CN114470229B - 一种无载体双药自组装纳米粒的制备及用途 - Google Patents
一种无载体双药自组装纳米粒的制备及用途 Download PDFInfo
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Abstract
本发明提供了一种无载体双药自组装纳米粒的制备及用途。本发明利用溶剂交换法将化疗药物索拉非尼与天然产物熊果酸分子通过π‑烷基键、烷基键、氢键自组装形成纳米粒,然后将吲哚菁绿物理吸附到纳米粒中,并在纳米粒表面修饰核酸适配体及细胞穿膜肽,从而制得所述无载体双药自组装纳米粒。本发明有效避免了传统高分子或无机载体的引入以及共修饰带来的潜在毒性,为纳米技术应用于癌症治疗领域提供了新途径。
Description
技术领域
本发明属于医药技术领域,具体涉及一种无载体自组装纳米粒的制备及其应用,特别是在制备治疗肝癌的药物中的应用。
背景技术
目前临床上各类癌症治疗主要还是采用手术和放化疗等治疗手段。其中化疗在多种癌症的治疗中,依旧是最为普遍的治疗手段,始终占据着重要的地位。
索拉非尼作为一种新型的多靶点抗肿瘤药物,是当前美国FDA已批准用于肝癌治疗的一线药物,在临床治疗中取得不错的成效。但肝癌的发展进程复杂,且长期大剂量的使用易导致耐药,单一的给药策略已经不能满足目前临床治疗的需求。因此,科研人员迫切探求一种安全有效、毒副作用小的治疗药物或联合治疗方案以解决当前肝癌治疗中存在的难题。
熊果酸是一种可从多种植物中提取的五环三萜类化合物,具有低毒高效、作用温和、多环节调控的特性。研究表明,UA能够显著提高肿瘤细胞对化疗药物的敏感性,产生协同增敏作用,尤其在多药耐药细胞中,可以克服肿瘤细胞的耐药性,使常规化疗药物能够更为有效地杀灭肿瘤细胞。申请人课题组前期将UA及其衍生物作为化疗增敏剂与索拉非尼联用,发现二者能够协同抑制肝癌细胞的增殖,且对人正常肝细胞杀伤作用较小,具有显著的协同增敏作用(授权发明专利号: ZL201610518377.5; ZL201610518371.8, 2018年授权)。
但是,熊果酸和索拉非尼均为疏水性药物,作为单一剂型联合给药存在代谢速度快、水溶性差、生物利用度低等缺点,进而限制了二者联用在临床上的开发应用。申请人课题组前期设计构建了一种 pH 敏感同时靶向 ASGPR 受体的介孔二氧化硅控释纳米颗粒用于共同递送索拉非尼及其增敏剂熊果酸,为实现肝癌的联合治疗提供一种有效干预策略,特别是应用于肝癌复发转移的化学预防领域(Biomaterials, 2017, 143: 1-16)。但一般的,诸如介孔二氧化硅等纳米载体通常是采用繁琐的化学合成及修饰反应获得,其制备过程复杂,且易造成催化剂和有机溶剂等有毒物质的残留,限制了有载体的纳米载药系统在临床中的应用。
科研人员一直致力于开发无载体的纳米药物自输送体系以规避成分复杂的载体带来的未知的体内代谢行为和系统毒性,从而达到更好、更安全的临床应用要求。此外,为使载药体系获得更佳的稳定性、更好的药物缓释性能及肿瘤主动靶向性,需要进一步对纳米药物表面进行功能化修饰,使之具备良好的生物兼容性、生理环境稳定性和溶酶体逃逸、主动靶向作用。因此,设计开发一种增敏索拉非尼的无载体自组装的纳米自输送系统,兼具靶向、成像和药物治疗一体化的多功能纳米药物系统,具有合理的现实开发意义。
发明内容
本发明的目的在于提供一种无载体自组装纳米粒的制备及用途。
为实现上述目的。本发明采用如下技术方案:
