA)修饰的聚合物纳米颗粒,有望将基因和药物递送到FR过表达的癌细胞,通过内吞作用进入肿瘤细胞,并释放治疗剂达到治疗效果。
一般癌症治疗的最大问题是无法将药物针对性地富集到癌症细胞上,从而不能最大程度上减少副作用。纳米生物材料是当前国际上生物工程技术领域的前沿和热点研究课题,在医学领域应用方面的研究尚处于初级阶段,却又有广阔的应用前景。自从70年代制备第一个纳米粒(nanoparticle,NP)以来,纳米在恶性肿瘤的靶向治疗取得了巨大的进展。纳米粒是利用天然高分子或合成的化学物质为载体制成的载药微粒,直径10-500nm。依据结构的不同,可分为纳米球(nanospheres)和纳米囊(nanocapsules)。近来,随着纳米技术的不断发展,纳米粒子有望用于靶向药物释放及同步肿瘤成像的研究。由于纳米粒子独特的药代动力学特性,即纳米粒子既不能被在短时间内肾脏***又不能被肝脏及脾脏中的网状内皮组织***显著吸收,因此尺寸在10-100nm之间的纳米粒子与其它小分子相比具有更长的体内循环时间。此外,研究表明肿瘤***发育不全且存在漏点,这使得尺寸小于100nm的纳米粒子可以穿过内皮细胞层进入肿瘤病灶。使用纳米粒子进行药物传递可以提高疏水药物的水溶性及生物利用度。由于纳米粒子具有较大的表面区域及多种多样的表面化学特性,纳米粒子与其他***相比,在肿瘤病灶部位同时进行多功能应用方面更具优势。此外,可以将在肿瘤细胞中高度表达的受体靶向性配体连接到纳米粒子上能直接向靶器官、靶细胞或细胞内靶结构输送药物,同时具有缓释、保护药物、提高疗效、降低毒副作用等优点。
目前,针对肿瘤细胞的靶向药仍然处于不断的研发中,如何制得治疗效果更好、体积更小、毒副作用更少的靶向药物仍然是相关科研人员持续关注的研究方向。
发明内容
为了克服现有技术的不足,本发明目的是提供一种双载体的阿霉素载药纳米材料的制备方法,该制备方法工艺简单,且制得的双载体的阿霉素载药纳米材料粒径小、稳定性强、分散度好,在细胞实验中抑制细胞效果眀显。
为了达到上述目的,本发明采用以下技术方案:
本发明提供一种双载体的阿霉素载药纳米材料的制备方法,包括以下步骤:
S1:称取二硬脂酰磷脂酰乙醇胺-聚乙二醇和叶酸完全溶解于四氢呋喃中并在室温下搅拌5min,然后以5s/d的速度滴加高纯水,滴加完成后继续搅拌至四氢呋喃完全挥发;
S2:将ZIF-8溶于乙醇中,再与步骤S1得到的混合溶液混合均匀,加入纯水,搅拌6h后收集得到的颗粒;
S3:将步骤S2收集的颗粒离心纯化15min,加入阿霉素,置于避光小烧瓶中,室温搅拌24小时,透析后冻干,即得双载体的阿霉素载药纳米材料。
相比于现有技术,本发明的制备方法步骤简单,操作方便,采用二硬脂酰磷脂酰乙醇胺-聚乙二醇和ZIF-8(沸石咪唑骨架8)两种载体,并用叶酸进行修饰,创造性地制得ZIF-8+Methyl-PEG2000-DSPE+FA+DOX纳米载药材料,大幅提高了材料的稳定性,同时避免单一载体可能带来的毒副作用。本发明制得的双载体的阿霉素载药纳米材料稳定性高、颗粒粒径小、分散性好,在细胞实验中,对乳腺癌细胞抑制效果明显,而对正常细胞的毒副作用小。
进一步地,步骤S1中,所述二硬脂酰磷脂酰乙醇胺-聚乙二醇和叶酸的质量比为2:1。
进一步地,步骤S1~S3中,搅拌速度均为300r/min。
进一步地,步骤S2中,所述ZIF-8和乙醇的质量体积比为1mg:2mL。
进一步地,步骤S3中,离心转速为7000rpm。
进一步地,所述二硬脂酰磷脂酰乙醇胺-聚乙二醇、叶酸、ZIF-8和阿霉素的质量比:10:5:75:2;所述四氢呋喃、高纯水、乙醇、纯水的体积比为1:10:225:215。
本发明还提供如上所述制备方法制备得到的双载体的阿霉素载药纳米材料。
进一步地,所述双载体的阿霉素载药纳米材料以二硬脂酰磷脂酰乙醇胺-聚乙二醇和ZIF-8作为双载体,并通过叶酸修饰,阿霉素颗粒均匀分布在所述双载体的阿霉素载药纳米材料内部。
进一步地,所述双载体的阿霉素载药纳米材料的粒径小于50nm。
