CN113368255B - 一种甜菜红素纳米脂质体及其制备方法与应用 - Google Patents
一种甜菜红素纳米脂质体及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开了一种甜菜红素纳米脂质体及其制备方法与应用,制备方法包括:将大豆卵磷脂和胆固醇溶于有机溶剂中,得溶液1;将甜菜红素溶于PBS溶液中,得到甜菜红素溶液;将溶液1和甜菜红素溶液混合,短时超声处理;旋蒸除掉有机溶剂,当达到胶态后加入吐温80的PBS溶液减压水合;再次短时超声处理,得甜菜红素纳米脂质体溶液。本发明制备的脂质体稳定性较高,脂质分子不易被水解或氧化;形态规则,粒径小,安全无毒;对人肝癌细胞HepG2的EC50值相比于甜菜红素的EC50值至少提高了18倍,具有良好的抗肿瘤效果。
Description
技术领域
本发明涉及保健食品和药品领域,具体涉及一种甜菜红素纳米脂质体及其制备方法与应用。
背景技术
现如今,癌症已成为人类的重大劲敌。在2019年世界卫生组织公布的世界十大死亡原因之中,癌症排名第六,肝癌尤为突出。现用于癌症治疗的抗癌药物均价格昂贵,且还会对患者的组织产生各种毒副作用。因此,迫切需要开发对生命系统副作用最小的有效抗癌药物。
甜菜红色素为一类水溶性含氮色素,甜菜苷是甜菜红素的主要成分,其中还包括前甜菜苷和异甜菜苷等成分。甜菜红素易溶于水,不溶于有机溶剂。甜菜红素对多种癌症都具有抑制作用,包括乳腺癌,肝癌和结肠癌等。但甜菜红素在外部条件影响下容易发生降解,如酶,高温,光照,pH,氧气等条件。此外,由于其低脂溶性,难以通过细胞膜被细胞吸收,因此甜菜红素的生物利用度较低,不利于口服吸收。
脂质体是由磷脂和胆固醇组成的双分子层膜的球形小泡,既可包载水溶性物质,亦可包载油溶性物质。其中水溶性物质位于脂质体的内部核心,油溶性物质嵌于磷脂双分子层中。传统脂质体在储存和加工过程中仍存在诸多问题,如传统脂质体容易发生聚集、融合;脂类成分的氧化水解导致药物泄露。针对这些问题,对脂质体进行表面修饰以提高脂质体的稳定性。壳聚糖是唯一一种天然线性阳离子多糖,溶于酸性溶液中,具有较好的生物相容性,可降解性,低毒性和粘膜粘附性,可通过静电相互作用和氢键与脂质体结合。壳聚糖修饰可增加脂质体的稳定性,保护脂类成分在外部刺激下不被降解;还可增加脂质体的缓释效果,从而增加被包载物质的活性。
现存脂质体为提高稳定性,多在制备过程中添加强抗氧化性物质,但在储藏和加工过程中,易发生药物泄露,并不能很好地防止脂质体中脂质分子的水解和氧化。而采用壳聚糖对脂质体进行修饰,壳聚糖主要与脂质体通过静电相互作用结合,相当于在脂质体表面增加一层保护层,从而防止脂质分子的氧化与水解。同时,壳聚糖修饰的脂质体表面带有正电荷,可增加与带负电的细胞膜的亲和力,从而增加细胞对甜菜红素的吸收,增强抗癌活性。
中国专利申请201810575687.X公开了一种高效抗癌抗氧化的复合脂质体及其制备方法。该方法制备的脂质体主要由蛋黄卵磷脂、薏苡仁油、β-胡萝卜素和胆固醇组成。脂质体中的磷脂分子易氧化和水解,虽然在过程中引入了β-胡萝卜素,起到一定的抗氧化作用,但随着储藏时间的延长,β-胡萝卜素易泄露,脂质体的稳定性并没有得到显著的提升。
