CN114569554A - 一种肿瘤靶向性雷公藤内酯醇乳液及其制备方法 - Google Patents

一种肿瘤靶向性雷公藤内酯醇乳液及其制备方法 Download PDF

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CN114569554A
CN114569554A CN202210188686.6A CN202210188686A CN114569554A CN 114569554 A CN114569554 A CN 114569554A CN 202210188686 A CN202210188686 A CN 202210188686A CN 114569554 A CN114569554 A CN 114569554A
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阙慧卿
林绥
郭舜民
李唯
钱丽萍
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Abstract

本发明提供了一种肿瘤靶向性雷公藤内酯醇乳液及其制备方法，所述肿瘤靶向性雷公藤内酯醇乳液的组分按质量百分数计包括：叶酸偶联壳聚糖雷公藤内酯醇复合物占0.25～3.0%，DSPE‑PEG‑SP94占0.2～0.8%，磷脂类混合基质占1.2～10%，丙三醇占1～3%，泊洛沙姆188占0.5～2%。该剂型性质稳定，制备工艺简单，具有优异的肿瘤靶向性。

Description

一种肿瘤靶向性雷公藤内酯醇乳液及其制备方法
技术领域
本发明属于一种肿瘤靶向性雷公藤内酯醇乳液与制备方法。
背景技术
雷公藤内酯醇（TP）又名雷公藤甲素，是中药材雷公藤中的主要有效成分之一，生理活性强，具有显著的抗炎、抗肿瘤、抗生育及免疫调节作用。可应用于许多自身免疫性疾病的治疗，但它又是一个毒性很强的药物，临床不良反应的发生频率远高于其他药物，对于这样的一个药物，其减毒增效的研究具有重要意义。纳米乳作为新型药物载体，具有对难溶性药物强大的增溶作用、缓释作用、靶向性及较高的生物利用度等优点，在药剂学领域有较好的应用前景。TP经制备成FA-CS-TP纳米乳，提高TP的溶解度；通过叶酸与叶酸配体的亲和力，发挥靶向作用；纳米载体包封可减缓TP的释放。目前，有报道将有机相和水相置于微流控中进行反应，透析，制备一种TP叶酸靶向纳米药物；采用离子交联法制备TP-叶酸-壳聚糖纳米粒，所制得的纳米药物粒径为170nm。本发明采用高压乳匀法制备TP-叶酸-壳聚糖纳米乳，所制得的纳米药物平均粒径为90.1nm，更利于肿瘤血管的渗透。
发明内容
本发明的目的在于提供一种肿瘤靶向性雷公藤内酯醇乳液与制备方法。
为实现上述目的，本发明采用如下技术方案：
一种肿瘤靶向性雷公藤内酯醇乳液，其组分按质量百分数计包括：叶酸偶联壳聚糖雷公藤内酯醇复合物占0.25～3.0%，DSPE-PEG-SP94占0.2～0.8%，磷脂类混合基质占1.2～10%，丙三醇占1～3%，泊洛沙姆188占0.5～2%。
进一步的，叶酸偶联壳聚糖雷公藤内酯醇复合物中，雷公藤内酯醇、叶酸和壳聚糖的质量比为0.03-0.2 : 1 : 1。
进一步的，所述磷脂类混合基质由大豆卵磷脂、胆固醇和植物油基质三者组合而成，三者的质量比例为2~5 : 1.5~4 : 0.5~1.5。
进一步的，所述的肿瘤靶向性雷公藤内酯醇乳液的制备方法，包括以下步骤：
（1）将叶酸用DMSO溶解，加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐（EDC），25℃避光环境搅拌1h，制得叶酸溶液；
（2）将壳聚糖用1wt%醋酸溶液溶解，制备壳聚糖溶液，缓慢滴入叶酸溶液，搅拌均匀，加入N-羟基琥珀酰亚胺（NHS）催化，避光搅拌2h，反应结束后，加入NaOH溶液调节pH至9.0，溶液转移至透析袋中透析，透析结束后，混合物冻干，制得叶酸壳聚糖复合物A。复合物A用醋酸溶解，调节pH至6.5，得复合物A溶液；
（3）将雷公藤内酯醇用甲醇溶解，缓慢滴加A溶液和多聚磷酸钠溶液，匀速搅拌2h，得到叶酸偶联壳聚糖雷公藤内酯醇FA-CS-TP复合物溶液；
（4）用FA-CS-TP复合物溶液溶胀DSPE-PEG-SP94；将磷脂类混合基质溶解于二氯甲烷，混合两种溶液，在50℃水浴下减压旋转蒸干溶剂，至形成均匀的黄色油相；
（5）量取适量超纯水，加入丙三醇和泊洛沙姆188，40℃水浴溶解，调节pH至6.5，制备水相溶液；
（6）将水相溶液加入油相中，恒温40℃使油相分散，然后通过高压均质机进行高压乳匀，制备肿瘤靶向性雷公藤内酯醇乳液。
本发明的优点在于：