与现有技术相比,本发明具有以下有益效果:
(1)本发明制得的双载体的阿霉素载药纳米材料的颗粒尺寸达到载药标准,粒径小于50nm,且颗粒分散度好,稳定性强,在细胞实验中对乳腺癌细胞的抑制细胞效果眀显,而对普通细胞的毒副作用较弱。此外,双载体的创新性结构使其有望同时搭载多种抗癌药物,在肿瘤病灶部位同时进行多功能应用方面更具优势。
(2)本发明的制备方法步骤简便,涉及工艺较为简单,操作难度低,有利于大规模批量生产。
附图说明
图1为本发明的双载体的阿霉素载药纳米材料合成原理示意图;
图2为实施例1制得的ZIF-8+Methyl-PEG2000-DSPE+FA+DOX纳米材料的TEM图;
图3为实施例1制得的ZIF-8+Methyl-PEG2000-DSPE+FA+DOX纳米材料的SEM图;
图4为测试例1得到的ZIF-8+Methyl-PEG2000-DSPE+FA+DOX纳米材料的电位图;
图5为测试例2得到的细胞毒性实验结果柱状图(24h);
图6为测试例2得到的细胞毒性实验结果柱状图(48h);
图7为测试例3得到的细胞毒性实验结果柱状图(24h);
图8为测试例3得到的细胞毒性实验结果柱状图(48h);
图9为测试例4得到的细胞荧光实验图像;
图10为测试例5得到的迁移实验显微镜图像。
现结合附图与具体实施例对本发明作进一步说明。
具体实施方式
以下实施例所用到的原料及试剂的纯度及厂商如表1所示:
表1原料及试剂的纯度及厂商
下面通过具体实施例以及附图对本发明作进一步阐释,但是本发明的技术方案不以具体实施例为限。
实施例1双载体的阿霉素载药纳米材料的制备
称量30mgMethyl-PEG2000-DSPE和15mg叶酸于50mL烧杯中,加入2mL THF使其完全溶解并在室温300r/min的速度下搅拌5min,然后以5s/d的速度加入20mL高纯水,滴加完成后继续搅拌至THF完全挥发(24h)。225mgZIF-8溶于450mL乙醇,与上述溶液混匀,加入430mL纯水,搅拌6h,收集颗粒,7000rpm离心纯化15min,加入6mgDOX搅拌,置于避光小烧瓶中,室温搅拌24小时,透析(分子截留量为7000,用纯水透析3天)后冻干(-80℃)。
请参阅图1,本发明采用Methyl-PEG2000-DSPE和ZIF-8双载体,叶酸(FA)作为修饰物,与药物阿霉素(DOX)经过化学反应进行结合,合成双载体的阿霉素载药纳米材料ZIF-8+Methyl-PEG2000-DSPE+FA+DOX,阿霉素颗粒均匀分布在纳米材料内部。
测试例1双载体的阿霉素载药纳米材料的表征
请参阅图2,其为实施例1制得的ZIF-8+METHYL-PEG2000-DSPE+FA+DOX的TEM图。从图中可以看出,制得的ZIF-8+METHYL-PEG2000-DSPE+FA+DOX颗粒较为均匀,分散度好,且粒径小,均小于50nm。图3为实施例1制得的ZIF-8+METHYL-PEG2000-DSPE+FA+DOX的SEM图,从图中可以看出,制得的ZIF-8+METHYL-PEG2000-DSPE+FA+DOX分散性好。
为了得到更准确的粒径分布和电位数据,利用纳米粒度电位仪(Nano-ZS)检测双载体的阿霉素载药纳米材料的粒径及电位。
表2ZIF-8+METHYL-PEG2000-DSPE+FA+DOX粒径分布表
如表2所示,ZIF-8+METHYL-PEG2000-DSPE+FA+DOX的粒径均小于50nm,平均粒径为29.14nm,达到纳米材料载药标准。
对ZIF-8+METHYL-PEG2000-DSPE+FA+DOX材料的电位测试结果如图4所示,可以看出材料带负电,而细胞表面带有正电,因此有利于纳米材料与细胞相结合。同时从电位数值可以看出该纳米材料的稳定性较好。
测试例2双载体的阿霉素载药纳米材料对MAD-MB-231细胞的毒性测定