本发明提供了一种无载体自组装纳米粒的制备方法,其是利用溶剂交换法将化疗药物索拉非尼与熊果酸通过疏水作用力(π-烷基键、烷基键)、氢键自组装形成纳米粒,然后将吲哚菁绿物理吸附到纳米粒中,并在纳米粒表面修饰核酸适配体及细胞穿膜肽,从而制得所述无载体双药自组装纳米粒。
上述一种无载体双药自组装纳米粒的制备方法,包括以下步骤:
(1)将熊果酸、索拉非尼及吲哚菁绿分别溶于良性溶剂中,得到熊果酸溶液、索拉非尼溶液和吲哚菁绿溶液;
(2)将熊果酸溶液、索拉非尼溶液和吲哚菁绿溶液按照一定体积比混合,得到混合溶液1;
(3)将混合溶液1滴加至超纯水中,室温下超声分散10~20 min,随后氮吹吹干良性溶剂,得到混合溶液2;
(4)将穿膜肽溶液与核酸适配体溶液按照一定体积比进行混合,室温孵育4 h,得到混合溶液3;
(5)将混合溶液3滴加至混合溶液2中,室温下超声分散10~20 min,随后在超纯水中透析过夜,即得到所述无载体双药自组装纳米粒的水溶液。
进一步的,上述制备方法的步骤(1)中,所述良性溶剂为无水甲醇、无水乙醇、二甲基亚砜中的任意一种;所述熊果酸溶液的浓度为4 mg/mL,所述索拉非尼溶液的浓度为4mg/mL,所述吲哚菁绿溶液的浓度为4 mg/mL。
进一步的,上述制备方法的步骤(2)中,所述熊果酸溶液:索拉非尼溶液:吲哚菁绿溶液的体积比为1:0.25:0.5~1:4:2。
进一步的,上述制备方法的步骤(3)中,所述混合溶液1:超纯水的体积比为1:10;所述超声功率为250 W,超声频率为40 kHz。
进一步的,上述制备方法的步骤(4)中,所述穿膜肽为低分子量鱼精蛋白LMWP,所述核酸适配体为EpCAM适配体,所述穿膜肽溶液浓度为2 mg/mL,所述核酸适配体溶液浓度为1.47 mg/mL;所述穿膜肽溶液:核酸适配体溶液的体积比为1:0.5~8。
进一步的,上述制备方法的步骤(5)中,所述混合溶液3:混合溶液2的体积比为1:50;所述超声功率为250 W ,超声频率为40 kHz。
本发明还提供了一种利用上述制备方法制得的无载体双药自组装纳米粒。
本发明还提供了上述一种无载体双药自组装纳米粒在制备治疗肝癌的药物中的应用。
本发明的有益效果在于:
1、本发明提出的一种增敏索拉非尼的无载体自组装纳米粒的制备方法,仅利用两种药物分子间的相互作用如疏水作用力(π-烷基、烷基-烷基相互作用)、氢键自组装形成“以药递药”的无载体自组装纳米粒,能有效避免传统高分子或无机载体的引入以及共修饰带来的潜在毒性,为纳米技术应用于癌症治疗领域提供了新途径。
2、本发明提供的药物均为疏水性药物,作为单一剂型联合给药限制了其在临床上的广泛应用,将二者通过纳米技术结合使药物纳米化,可以提高两者的生物利用度,具有潜在的应用价值。
3、将熊果酸与索拉非尼二者连用,可提高索拉非尼对肝癌细胞增殖的抑制作用,可以降低索拉非尼用量,具有协同增效的作用。
4、纳米系统通过荧光染料、核酸适配体/穿膜肽介导的主动靶向和纳米材料特有的EPR效应,不仅降低药物所带来的毒副作用,提高药物生物利用度,同时利用药物/分子靶向/成像等实现不同机制治疗剂的靶向递送及诊疗一体化作用。
附图说明
图1为纳米-1、纳米-2及纳米-3的水合粒径结果图。
图2为纳米-1、纳米-2及纳米-3的原子力观察结果。
图3为纳米-1、纳米-2及纳米-3的粒径稳定性结果图。
图4为纳米-1、纳米-2及纳米-3对抑制HepG2细胞增殖生长的联合指数计算结果图。
图5为纳米-4、纳米-5的水合粒径结果图。