中国专利申请201710338465.1公开了一种羧甲基壳聚糖包覆的南极磷虾油纳米脂质体及其制备方法。该方法是以南极磷虾油为原料,采用高压均质的方法制得南极磷虾油纳米脂质体,再采用滴定法将南极磷虾油纳米脂质体滴入羧甲基壳聚糖溶液中制得羧甲基壳聚糖包覆得南极磷虾油纳米脂质体。该法制备的脂质体对分散体系中的pH环境要求较高,在实际的应用中受到较大的限制。
并且,目前未有关于甜菜红素纳米脂质体的相关研究报道。
发明内容
针对现有产品的功能以及技术缺陷,本发明的目的在于提供一种甜菜红素纳米脂质体制剂,该制剂一方面能够提高甜菜红素的稳定性和生物利用度,保护其不被降解;另一方面可提高脂质体制剂的稳定性,增加肝癌细胞对脂质体制剂的吸收,从而增强抗癌活性。
本发明另一目的提供上述甜菜红素纳米脂质体的制备方法和应用。
本发明的目的通过以下技术方案实现:
一种甜菜红素纳米脂质体的制备方法,包括以下步骤:
(1)将大豆卵磷脂和胆固醇溶于有机溶剂中,得溶液1;
(2)将甜菜红素溶于PBS溶液中,得到甜菜红素溶液;
(3)将步骤(1)所述的溶液1和步骤(2)所述的甜菜红素溶液混合,短时超声处理,形成W/O乳液;
(4)将步骤(3)所述W/O乳液旋蒸除掉有机溶剂,当达到胶态后加入吐温80的PBS溶液减压水合;
(5)将步骤(4)水合后的混悬液短时超声处理,得甜菜红素纳米脂质体溶液。
优选地,步骤(1)所述大豆卵磷脂和胆固醇的质量比为2-10:1;
优选地,所述大豆卵磷脂和有机溶剂的质量体积比40-80:1g/L;
优选地,所述有机溶剂为乙醚;
优选地,步骤(2)所述PBS溶液的pH为6.5-7.1,浓度为0.03-0.07mM;
优选地,所述甜菜红素溶液的浓度为2-10mg/mL。
优选地,步骤(3)所述溶液1和甜菜红素溶液的体积比为6-12:3;
优选地,所述短时超声处理使用细胞破碎仪;
优选地,所述短时超声处理为冰浴环境,所述短时超声处理的时间为2-10min,所述短时超声处理的超声功率为150-500w;进一步优选的,短时超声处理的时间为6min,短时超声处理的超声功率为350W。
优选地,所述短时超声处理为重复进行开0.5-1.5s、关0.5-1.5s;进一步优选的,短时超声处理为重复进行开1s、关1s。
优选地,步骤(4)所述吐温80的PBS溶液中吐温80的浓度为20-25g/mL;
优选地,所述吐温80与步骤(2)所述甜菜红素的质量比为10-20:1;
优选地,所述减压水合的时间为10-60min,真空度小于0.02Mpa;
优选地,所述旋蒸的温度为30-40℃,转速为100-200rpm;进一步优选的,所述旋蒸的温度为35℃,转速为150rpm。
优选地,步骤(5)所述短时超声处理使用细胞破碎仪;
优选地,所述短时超声处理为冰浴环境,所述短时超声处理的时间为1-5min,所述短时超声处理的超声功率为100-300w,进一步优选的,短时超声处理的时间为3min,短时超声处理的超声功率为165W。
优选地,所述短时超声处理为重复进行开0.5-1.5s、关0.5-1.5s;进一步优选的,短时超声处理为重复进行开1s、关1s。
优选地,将所述甜菜红素纳米脂质体溶液过0.18-0.26M水相滤膜;进一步优选的,水相滤膜为0.22M。