采用细胞计数试剂盒测定DSPE-PEG2000(CCK-8;型号公司:美仑),先取100μLMAD-MB-231细胞悬液(8X104细胞/mL)接种于96孔板,与不同浓度的ZIF-8+Methyl-PEG2000-DSPE+FA+DOX在37℃条件下分别培养24h、48h,然后每孔加入CCK-8试剂(10μL),得到的混合物在37℃条件下分别培养1h。记录混合物在450nm处的吸光度并计数细胞活力。同时设置相同浓度(以阿霉素含量计)的阿霉素纯药组进行对照。
结果如图5和图6所示,可以看出24h时,不同浓度的ZIF-8+Methyl-PEG2000-DSPE+FA+DOX材料对细胞的抑制作用均比相同浓度下的阿霉素纯药更强,且随着浓度的提高,抑制效果领先阿霉素纯药的幅度也更大。而48h时,除了低浓度下(7.8125μg/mL)阿霉素纯药对细胞的抑制作用更强之外,随着浓度的提高,ZIF-8+Methyl-PEG2000-DSPE+FA+DOX材料对MAD-MB-231细胞的抑制作用明显增强,在大浓度下抑制效果远远超过阿霉素纯药。
测试例3双载体的阿霉素载药纳米材料对Hacat细胞(角质细胞)的毒性测定
采用细胞计数试剂盒测定DSPE-PEG2000(CCK-8;型号公司:美仑),先取100μLHacat细胞悬液(8X104细胞/mL)接种于96孔板,与不同浓度的ZIF-8+Methyl-PEG2000-DSPE+FA+DOX在37℃条件下分别培养24h、48h,然后每孔加入CCK-8试剂(10μL),得到的混合物在37℃条件下分别培养1h。记录混合物在450nm处的吸光度并计数细胞活力。同时设置相同浓度(以阿霉素含量计)的阿霉素纯药组进行对照。
结果如图7和图8所示,可以看出,不同浓度的ZIF-8+Methyl-PEG2000-DSPE+FA+DOX材料对Hacat细胞的抑制作用均比相同浓度下的阿霉素纯药弱,可见ZIF-8+Methyl-PEG2000-DSPE+FA+DOX材料相比于阿霉素纯药对正常细胞的毒性更弱,安全性更好。
测试例4双载体的阿霉素载药纳米材料对MAD-MB-231细胞的荧光测试
采用以下步骤进行荧光测试:
第一天,铺板30万/孔(6孔板)MDA-MB-231
第二天,加药ZIF-8+Methyl-PEG2000-DSPE+FA+DOX(50μg/mL)(材料组);同时设置空白组(不加药);24h;
第三天,吸去培养基(保留原培养基),pbs洗2-3次,加4%多聚甲醛(meilunbio)固定30min,pbs清洗2-3次,加入pbs稀释的0.25%Triton-x 10min(aladdin),pbs洗2-3次,按1:1000稀释DAPI(10mg/mL)加入细胞培养基,37℃培养细胞10-20min,pbs洗2次,置于荧光显微镜(奥林巴斯,基因生物技术国际贸易公司)下观察,激发波长360-400nm。
如图9所示,其中,图(a)为空白组明场荧光图,图(b)为空白组DAPI荧光图,图(c)为材料组明场荧光图,图(d)为材料组DAPI荧光图。从图中可以看出,材料组相比空白组细胞变圆、细胞核变大,这是由于ZIF-8+Methyl-PEG2000-DSPE+FA+DOX纳米材料进入了MAD-MB-231细胞的细胞核,促使细胞凋亡,细胞核破解从而导致细胞变圆。
测试例5双载体的阿霉素载药纳米材料对MAD-MB-231细胞的迁移实验
进一步采用以下方法进行迁移实验:具体步骤为:
第一天铺板6孔板35万/孔MAD-MB-231细胞;
第二天:用白色枪头划痕,PBS缓冲液清洗2-3次,加入1%血清,然后加入ZIF-8+METHYL-PEG2000-DSPE+FA+DOX,浓度分别为15μg/mL和30μg/mL;在长满的单层细胞(HaCaT)中人为制造空白区域,细胞会自动向空白区域迁移。在划痕之后不同时间点(0,24,48,72h)检测划痕宽度,比较细胞迁移效率。分别在不同时间点(0,24,48,72h)采用显微镜进行拍照,测得空白区域面积,并计算迁移率。同时设置空白组(第二天未加入ZIF-8+METHYL-PEG2000-DSPE+FA+DOX)采用相同方法进行迁移实验,后将三组数据进行对比。结果如表3和图10所示。
