CN113599532A - 负载药物和胶原蛋白酶的白蛋白复合纳米颗粒、制备及应用 - Google Patents
负载药物和胶原蛋白酶的白蛋白复合纳米颗粒、制备及应用 Download PDFInfo
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Abstract
本发明公开了一种负载苦参碱衍生物Flavesine G和胶原蛋白酶的白蛋白复合纳米颗粒、制备及其在制备抗肿瘤药物中的应用,属于抗肿瘤药物技术领域。本发明首次发现Flavesine G具有高效的声动力效应,并采用超声法制备了负载中药单体苦参碱衍生物Flavesine G和胶原蛋白酶的白蛋白复合纳米颗粒。此方法操作简单、步骤少、重复性好、制备的复合纳米颗粒解决了Flavesine G的水溶性问题,并且在胶原蛋白酶的作用下提高了肿瘤靶向性;且Flavesine G在超声作用下对肿瘤细胞具有高效的杀伤性,表明其负载于白蛋白分子后具有广阔的抗肿瘤应用前景。本发明还公开了包含上述复合纳米颗粒的药物组合物、声敏剂以及声敏剂递药系统。
Description
技术领域
本发明涉及抗肿瘤药物技术领域,尤其涉及一种负载中药单体苦参碱衍生物Flavesine G和胶原蛋白酶的白蛋白复合纳米颗粒、制备方法及应用。
背景技术
近年来,恶性肿瘤的发病率逐年升高,已经成为我国致死率最高的疾病。目前的恶性肿瘤的治疗方法主要为手术切除、化疗和放疗等。但是恶性肿瘤常呈浸润性生长,手术切除难以全部精确切除干净,加上化疗药物的肿瘤靶向性不佳,大部分化疗药物难以有效地达到病灶位置,这种缺乏特异性的化疗和放射治疗不仅能把肿瘤组织杀死还对正常组织强烈的损伤,因此会造成严重的副作用,却依然无法阻止恶性肿瘤复发并快速增殖。由于实体瘤具备纤维组织的物理屏障,屏障内的肿瘤微环境是低氧、低pH、营养缺陷、高渗透压的环境,恶性肿瘤的治疗仍面临重重挑战。因此,发展高特异性和高效低毒的癌症治疗手段去减少化疗药物的毒副作用,增强治疗效果,是近年来肿瘤治疗急需解决的问题。
近年来,超声波由于其强的组织穿透性被广泛关注。声动力治疗(SDT)就是依赖超声波和声敏剂使氧气变为具有细胞毒性的活性氧(ROS),从而起到杀伤肿瘤细胞的作用。超声可以穿透组织的深度大于10cm,其深的穿透特性,非侵入和时空可控的优势而成为肿瘤治疗领域的研究热点。因此,声动力疗法在深层恶性瘤治疗中具有重大意义。
中国医药博大精深,为现代药物的发现和发展提供了丰富的基础。目前,美国FDA批准的中药制剂共有97种,例如,用作抗哮喘药物的麻黄素,这来源于中医草药黄马;疟疾的一线药物青蒿素(青蒿素),来源于中药青蒿等等。目前有文献报道,某些中药所含有的活性成分如姜黄素、竹红菌乙素、叶绿素衍生物、金丝桃素和黄连素等具有良好的声敏活性,且安全低毒,可作为潜在的声敏剂,因此中药中的有效成分并进一步剖析其作用机制为新的治疗方法提供了一个有前景的起点。
研究证明,以纳米载药系统为核心的靶向药物在肿瘤治疗研究领域凸显了其优异的治疗效果。主要通过以下几个方面体现:首先,纳米技术可提高水难溶性药物在水溶液中的溶解性,达到增溶的目的,有效提高给药剂量。其次,粒径在30-200nm的颗粒可通过实体瘤血管的高通透和淋巴回流的滞留性(EPR效应)被动靶向到肿瘤组织;重要的是,纳米颗粒包载的药物在体内长循环中,降低了跟血液接触的机会,导致药物在血液循环中的半衰期显著提高。因此,纳米药物在靶向抗肿瘤研究具有优异的应用前景。人血清白蛋白是人血浆中的一种重要组成成分,具有很高的生物利用度、生物相容性、生物降解能力。结合纳米颗粒的载药功能和白蛋白的内源性两方面优势,白蛋白纳米载药系统近年来受到广泛关注,成为药物递送系统的研究热点。目前,紫杉醇白蛋白纳米颗粒注射液已于2005年1月获得美国FDA的批准上市,显示了人血清白蛋白作为静脉应用载体的广阔前景及临床应用价值。