图6为HepG2细胞、LO2细胞的激光共聚焦摄取结果图。
图7为HepG2细胞增殖生长抑制结果图。
具体实施方式
为了使本发明所述的内容更加便于理解,下面结合具体实施方式对本发明所述的技术方案做进一步的说明,但是本发明不仅限于此。
以下实施例中所用到的穿膜肽为低分子量鱼精蛋白LMWP,购自上海生工生物,其序列为VSRRRRRRGGRRRR。
以下实施例中所用到的核酸适配体为EpCAM适配体,购自上海生工生物,其序列为CACTACAGAGGTTGCGTCTGTCCCACGTTGTCATGGGGGGTTGGCCTG。
实施例1 熊果酸与索拉非尼无载体自组装纳米粒的制备
精密称取 8 mg熊果酸粉末,溶于2 mL甲醇中,配置成 4 mg/mL的熊果酸甲醇溶液;精密称取8 mg索拉非尼粉末,溶于2 mL甲醇中,配置成4 mg/mL的索拉非尼甲醇溶液;将4 mg/mL 的熊果酸甲醇溶液与4 mg/mL的索拉非尼甲醇溶液按照4:1的体积比混合均匀,作为有机相;将0.0625 mL有机相匀速滴加至1 mL超纯水中,在室温(25℃)、超声频率40 kHz、超声功率250 W 条件下超声分散10~20 min 后,用氮吹仪吹干甲醇,即得熊果酸/索拉非尼无载体自组装纳米粒的水溶液,将该纳米粒记为纳米-1。
精密称取8 mg熊果酸粉末,溶于2 mL甲醇中,配置成4 mg/mL的熊果酸甲醇溶液;精密称取8 mg索拉非尼粉末,溶于2 mL甲醇中,配置成4 mg/mL的索拉非尼甲醇溶液;将4mg/mL的熊果酸甲醇溶液与4 mg/mL的索拉非尼甲醇溶液按照1:1 的体积比混合均匀,作为有机相;将0.1 mL有机相匀速滴加至1 mL超纯水,在室温(25℃)、超声频率40 kHz、超声功率250 W条件下超声分散10~20 min后,用氮吹仪吹干甲醇,即得熊果酸/索拉非尼无载体自组装纳米粒的水溶液,将该纳米粒记为纳米-2。
精密称取 8 mg熊果酸粉末,溶于2 mL甲醇中,配置成4 mg/mL的熊果酸甲醇溶液;精密称取 8 mg索拉非尼粉末,溶于2 mL甲醇中,配置成4 mg/mL的索拉非尼甲醇溶液;将4mg/mL的熊果酸甲醇溶液与4 mg/mL的索拉非尼甲醇溶液按照1:4的体积比混合均匀,作为有机相;将 0.0625 mL有机相匀速滴加至1 mL超纯水,在室温(25℃)、超声频率40 kHz、超声功率250 W 条件下超声分散10~20 min后,用氮吹仪吹干甲醇,即得熊果酸/索拉非尼无载体自组装纳米粒的水溶液,将该纳米粒记为纳米-3。
采用动态光散射粒径仪测定纳米-1、纳米-2及纳米-3的粒径及多分散指数(PDI)。
结果如图1所示,熊果酸与索拉非尼可以通过简单的溶剂交换法制备得到无载体自组装纳米粒。
实施例2 熊果酸/索拉非尼无载体自组装纳米粒的外观形态观察
取20 μL实施例1制备的熊果酸/索拉非尼无载体自组装纳米粒水溶液滴加至新鲜云母片表面,并在室温下静置30 min,随后用超纯水洗涤3次以去除表面杂质,最后用氮气吹干,在原子力显微镜下采集纳米粒表面图像,以确认样品周围的形态。
结果如图2所示,原子力图像结果表明,纳米-1、纳米-2及纳米-3的形貌均近似球形,分散性均较好。
实施例3 熊果酸/索拉非尼无载体自组装纳米粒的稳定性考察
将实施例1制备的熊果酸/索拉非尼无载体自组装纳米粒分散在超纯水中或分散在含体积分数10% 胎牛血清(FBS)的DMEM 培养基中,于4℃条件下保存,每天取出等体积份数的纳米溶液,用动态光散射粒径仪测量其粒径并记录数据。