优选地,将壳聚糖溶于冰醋酸溶液中配制壳聚糖溶液;将所述壳聚糖溶液加入到所述的甜菜红素纳米脂质体溶液中,搅拌,制得壳聚糖修饰的甜菜红素纳米脂质体溶液。进一步优选地,所述壳聚糖溶液中壳聚糖的质量浓度为0.2-1%,所述冰醋酸溶液的质量浓度为0.5-1.5%;所述壳聚糖溶液与甜菜红素纳米脂质体溶液的体积比为1:0.5-1.5;所述搅拌的转速为200-500rpm,搅拌的时间为10-50minh。更优选地,所述壳壳聚糖溶液中壳聚糖的质量浓度为0.6%。
进一步优选地,将所述壳聚糖修饰的甜菜红素纳米脂质体溶液静置、离心,弃掉上清液,加入磷酸盐缓冲溶液重悬。
进一步优选地,所述静置的时间为0.5-1.5h;所述离心的离心力为2000-4000g,温度为2-6℃。
上述的制备方法制备的甜菜红素纳米脂质体。
上述的甜菜红素纳米脂质体作为抗肿瘤药物的应用。
发明提供了一种由上述方法制备的高效抗癌的甜菜红素纳米脂质体。本发明对包埋体系进行了创新性设计,针对甜菜红素稳定性低和生物利用度低的问题,采取了脂质体包埋的形式提高了甜菜红素的稳定性和生物利用度,改善甜菜红素的脂溶性;其次对于脂质体的脂质分子易水解和氧化的问题,引入了壳聚糖,壳聚糖与脂质体通过静电相互作用结合,一方面在脂质体表面形成保护层,另一方面壳聚糖修饰的脂质体表面带正电荷,可增强与带负电荷的细胞膜的亲和力,从而增加癌细胞对脂质体的吸收,有助于提升抗癌效果。
此外,本发明采取了二次超声的方式,使得制备的脂质体更加的均匀,粒径更小,更容易进入细胞内部。壳聚糖修饰的甜菜红素脂质体包埋率高达42.67%,平均粒径为194.60nm,PDI为0.29,zeta电位为5.80mv。
与现有技术相比,本发明具有如下优点和有益效果:
(1)本发明所制备的甜菜红素纳米脂质体可改善甜菜红素的脂溶性。
(2)本发明所制备的脂质体稳定性较高,脂质分子不易被水解或氧化,所制备的脂质体制剂在室温下放置8个月,4℃条件下放置24个月仍未见明显的分层现象。
(3)本发明制备的脂质体形态规则,粒径小,安全无毒。
(4)所制备的脂质体制剂经细胞实验证实对癌细胞的抑制显著高于甜菜红素,未经壳聚糖修饰的脂质体制剂对人肝癌细胞HepG2的EC50值相比于甜菜红素的EC50值至少提高了18倍;脂质体制剂对人肝癌细胞HepG2的EC50值相比于甜菜红素的EC50值至少提高了28倍,具有良好的抗肿瘤效果,由较好的应用前景。
附图说明
图1是亚甲基蓝法检测对比例1对人肝癌细胞HepG2的增殖抑制作用和毒性曲线图。
图2是亚甲基蓝法检测实施例6对人肝癌细胞HepG2的增殖抑制作用和毒性曲线图。
图3是亚甲基蓝法检测实施例3对人肝癌细胞HepG2的增殖抑制作用和毒性曲线图。
具体实施方式
下面结合实施例对本发明进行具体地描述,但本发明的实施方式和保护范围不限于以下实施例。
实施例1
(1)将540mg大豆卵磷脂和90mg胆固醇溶于9mL乙醚中;
(2)甜菜红素溶于pH 6.8,0.05mM的PBS溶液中,配制成10mg/mL的甜菜红素溶液;
(3)向步骤(1)的大豆卵磷脂和胆固醇的乙醚溶液中加入3mL步骤(2)的甜菜红素溶液,用细胞破碎仪短时冰浴超声处理6min,超声功率为330w,开1s,关1s,形成稳定的W/O乳液;