传统声敏剂从光敏剂发展而来,面临声动力性能差、靶向差、氧依赖、光漂白等问题,且其水溶性和生物相容性差等缺点,严重限制了其在生物学领域的应用。然而,目前研发的纳米声敏剂仅针对声动力治疗的靶向或者增氧进行改进,却难以实现实质性的声动力性能的提升。本发明的目的以中药单体苦参碱衍生物Flavesine G作为声敏剂,同时为了解决Flavesine G的水溶性和靶向性问题,合成中药单体苦参碱衍生物Flavesine G的纳米颗粒(Flavesine G-CGsNPs,FCNPs)构筑靶向高效纳米声敏剂来提高声动力疗效,为中药单体声敏剂纳米颗粒的合成及在生物学上的应用提供新的思路。
发明内容
针对上述技术问题,本发明目的是提供一种可作为声敏剂的负载中药单体苦参碱衍生物Flavesine G和胶原蛋白酶的白蛋白复合纳米颗粒的制备及应用。
为实现上述目的,本发明采取的技术方案为:
本发明第一方面提供一种负载药物和胶原蛋白酶的白蛋白复合纳米颗粒,由白蛋白作为载体包裹药物和胶原蛋白酶,所述白蛋白、所述药物、所述胶原蛋白酶共价结合;其中所述药物为中药单体苦参碱衍生物Flavesine G,具有式(I)所示结构:
在本发明的技术方案中,所述白蛋白来源于哺乳动物,优选为人血清白蛋白。
本发明第二方面提供上述白蛋白复合纳米颗粒的制备方法,包括如下步骤:
①称取药物溶解在有机溶剂中;
②分别称取白蛋白20-40mg和胶原蛋白酶5-10mg于H2O中,轻摇至全溶;
③将步骤①所得的溶液加入到步骤②得到的混合溶液中;
④超声去除有机溶剂,同时得到纳米复合体系;
⑤向步骤④得到的纳米复合体系中加入碳酸钠溶液,经超声清洗波中超声处理后,得到纳米颗粒水溶液;
⑥超滤和/或透析去除纳米体系中游离小分子;
⑦过滤后,即得负载药物和胶原蛋白酶的白蛋白复合纳米颗粒。
在本发明的技术方案中,步骤①中,所述药物为中药单体苦参碱衍生物FlavesineG;所述有机溶剂为甲醇与氯仿体积比1:3~6的混合溶剂;所述药物在所述有机溶剂中的浓度为0.5-2mg/ml。
步骤②中,所述白蛋白在水中的浓度为20-40mg/mL,所述胶原蛋白酶在水中的浓度为5-10mg/mL。
步骤④中,所述超声为间歇超声,优选为冰水浴保护下间歇超声;具体可为超声1~2s,间隔1~2s,时长5-10分钟。
步骤⑤中,每2毫升纳米复合体系中加入0.1mol/L的碳酸钠100-200μL;所述超声时间为5-10分钟。
步骤⑦中,所述过筛为经0.22μm的过滤膜过筛。
在本发明的技术方案中,通过上述方法制备的白蛋白复合纳米颗粒粒径范围在68-300nm,具体可为68nm、100nm、150nm、200nm、250nm、300nm或它们之间的任意数值。
本发明第三方面提供上述白蛋白复合纳米颗粒在制备抗肿瘤药物中的应用。
具体地,在制备声动力抗肿瘤药物中的应用。
本发明第四方面提供包含上述白蛋白复合纳米颗粒的药物组合物,所述药物组合物为声动力抗肿瘤靶向药物组合物。
本发明第五方面提供一种声敏剂,所述声敏剂包含上述白蛋白复合纳米颗粒。
本发明第六方面提供一种包含上述白蛋白复合纳米颗粒的声敏剂递药系统,所述递药系统通过胶原蛋白酶破坏实体肿瘤组织内部的病理屏障使药物进入肿瘤组织,并利用人血清白蛋白的营养靶向和淋巴回流的滞留性(EPR效应)使所述声敏剂滞留于肿瘤组织。
上述技术方案具有如下优点或者有益效果:
本发明首次发现中药单体苦参碱衍生物Flavesine G的声动力效应,并利用白蛋白作为载体,构建一种包裹胶原蛋白酶和中药单体苦参碱衍生物Flavesine G的复合纳米颗粒(Flavesine G-CGsNPs,FCNPs),具有良好的生物相容性和肿瘤靶向性,可作为新型纳米声敏剂递药系统应用于抗肿瘤治疗。其中,Flavesine G作为中药单体和白蛋白、胶原蛋白酶均具有良好的生物相容性。且中药单体苦参碱衍生物Flavesine G作为平面大分子具有特殊的光电性能,在光、声动力条件下具有杀伤肿瘤的作用。胶原蛋白酶则可以剪切实体肿瘤纤维组织的物理屏障-胶原蛋白,使更多的纳米颗粒进入肿瘤部位,同时改善肿瘤的缺氧微环境进一步增强纳米声敏剂的声动力治疗效果,而白蛋白则具有营养靶向特点,赋予纳米颗粒以肿瘤靶向性,促使更多的纳米颗粒进入肿瘤中,增强纳米颗粒对肿瘤细胞的靶向性。本发明进一步揭示声动力治疗肿瘤的分子生物学机制,为中药单体应用在肿瘤的精准的无创的声动力治疗提供新的思路。