结果如图3所示,稳定性结果表明,熊果酸/索拉非尼无载体自组装纳米粒分散在超纯水和DMEM+10%FBS中时,其粒径均仍然保持了相对稳定的状态,可为后续的细胞实验的开展提供实验基础。
实施例4 熊果酸/索拉非尼无载体自组装纳米粒的体外细胞毒性实验
通过3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴化物(MTT)法测定实施例1制备的熊果酸/索拉非尼无载体自组装纳米粒对HepG2细胞的增殖抑制活性,具体步骤为:取处于对数生长期状态良好的HepG2细胞,经胰蛋白酶(含EDTA)消化后,以1.0×104个/孔的密度接种到96孔板中,置于37℃、5%CO2培养箱中培养24 h;设定游离熊果酸、游离索拉非尼、游离熊果酸+游离索拉非尼、熊果酸/索拉非尼无载体自组装纳米粒组别,去除旧的培养基,每孔加入100 μL不同浓度梯度的含样品的DMEM培养基,于培养箱中继续孵育24 h后,移除旧培养基,于每孔中加入100 μL 0.5 mg/mL MTT溶液,避光孵育4 h;取出96孔板终止培养,用移液枪轻轻吸去96孔板中的上清液,每孔加入100 μL DMSO,振荡摇匀,使蓝紫色结晶全部溶解,用酶标仪于490 nm波长处测定每孔的吸光度值,计算细胞存活率。为了量化熊果酸和索拉非尼之间的协同作用,用Compusyn软件计算熊果酸/索拉非尼作用的联合指数(CI)。当CI>1时,表示二者有拮抗作用;当CI=1时,表示二者有相加作用;当CI<1时,表示二者有协同作用。
结果如图4所示,联合指数计算结果表明,熊果酸/索拉非尼无载体自组装纳米粒-1在Fa≥0.4时,熊果酸和索拉非尼在HepG2细胞作用后的CI<1,即说明熊果酸和索拉非尼在抑制肝癌细胞增殖生长具有协同作用。
实施例5 荧光染料、穿膜肽、核酸适配体功能化修饰的自组装纳米系统的构建
为使熊果酸/索拉非尼无载体自组装纳米粒兼具成像作用,引入荧光染料吲哚菁绿(标记为纳米-4)。具体地,将4 mg/mL的吲哚菁绿甲醇溶液与4 mg/mL的熊果酸甲醇溶液、4 mg/mL的索拉非尼甲醇溶液按1:2:0.5的体积比混合均匀后,取0.0875 mL混合溶液匀速滴加至 1 mL超纯水中,在室温、超声频率40 kHz、超声功率250 W 条件下超声分散,用氮吹仪吹干甲醇,即得吲哚菁绿标记的熊果酸/索拉非尼无载体自组装纳米粒的水溶液,将该纳米粒标记为纳米-4。
同时为了使纳米-4具有更好的细胞摄取及靶向效果,利用穿膜肽与核酸适配体正负电荷之间的吸引力,制备穿膜肽/核酸适配体复合物,具体为:将2 mg/mL的穿膜肽溶液与1.47 mg/mL的核酸适配体溶液按照1:0.5~8的体积比进行混合,在室温孵育4 h后,取0.02mL混合溶液逐滴加入至 1 mL纳米-4的水溶液中,随后置于超声仪中室温超声10~20 min,超声频率为40 kHz ,超声功率250 W,再在超纯水中透析过夜以除去游离的药物,即得穿膜肽/核酸适配体修饰的自组装纳米粒的水溶液,将该纳米粒标记为纳米-5。
实施例6 体外细胞摄取实验
以游离吲哚菁绿(0.005 mg/mL ICG)作为对照,通过观察细胞内的荧光强弱考察LO2细胞(阴性细胞)与HepG2 细胞(阳性细胞)对纳米粒的摄取情况,具体步骤为:将细胞以5.0×104个/孔的密度铺在24孔板内,置于37℃、5%CO2培养箱中过夜培养至细胞贴壁;去除旧培养基,每孔加入1 mL 含有不同纳米粒的DMEM培养基或是RPMI 1640与细胞在37 ℃下共孵育2 h后,用生理盐水清洗细胞两遍;用4%多聚甲醇进行固定后,将细胞与Hoechst33342细胞核染料孵育20 min,再用共聚焦显微镜进行观察。