(4)旋转蒸发仪除掉乙醚,当达到胶态后加入2mL的含有45mg吐温80的PBS溶液减压水合半小时,真空度小于0.02MPa;
(5)步骤(4)水合后的混悬液再一次用细胞破碎仪短时冰浴超声处理3min以缩小脂质体粒径,超声功率为165w,开1s,关1s。
(6)将步骤(5)超声后的脂质体悬液过0.22M水相滤膜。
(7)将壳聚糖溶于1%的冰醋酸溶液中配制成0.2%的壳聚糖溶液;将壳聚糖溶液按照1:1的体积比逐滴加入到步骤(6)所得的脂质体溶液中,并以300rpm搅拌0.5h,之后静置1h,得到的脂质体溶液于3000g 4℃条件下离心。弃掉上清液,加入磷酸盐缓冲溶液重悬。制得壳聚糖修饰的甜菜红素纳米脂质体溶液(CS-NL),将其储存在4℃冰箱中备用。
将上述制备的壳聚糖修饰的甜菜红素脂质体溶液(CS-NL)在室温下放置8个月,4℃条件下放置24个月仍未见明显的分层现象;说明脂质体稳定性较高,脂质分子不易被水解或氧化。
实施例2
调整壳聚糖浓度为0.4%,其他操作均与实施例1相同,制得壳聚糖修饰的甜菜红素纳米脂质体。
实施例3
调整壳聚糖浓度为0.6%,其他操作均与实施例1相同,制得壳聚糖修饰的甜菜红素纳米脂质体。
实施例4
调整壳聚糖浓度为0.8%,其他操作均与实施例1相同,制得壳聚糖修饰的甜菜红素纳米脂质体。
实施例5
调整壳聚糖浓度为1.0%,其他操作均与实施例1相同,制得壳聚糖修饰的甜菜红素纳米脂质体。
实施例6
(1)将540mg大豆卵磷脂和90mg胆固醇溶于9mL乙醚中;
(2)甜菜红素溶于pH 6.8 0.05mM的PBS溶液中,配制成10mg/mL的甜菜红素溶液;
(3)向步骤(1)的大豆卵磷脂和胆固醇的乙醚溶液中加入3mL步骤(2)的甜菜红素溶液,用细胞破碎仪短时冰浴超声处理6min,超声功率为330w,开1s,关1s,形成稳定的W/O乳液;
(4)旋转蒸发仪除掉乙醚,当达到胶态后加入2mL的含有45mg吐温80的PBS溶液减压水合半小时,真空度小于0.02MPa;
(5)步骤(4)水合后的混悬液再一次用细胞破碎仪短时冰浴超声处理3min以缩小脂质体粒径,超声功率为165w,开1s,关1s。过0.22μm水相滤膜,得未经壳聚糖修饰的甜菜红素纳米脂质体溶液(NL)。
对比例1
将甜菜红素溶于培养基中,配制成甜菜红素溶液。
包封率和载药量测定
测定实施例3的包封率和载药量,取适量脂质体混悬液至于透析袋中,封口,按照1:100(透析内液:透析外液)的比例用pH 6.8 0.05mM的PBS溶液透析,温和搅拌,每2h换一次透析外液,直至透析外液变为无色。分别取透析后和透析前的脂质体混悬液加入10%Trolox-100溶液,溶解脂质,在538nm下测定吸光度,计算甜菜红素的浓度,包封率和载药率的计算公式如下:
W1为透析液中甜菜红素量(mg/mL);W2为脂质体原液中甜菜红素量(mg/mL);W总为投入的总脂质量(mg);
称取10mg的甜菜红素,用PBS(pH 6.8 0.05mM)溶液溶解并稀释至5-50μg/mL甜菜红素溶液,以PBS溶液作为空白,在538nm下测定吸光值得到的甜菜红素标准曲线回归方程为:y=0.0159x+0.0143,R2=0.9997。
实施例3的包封率为42.67±1.67%,载药量为2.63±0.42%。
电位和粒径测定