本发明制备的肿瘤靶向性TP乳液，该剂型性质稳定，制备工艺简单，载药纳米乳液对人前列腺癌细胞PC-3，人肝癌细胞HepG2，人乳腺癌细胞MCF-7的半数抑制浓度（IC50）分别为51.38nM，536.7nM，137.3nM，且在5μM时对PC-3、HepG2、MCF-7细胞的增值抑制率分别为78.04%、80.12%和77.50%。可通过调节偶联叶酸的个数调节肿瘤靶向性。
100nm左右的脂质体在肿瘤细胞中的保留效果最好，本发明采用高压乳匀技术制备肿瘤靶向性TP乳液，载药纳米乳（FA-CS-TP）均匀性好，平均粒径为90.1 nm，适宜的粒径提高其在靶组织的浓度，使其易在肿瘤组织集聚。
本发明在处方中加入肝癌靶向肽DSPE-PEG-SP94，使制得的脂质体既能通过肿瘤细胞表面过度表达的叶酸受体结合，诱导TP发挥抗肿瘤作用，同时通过DSPE-PEG-SP94具有与肝癌特异性结合的特性，促进肿瘤细胞凋亡和减少肿瘤血管生成来提高TP的抗肝癌疗效。
附图说明
图1为FA-CS-TP纳米乳平均粒径；
图2为FA-CS-TP纳米乳平均电位。
具体实施方式
为让本发明的上述特征和优点能更明显易懂，下文特举实施例，作详细说明。本发明的方法如无特殊说明，均为本领域常规方法。
实施例1
一种肿瘤靶向性雷公藤内酯醇乳液，其组分按质量百分数计包括：叶酸偶联壳聚糖雷公藤内酯醇复合物占1.3%，DSPE-PEG-SP94占0.25%，磷脂类混合基质占4%，丙三醇占2.5%，泊洛沙姆188占0.5%。
所述磷脂类混合基质由大豆卵磷脂、胆固醇和大豆油基质三者组合而成，三者的质量比例为4:3:1。
所述肿瘤靶向性雷公藤内酯醇乳液的制备方法，包括以下步骤：
（1）称取叶酸2.2g于烧杯中，用100 ml DMSO溶解，加入 3.0g EDC，25℃避光环境搅拌2h，制得叶酸活性酯溶液。取壳聚糖1.8g，加入1wt%醋酸溶液，搅拌溶解，制备2.0mg/ml壳聚糖溶液，以每秒1滴的速度缓慢滴加叶酸溶液，搅拌均匀，加入3.0g NHS催化，避光搅拌2h，反应结束后，加入1wt% NaOH溶液调节pH至9.0，溶液转移至截留分子质量为10kDa的透析袋中透析48h，每8h换一次水。透析结束后，混合物冻干，制得叶酸壳聚糖复合物A。
（2）将3.6g复合物A溶解于10ml 1%的醋酸溶液中，调节pH 6.5，制得360mg/ml的FA-CS溶液。精密称取0.3020克雷公藤内酯醇用5ml甲醇完全溶解，以每秒1滴的速度缓慢滴入 A 液，以相同速度滴加2.0 mg/ml多聚磷酸钠溶液2ml，匀速搅拌2h，制备叶酸偶联壳聚糖雷公藤内酯醇复合物FA-CS-TP溶液；
（3）取（2）所得的FA-CS-TP复合物溶液（含FA-CS-TP 3.9g，FA:CS:TP=6:6:1质量比）溶胀0.15克DSPE-PEG-SP94；磷脂类混合基质（用量12g）用二氯甲烷溶解，将两种溶液混合，在50℃水浴下减压旋转蒸干溶剂，制得淡黄色油相B；
（4）另量取超纯水300ml，加入7.5克丙三醇和1.5克泊洛沙姆188，40℃水浴溶解，醋酸-醋酸钠缓冲盐调节pH=6.5，制备水相溶液C；
（5）将C溶液加入油相B中，恒温40℃使油相充分溶胀，所得溶液通过高压均质机进行高压乳匀，制备肿瘤靶向性FA-CS-TP纳米乳。
如图1和图2所示，FA-CS-TP纳米乳中FA-CS-TP复合物的平均粒径为90.1nm，平均Zeta电位为-28.37mV。
应用例
肿瘤靶向性FA-CS-TP纳米乳液抗肿瘤作用考察，包括以下步骤：
（1）细胞培养：贴壁培养PC-3、HepG2、MCF-7细胞。取对数生长期的PC-3，HepG2，MCF-7分别接种至96孔板，每孔为5×103个细胞，约100ul悬液，每组设3个复孔。
（2）给药：给药组加入FA-CS-TP纳米乳，浓度分别为1u mol/l、0.5u mol/l、0.1umol/l、0.05u mol/l、0.01u mol/l、0.005u mo/l、0.003u mol/l、0.002u mol/l、0.001umol/l，阳性对照组给予与FA-CS-TP纳米乳组等量的TP， FA-CS-TP纳米乳阴性对照组（不含TP）稀释倍数与给药组相同，空白对照孔A(只加培养基) 、空白对照孔B(加培养基及等浓度DMSO)作为阴性对照，继续培养72hr。
（3）测定：读取540nm处的吸光度值（OD值），计算不同摩尔浓度下FA-CS-TP纳米乳液对PC-3，HepG2，MCF-7细胞的增殖抑制率，并采用graphpad prism7.0计算半数抑制浓度（IC50），增值抑制率（%）=（1-实验组OD值/对照组OD值）×100%。结果见附表1。
表1 TP与FA-CS-TP纳米乳肿瘤增殖抑制表
Figure DEST_PATH_IMAGE002
以上所述仅为本发明的较佳实施例，凡依本发明申请专利范围所做的均等变化与修饰，皆应属本发明的涵盖范围。