本发明提供的复合纳米颗粒的制备方法,快速简洁,无需引入其它有机分子,不需要使用有毒性的化学连接剂,且制备出来的复合纳米颗粒尺寸可控、性质稳定,解决了中药单体的水溶性和生物相容性问题,为中药单体新型声敏剂纳米颗粒的合成及在抗肿瘤治疗的应用提供新的思路。
附图说明
图1为实施例2中的负载中药单体苦参碱衍生物Flavesine G和胶原蛋白酶的白蛋白复合纳米颗粒(FCNPs)的合成及结构示意图。
图2为实施例1和实施例2中的Flavesine G白蛋白纳米颗粒(FNPs)和Flavesine G和胶原蛋白酶白蛋白纳米颗粒(FCNPs)的粒径图。
图3为实施例3中对Flavesine G白蛋白纳米颗粒(FNPs)和Flavesine G和胶原蛋白酶白蛋白纳米颗粒(FCNPs)的稳定性考察图。
图4为实施例4中对Flavesine G白蛋白纳米颗粒(FNPs)和Flavesine G和胶原蛋白酶白蛋白纳米颗粒(FCNPs)的超声激发产生的ROS强度曲线。
图5为实施例5中对Flavesine G白蛋白纳米颗粒(FNPs)和Flavesine G和胶原蛋白酶白蛋白纳米颗粒(FCNPs)对肿瘤细胞增殖的抑制作用。
具体实施方式
下述实施例仅仅是本发明的一部分实施例,而不是全部的实施例。因此,以下提供的本发明实施例中的详细描述并非旨在限制要求保护的本发明的范围,而是仅仅表示本发明的选定实施例。基于本发明的实施例,本领域技术人员在没有作出创造性劳动的前提下所获得的所有其他实施例,都属于本发明的保护范围。
下述实施例中,间歇超声具体为功率为30w,超声2s,间隔2s。
实施例1:中药单体苦参碱衍生物Flavesine G白蛋白纳米颗粒(FNPs)的合成
称取中药单体苦参碱衍生物Flavesine G 1mg溶解在200μL分析纯的氯仿和甲醇(氯仿:甲醇=3:1)混合液中;称取人血清白蛋白40mg于4mL H2O中,轻摇至全溶;将中药单体苦参碱衍生物Flavesine G的混合溶液加入到白蛋白溶液中;冰浴保护,间歇超声破碎5分钟,去除有机溶剂,同时得到纳米体系;加入0.1M的碳酸钠水溶液100μL,超声清洗波中超声5分钟,得到透明澄清纳米颗粒水溶液;超滤去除纳米体系中游离小分子;用0.22μm的过滤筛过滤后,得中药单体苦参碱衍生物的白蛋白纳米颗粒(FNPs),粒径范围在68-300nm,如图2所示,避光保存备用。
实施例2:中药单体苦参碱衍生物Flavesine G和胶原蛋白酶白蛋白纳米颗粒(FCNPs)的合成
称取中药单体苦参碱衍生物Flavesine G 1mg溶解在200μL分析纯的氯仿和甲醇(氯仿:甲醇=3:1)混合液中;称取人血清白蛋白40mg和胶原蛋白酶10mg于4mL H2O中,轻摇至全溶;将中药单体苦参碱衍生物Flavesine G的混合溶液加入到白蛋白和胶原蛋白酶混合溶液中;冰浴保护,间歇超声破碎5分钟,去除有机溶剂,同时得到纳米68-300nm体系;加入0.1M的碳酸钠水溶液100μL,超声清洗波中超声5分钟,得到透明澄清纳米颗粒水溶液;超滤去除纳米体系中游离小分子;用0.22μm的过滤筛过滤后,得中药单体苦参碱衍生物和胶原蛋白酶白蛋白纳米颗粒(FCNPs),避光保存备用。通过确定最佳的药物和载体的比例、超声的最佳时间和通过过滤筛整粒,保证了粒径的可控性。采用马尔文激光粒度仪检测粒径范围在68-300nm,如图2所示,FNPs和FCNPs的粒径没有明显差异,说明FNPs和FCNPs的制备方法稳定可控。收集的纳米颗粒避光保存备用。