测定实施例1,2,3,4,5,6的脂质体平均粒径,多分散指数(PDI)和zeta电位。
电位和粒径测定:取一定量的纳米脂质体(NL)和壳聚糖修饰的纳米脂质体(CS-NL)用去离子水稀释20倍,在25℃下采用Zetasizer Nano ZS型纳米粒度仪测定粒径、PDI和电位,折射指数为1.420±0.001,每个样品重复测定三次。
数据如表1所示。随着壳聚糖浓度的增加,脂质体的粒径逐渐增加,PDI小幅增加。脂质体的zeta电位由负变正,显示壳聚糖与脂质体成功结合。随着壳聚糖浓度的增加,脂质体的zeta电位在壳聚糖浓度为0.6%时达到最大值,之后随着壳聚糖浓度的增加略微减小。
表1不同壳聚糖浓度对甜菜红素纳米脂质体平均粒径,PDI和zeta电位的影响
抗增殖活性和毒性测试
将本发明实施例3制备的壳聚糖修饰的脂质体,实施例6制备的甜菜红素脂质体,对比例1的甜菜红素溶液进行HepG2细胞的抗增殖活性和毒性测试,其结果见说明书附图1,2,3和表2。
亚甲基蓝法检测细胞毒性:采用高糖DMEM培养基培养癌细胞,代数为12-30代。高糖DMEM培养基中含有10%胎牛血清,1%青霉素-链霉素溶液。细胞置于37℃,含5%CO2的加湿二氧化碳培养箱中培养。癌细胞以2.5×104/孔的密度接种到96孔板中,置于培养箱中孵育12h,之后弃掉培养基,加入不同浓度的用培养基稀释样品,空白孔为不含药物的培养基溶液,药物处理24h,24h后,弃掉培养基每孔加入50mL亚甲基蓝染液,置于培养箱中孵育1h,使得活细胞被亚甲基蓝充分染色。除去亚甲基蓝染液,每孔加入100mL洗脱缓冲液(49%PBS,50%乙醇,1%乙酸),振荡混合均匀。在570nm下测定每孔的吸光度。
细胞毒性按照公式(3)计算:
其中,Ac为空白组的吸光度,As为加药组的吸光度。
亚甲基蓝法检测药物抗增殖活性:根据Wen等人报道的方法测定脂质体的抗增殖活性。癌细胞以1.5×104/孔的密度接种到96孔板中,放入培养箱中孵育4h,待细胞完全贴壁后,后弃掉培养基,加入不同浓度的用培养基稀释的脂质体溶液,空白孔为不含药物的培养基溶液,药物处理72h。弃掉培养基,再按照细胞毒性方法采用亚甲基蓝法染色。将96孔板置于酶标仪中,在570nm下测定每孔的吸光度。细胞存活率按照公式(4)计算:
其中,Ac为空白组的吸光度,As为加药组的吸光度。
图1,2和3分别表示甜菜红素,甜菜红素脂质体和壳聚糖修饰的甜菜红素纳米脂质体对HepG2细胞的量效关系图。表2表示甜菜红素,甜菜红素脂质体和壳聚糖修饰的甜菜红素纳米脂质体对HepG2细胞的EC50和CC50值。EC50表示药物对细胞产生50%抑制作用时的药物浓度,CC50表示药物对细胞产生对细胞产生50%毒性时的浓度。
表2
甜菜红素,甜菜红素纳米脂质体(NL)和壳聚糖修饰的甜菜红素纳米脂质体(CS-NL)对HepG2细胞的毒性和抗增殖作用如图1,2和3所示。从图中可以看出,甜菜红素,NL和CS-NL对HepG2细胞都具有抗增殖作用,并且都具有一定的细胞毒性。同时对HepG2细胞的细胞增殖抑制率和毒性作用随着甜菜红素浓度的增加而增加。甜菜红素,NL和CS-NL对HepG2细胞的EC50,CC50和SI值如表2所示,CS-NL呈现最低的EC50值,为69.46±1.75μg/mL,对HepG2细胞的抑制效果最好。CS-NL的CC50值大于240μg/mL,SI值大于2,说明CS-NL对HepG2细胞的抑制作用是由其抗增殖活性而不是细胞毒性引起。