Claims (5)

1.一种肿瘤靶向性雷公藤内酯醇乳液，其特征在于，所述肿瘤靶向性雷公藤内酯醇乳液的组分按质量百分数计包括：叶酸偶联壳聚糖雷公藤内酯醇复合物占0.25～3.0%，DSPE-PEG-SP94占0.2～0.8%，磷脂类混合基质占1.2～10%，丙三醇占1～3%，泊洛沙姆188占0.5～2%。
2.根据权利要求1所述的肿瘤靶向性雷公藤内酯醇乳液，其特征在于，叶酸偶联壳聚糖雷公藤内酯醇复合物中，雷公藤内酯醇、叶酸和壳聚糖的质量比为0.03~0.2 : 1 : 1。
3.根据权利要求2所述的肿瘤靶向性雷公藤内酯醇乳液，其特征在于，所述叶酸偶联壳聚糖雷公藤内酯醇复合物的制备方法，包括以下步骤：
1）将叶酸用DMSO溶解，加入EDC，25℃避光环境搅拌2h，制得叶酸溶液；
2）将壳聚糖用1wt%醋酸溶液溶解，制备壳聚糖溶液，缓慢滴入叶酸溶液，搅拌均匀，加入NHS催化，避光搅拌2h，反应结束后，加入NaOH溶液调节pH至9.0，溶液转移至透析袋中透析，透析结束后，混合物冻干，制得叶酸壳聚糖复合物A，复合物A用醋酸溶解，调节pH至6.5，得复合物A溶液；
3）将雷公藤内酯醇用甲醇溶解，缓慢滴入A液和多聚磷酸钠溶液，匀速搅拌2h，得到叶酸偶联壳聚糖雷公藤内酯醇FA-CS-TP复合物溶液。
4.根据权利要求1所述的肿瘤靶向性雷公藤内酯醇乳液，其特征在于，所述磷脂类混合基质由胆固醇、大豆卵磷脂和植物油基质三者组合而成，三者的质量比例为2~5 : 1.5~4 :0.5~1.5。
5.根据权利要求3所述的肿瘤靶向性雷公藤内酯醇乳液的制备方法，其特征在于，包括以下步骤：
（1）用FA-CS-TP复合物溶液溶胀DSPE-PEG-SP94；将磷脂类混合基质溶解于二氯甲烷，混合两种溶液，在50℃水浴下减压旋转蒸干溶剂，至形成均匀的黄色油相；
（2）量取适量超纯水，加入丙三醇和泊洛沙姆188，40℃水浴溶解，调节pH至6.5，制备水相溶液；
（3）将水相溶液加入油相中，恒温40℃使油相分散，然后通过高压均质机进行高压乳匀，制备肿瘤靶向性雷公藤内酯醇乳液。
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