实施例3:中药单体苦参碱衍生物Flavesine G和胶原蛋白酶白蛋白纳米颗粒稳定性考察
分别取新鲜制备的2mL含中药单体苦参碱衍生物Flavesine G 50μg/mL的中药单体苦参碱衍生物和胶原蛋白酶白蛋白纳米颗粒(FCNPs)和中药单体苦参碱衍生物白蛋白纳米颗粒(FNPs),分别在制备后的第1、4、7、10天用马尔文激光粒度仪检测其粒径大小,从而对纳米颗粒进行稳定性评价。结果如图3中显示,中药单体苦参碱衍生物和胶原蛋白酶白蛋白纳米颗粒(FCNPs)与中药单体苦参碱衍生物白蛋白纳米颗粒(FNPs)稳定性相当,具有较优的稳定性。
实施例4:中药单体苦参碱衍生物和胶原蛋白酶白蛋白纳米颗粒(FCNPs)在超声波触发下活性氧簇的产生
暗光条件下,在2mL含Flavesine G 50μg/mL的FCNPs中加入4μL 10μM2′,7′-二氯荧光素二乙酸盐(DCFH-DA)荧光探针,再加以超声(2MHz,2W)处理,检测超声不同时间产生活性氧簇。如图4所示,其中FCNPs为负载Flavesine G和胶原蛋白酶的白蛋白复合纳米颗粒,FNPs为负载Flavesine G的白蛋白纳米颗粒,H2O为无处理的对照组。超声后,中药单体苦参碱衍生物苦参碱和胶原蛋白酶白蛋白纳米颗粒(FCNPs)与中药单体苦参碱衍生物白蛋白纳米颗粒(FNPs)产生的活性氧簇均呈超声时间增加而增加,且FCNPs的累计产生量要优于FNPs,因此FCNPs可实现高效的声动力效果。
实施例5:中药单体苦参碱衍生物和胶原蛋白酶白蛋白纳米颗粒(FCNPs)在超声波激发下对肿瘤细胞增殖的抑制作用
设置实验组(FCNPs+US):将处于对数生长期的乳腺癌细胞MDA-MB-231细胞,以5×104个/孔接种于96孔板中,每孔加入1mL细胞悬液,于37℃培养箱中(含5%CO2)孵育24小时后,将纳米颗粒用培养基稀释到一定浓度后加入到细胞中。同时设置对照组:培养细胞不加胶原蛋白酶组(FNPs,FNPs+US)或无超声组(FCNPs)。继续孵育3小时后,将96孔板中需要超声处理的孔置于平面超声探头下,超声激发(2MHz,2W)2min,继续放置于培养箱中培养24小时后,加入MTT,4小时后去掉旧培养基,加入150-200μL DMSO然后放置于摇床震荡混匀15-20min,最后用多功能酶标仪检测OD(490)值,进而对肿瘤细胞的杀伤活性进行评价。
如图5所示,实验组(FCNPs+US)相对于对照组(FNPs+US)具有对肿瘤细胞的更强的杀伤效果,因此FCNPs具有声动力抗肿瘤效果,可作为肿瘤治疗的声动力治疗中的声敏剂。
以上所述仅为本发明的优选实施例,并非因此限制本发明的专利范围,凡是利用本发明说明书及附图内容所作的等效变换,或直接或间接运用在其他相关的技术领域,均同理包括在本发明的专利保护范围内。
Claims (10)
2.根据权利要求1所述的负载药物和胶原蛋白酶的白蛋白复合纳米颗粒,其特征在于,所述白蛋白来源于哺乳动物,优选为为人血清白蛋白。
3.根据权利要求1或2所述的负载药物和胶原蛋白酶的白蛋白复合纳米颗粒的制备方法,其特征在于,包括如下步骤:
①称取药物溶解在有机溶剂中;
②分别称取白蛋白20-40mg和胶原蛋白酶5-10mg于H2O中,轻摇至全溶;
③将步骤①所得的溶液加入到步骤②得到的混合溶液中;
④超声去除有机溶剂,同时得到纳米复合体系;
⑤向步骤④得到的纳米复合体系中加入碳酸钠溶液,经超声清洗波中超声处理后,得到纳米颗粒水溶液;
⑥超滤和/或透析去除纳米体系中的游离小分子;
⑦过滤后,即得负载药物和胶原蛋白酶的白蛋白复合纳米颗粒。
4.根据权利要求3所述的制备方法,其特征在于:
步骤①中,所述药物为中药单体苦参碱衍生物Flavesine G;所述有机溶剂为甲醇与氯仿体积比1:3-6的混合溶剂;所述药物在所述有机溶剂中的浓度为0.5-2mg/mL;
步骤②中,所述白蛋白在水中的浓度为20-40mg/mL;所述胶原蛋白酶在水中的浓度为5-10mg/mL;