从图1,2,3和表2中可以看出本发明制备甜菜红素纳米脂质体显著提高了抗增殖活性;其中,壳聚糖修饰的甜菜红素纳米脂质体显著提高了抗增殖活性,相比于游离的甜菜红素,对HepG2细胞的抑制效果提升28倍以上。
以上实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (6)
1.一种壳聚糖修饰的甜菜红素纳米脂质体在制备抗肿瘤药物中的应用,其特征在于,所述的壳聚糖修饰的甜菜红素纳米脂质体的制备方法包括以下步骤:
(1)将大豆卵磷脂和胆固醇溶于有机溶剂中,得溶液1;所述大豆卵磷脂和胆固醇的质量比为2-6:1;所述大豆卵磷脂和有机溶剂的质量体积比40-60:1 g/L;所述有机溶剂为乙醚;
(2)将甜菜红素溶于PBS溶液中,得到甜菜红素溶液;所述PBS溶液的pH 为6.5-7.1,浓度为0.03-0.07 mM;所述甜菜红素溶液的浓度为2-10mg/mL;
(3)将步骤(1)所述的溶液1和步骤(2)所述的甜菜红素溶液混合,短时超声处理, 形成W/O乳液;所述溶液1和甜菜红素溶液的体积比为6-12:3;所述短时超声处理的时间为6-10min;
(4)将步骤(3)所述W/O乳液旋蒸除掉有机溶剂,当达到胶态后加入吐温80的PBS溶液减压水合;所述吐温80的PBS溶液中吐温80的浓度为20-25g/mL;所述吐温80与步骤(2)所述甜菜红素的质量比为10-20:1;所述减压水合的时间为10-60min,真空度小于0.02Mpa;
(5)将步骤(4)水合后的混悬液短时超声处理,得甜菜红素纳米脂质体溶液;所述短时超声处理的时间为1-5 min;
将壳聚糖溶于冰醋酸溶液中配制壳聚糖溶液;将所述壳聚糖溶液加入到所述的甜菜红素纳米脂质体溶液中,搅拌,制得壳聚糖修饰的甜菜红素纳米脂质体溶液;所述壳聚糖溶液中壳聚糖的质量浓度为0.4-1%;所述壳聚糖溶液与甜菜红素纳米脂质体溶液的体积比为1:0.5-1.5;搅拌的时间为10-50min。
2.根据权利要求1所述的应用,其特征在于,步骤(3)所述短时超声处理使用细胞破碎仪,所述短时超声处理为冰浴环境,所述短时超声处理的超声功率为150-500 w,所述短时超声处理为重复进行开0.5-1.5s、关0.5-1.5 s。
3.根据权利要求1所述的应用,其特征在于,步骤(5)所述短时超声处理的超声功率为100-300w,所述短时超声处理为重复进行开0.5-1.5s、关0.5-1.5 s;将所述甜菜红素纳米脂质体溶液过0.18-0.26 M水相滤膜。
4.根据权利要求1所述的应用,其特征在于,所述冰醋酸溶液的质量浓度为0.5-1.5%;所述搅拌的转速为200-500rpm。
5.根据权利要求1所述的应用,其特征在于,将所述壳聚糖修饰的甜菜红素纳米脂质体溶液静置、离心,弃掉上清液,加入磷酸盐缓冲溶液重悬。
6.根据权利要求5所述的应用,其特征在于,所述静置的时间为0.5-1.5h;所述离心的离心力为2000-4000g,温度为2-6℃。
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