如图6所示,当用游离吲哚菁绿处理LO2细胞与HepG2 细胞时,细胞内仅可产生较弱的红色荧光;而用吲哚菁绿标记的纳米-4与纳米-5处理LO2细胞与HepG2 细胞时,在 LO2细胞和HepG2细胞内可观察到较强的红色荧光。由此可证明,纳米-4与纳米-5进入LO2细胞、HepG2 细胞的量要比游离吲哚菁绿多;同时,HepG2细胞高表达适配体,因此穿膜肽/核酸适配体功能化修饰的自组装纳米-5在HepG2 细胞中的红色荧光强于低表达适配体的LO2细胞,证明其靶向性。
同时按照实施例4的方法,测定细胞活力以评估游离熊果酸,游离索拉非尼,纳米-1、游离熊果酸+游离索拉非尼、纳米-5对HepG2细胞的增殖抑制活性。如图7所示,结果表明,随着药物浓度的增加,HepG2细胞的存活率降低,但因纳米-5表面修饰适配体,其对HepG2细胞毒性强于其他纳米组,再次表明了纳米-5的良好靶向性。
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 (3)
1.一种靶向抑制HepG2肝癌细胞的无载体双药自组装纳米粒的制备方法,其特征在于:其是利用溶剂交换法将化疗药物索拉非尼与天然产物熊果酸通过π-烷基键、烷基键、氢键自组装形成纳米粒,然后将吲哚菁绿物理吸附到纳米粒中,并在纳米粒表面修饰核酸适配体及细胞穿膜肽,从而制得所述无载体双药自组装纳米粒;
所述无载体双药自组装纳米粒的制备方法具体包括以下步骤:
1)将熊果酸、索拉非尼及吲哚菁绿分别溶于良性溶剂中,得到熊果酸溶液、索拉非尼溶液和吲哚菁绿溶液;
2)将熊果酸溶液、索拉非尼溶液和吲哚菁绿溶液按照一定体积比混合,得到混合溶液1;
3)将混合溶液1滴加至超纯水中,室温下超声分散10 ~ 20 min,随后氮吹吹干良性溶剂,得到混合溶液2;
4)将穿膜肽溶液与核酸适配体溶液按照一定体积比进行混合,室温孵育4 h,得到混合溶液3;
5)将混合溶液3滴加至混合溶液2中,室温下超声分散10 ~ 20 min,随后在超纯水中透析过夜,即得到所述无载体双药自组装纳米粒的水溶液;
步骤1)中,所述良性溶剂为无水甲醇、无水乙醇、二甲基亚砜中的任意一种,所述熊果酸溶液的浓度为4 mg/mL,所述索拉非尼溶液的浓度为4 mg/mL,所述吲哚菁绿溶液的浓度为4 mg/mL;
步骤2)中,所述熊果酸溶液:索拉非尼溶液:吲哚菁绿溶液的体积比为1:0.25:0.5;
步骤3)中,所述混合溶液1:超纯水的体积比为1:10;所述超声功率为250 W,超声频率为40 kHz;
步骤4)中,所述穿膜肽为低分子量鱼精蛋白LMWP,所述核酸适配体为EpCAM适配体,所述穿膜肽溶液浓度为2 mg/mL,所述核酸适配体溶液浓度为1 .47 mg/mL;所述穿膜肽溶液:核酸适配体溶液的体积比为1:0.5 ~ 8;
步骤5)中,所述混合溶液3:混合溶液2的体积比为1:50;所述超声功率为250 W,超声频率为40 kHz。
2.一种利用权利要求1所述制备方法制得的无载体双药自组装纳米粒。
3.如权利要求2所述的无载体双药自组装纳米粒在制备治疗肝癌的药物中的应用。
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