步骤④中,所述超声为间歇超声,优选为冰水浴保护下间歇超声;
步骤⑤中,每2毫升纳米复合体系中加入0.1mol/L的碳酸钠100-200μL;优选地,所述超声时间为5-10分钟。
5.根据权利要求2所述的制备方法,其特征在于,所述白蛋白复合纳米颗粒粒径为68-300nm。
6.根据权利要求1或2所述的负载药物和胶原蛋白酶的白蛋白复合纳米颗粒在制备抗肿瘤药物中的应用。
7.根据权利要求6所述的应用,其特征在于,在制备声动力抗肿瘤药物中的应用。
8.包含权利要求1或2所述的负载药物和胶原蛋白酶的白蛋白复合纳米颗粒的药物组合物,其特征在于,所述药物组合物为声动力抗肿瘤靶向药物组合物。
9.一种声敏剂,其特征在于,包含权利要求1或2所述的负载药物和胶原蛋白酶的白蛋白复合纳米颗粒。
10.包含权利要求1或2所述的负载药物和胶原蛋白酶的白蛋白复合纳米颗粒的声敏剂递药系统。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115381793A (zh) * | 2022-08-22 | 2022-11-25 | 吉林大学 | 白蛋白负载阿苯达唑纳米药及其制备方法 |
CN115716830A (zh) * | 2022-09-01 | 2023-02-28 | 暨南大学附属第一医院(广州华侨医院) | 一种苦参碱型生物碱及其制备方法与在制备具有抗肺癌作用的药物中的应用 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112245580A (zh) * | 2020-10-26 | 2021-01-22 | 深圳先进技术研究院 | 一种靶向载氧纳米酶制剂及其制备方法 |
-
2021
- 2021-08-12 CN CN202110924707.1A patent/CN113599532A/zh active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112245580A (zh) * | 2020-10-26 | 2021-01-22 | 深圳先进技术研究院 | 一种靶向载氧纳米酶制剂及其制备方法 |
Non-Patent Citations (4)
Title |
---|
何伟;洪怡;李红艳;古禹;薛大权;: "苦参碱缓释微球的制备及体外释药研究", 中国医院药学杂志, no. 18 * |
孙佳星;李经纬;蔡爱露;: "低频超声联合苦参素对人卵巢癌OVCAR-3细胞生物学特性影响", 临床军医杂志, no. 01 * |
谭书想;: "苦参碱抗肿瘤作用及其机制研究进展", 中国医院用药评价与分析, no. 07 * |
郭跃虎;高毅;陈建锋;: "苦参碱对于人肝细胞冻存保护效应的实验性研究", 实用医学杂志, no. 12 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115381793A (zh) * | 2022-08-22 | 2022-11-25 | 吉林大学 | 白蛋白负载阿苯达唑纳米药及其制备方法 |
CN115381793B (zh) * | 2022-08-22 | 2023-11-21 | 吉林大学 | 白蛋白负载阿苯达唑纳米药及其制备方法 |
CN115716830A (zh) * | 2022-09-01 | 2023-02-28 | 暨南大学附属第一医院(广州华侨医院) | 一种苦参碱型生物碱及其制备方法与在制备具有抗肺癌作用的药物中的应用 |
CN115716830B (zh) * | 2022-09-01 | 2024-03-19 | 暨南大学附属第一医院(广州华侨医院) | 一种苦参碱型生物碱及其制备方法与在制备具有抗肺癌作用的药物中的应用 |
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