表3细胞迁移实验数据表
从表3和图10可以看出,空白组在划痕72h后被完全填充,而材料组抑制细胞迁移效率明显,且浓度越高抑制效果越明显。
测试例6双载体的阿霉素载药纳米材料载药率测试
采用高效液相法对实施例1制得的ZIF-8+METHYL-PEG2000-DSPE+FA+DOX进行载药率测试,实验条件为:
仪器:岛津LC-20AD
色谱柱:Ultimate XB-C18 4.6*100mm 5um
流速:1.0ml/min
柱温:35
检测波长:222nm
进样量:5ul
流动相:10mM乙酸钠PH3.40-甲醇=40-60
样品配置:
对照溶液:精密称取对照品适量,加甲醇溶解稀释至各浓度,详见EXCEL表格
样品溶液:精密称取样品2.00mg,加1.0ml水,超声15min,摇匀,过膜,即得。
表4ZIF-8+METHYL-PEG2000-DSPE+FA+DOX载药率数据表
经过测试,ZIF-8+METHYL-PEG2000-DSPE+FA+DOX的载药率为0.05891%。尽管载药率较低,但从前面几个测试例可以看出,该载药纳米材料对肿瘤细胞的抑制效果突出,对正常细胞的毒副作用明显弱于阿霉素纯药,安全性较强,有利于应用于肿瘤的靶向治疗中。
相比于现有技术,本发明的制备方法步骤简单,操作方便,采用METHYL-PEG2000-DSPE和ZIF-8(沸石咪唑骨架8)两种载体,并用叶酸进行修饰,制得的双载体的阿霉素载药纳米材料稳定性高、颗粒粒径小、分散性好,在细胞实验中,对乳腺癌细胞抑制效果明显,对正常细胞的毒副作用较低。
本发明并不局限于上述实施方式,如果对本发明的各种改动或变型不脱离本发明的精神和范围,倘若这些改动和变型属于本发明的权利要求和等同技术范围之内,则本发明也意图包含这些改动和变动。
Claims (9)
1.一种双载体的阿霉素载药纳米材料的制备方法,其特征在于,包括以下步骤:
S1:称取二硬脂酰磷脂酰乙醇胺-聚乙二醇和叶酸完全溶解于四氢呋喃中并在室温下搅拌5min,然后以5s/d的速度滴加高纯水,滴加完成后继续搅拌至四氢呋喃完全挥发;
S2:将ZIF-8溶于乙醇中,再与步骤S1得到的混合溶液混合均匀,加入纯水,搅拌6h后收集得到颗粒;
S3:将步骤S2收集的颗粒离心纯化15min,加入阿霉素,置于避光小烧瓶中,室温搅拌24小时,透析后冻干,即得双载体的阿霉素载药纳米材料。
2.根据权利要求1所述的双载体的阿霉素载药纳米材料的制备方法,其特征在于:步骤S1中,所述二硬脂酰磷脂酰乙醇胺-聚乙二醇和叶酸的质量比为2:1。
3.根据权利要求1所述的双载体的阿霉素载药纳米材料的制备方法,其特征在于:步骤S1~S3中,搅拌速度均为300r/min。
4.根据权利要求2所述的双载体的阿霉素载药纳米材料的制备方法,其特征在于:步骤S2中,所述ZIF-8和乙醇的质量体积比为1mg:2mL。
5.根据权利要求1所述的双载体的阿霉素载药纳米材料的制备方法,其特征在于:步骤S3中,离心转速为7000rpm。
6.根据权利要求4所述的双载体的阿霉素载药纳米材料的制备方法,其特征在于:所述二硬脂酰磷脂酰乙醇胺-聚乙二醇、叶酸、ZIF-8和阿霉素的质量比:10:5:75:2;所述四氢呋喃、高纯水、乙醇、纯水的体积比为1:10:225:215。
7.一种根据权利要求1~6任一项所述的制备方法制得的双载体的阿霉素载药纳米材料。
8.根据权利要求7所述双载体的阿霉素载药纳米材料,其特征在于:其以二硬脂酰磷脂酰乙醇胺-聚乙二醇和ZIF-8作为双载体,并通过叶酸修饰,阿霉素颗粒均匀分布在所述双载体的阿霉素载药纳米材料内部。
9.根据权利要求7所述双载体的阿霉素载药纳米材料,其特征在于:所述双载体的阿霉素载药纳米材料的粒径小于50nm。
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