CN113797340A - 一种抗肿瘤双药纳米制剂及其制备方法和应用 - Google Patents

一种抗肿瘤双药纳米制剂及其制备方法和应用 Download PDF

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CN113797340A
CN113797340A CN202010533049.9A CN202010533049A CN113797340A CN 113797340 A CN113797340 A CN 113797340A CN 202010533049 A CN202010533049 A CN 202010533049A CN 113797340 A CN113797340 A CN 113797340A
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张强
柳懿桓
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Abstract

本发明公开了一种抗肿瘤的双药纳米制剂，包括高分子材料、大蒜素、活性氧自由基产生剂等。该纳米药剂利用高分子材料包裹两种可诱导肿瘤细胞内活性氧自由基水平升高的药物，其中一种药物促进肿瘤细胞内生成更多的活性氧自由基，另一种药物抑制肿瘤细胞内的抗氧化系统功能，通过两种药物的协同效应，可显著提高肿瘤细胞内活性氧自由基水平，从而实现高效杀灭肿瘤细胞的效果。

Description

一种抗肿瘤双药纳米制剂及其制备方法和应用
技术领域
本发明属于医药技术领域，涉及一种抗肿瘤双药纳米制剂(药剂)及其制备方法和应用。
背景技术
癌症目前已经成为人类死亡的主要疾病之一。根据美国癌症学会报道，仅2018年全球癌症新增病例及癌症死亡病例就高达2760万，而2018年2月，我国国家癌症中心发布的数据显示，我国癌症新增病例数以及死亡病例数占据全球癌症新发病人数的20％以上，癌症治疗现状十分严峻。目前，临床上针对癌症的疗法主要有手术、化学药物疗法、放射疗法、光热治疗、光动力治疗、免疫治疗和生物分子靶向治疗、声动力治疗等，而这些疗法均存在各种缺陷，如毒副作用大，对转移肿瘤疗效差，极易产生耐药性等。因此，急需开发新型的抗肿瘤药剂。
近年来活性氧自由基的生物学功能及其在癌症发展中的潜在作用已经有很多报道。活性氧自由基是由所有需氧生物产生的具有高反应活性的小分子，包括过氧化氢，超氧化物和羟基自由基等。活性氧自由基同时也是一种重要的胞内信号分子，参与许多细胞生物过程的调节，例如免疫防御机制，细胞信号传导，细胞发育，药物代谢，病毒感染机制，以及癌症的发展等。活性氧自由基作为氧代谢的副产物，在生物体内通过各种复杂的合成和降解途径不断地在细胞中产生和从细胞中除去。活性氧自由基的生产和清除之间的动态平衡至关重要，而当这种平衡遭到破坏时，高浓度存在的活性氧自由基会使细胞产生一系列的氧化应激，而增加的氧化应激通过改变细胞内氧化还原状态、氧化修饰关键氨基酸残基来破坏细胞蛋白质，脂质和DNA，从而在细胞中产生衰老，退行或致命的病变，这些病变与许多人类疾病有关，包括癌症，心血管和神经-退行性疾病等。
选择性治疗在癌症治疗中是必不可少的。活性氧自由基在细胞内存在“阈值概念”。阈值概念认为适度增加活性氧自由基可促进细胞增殖和存活。然而，当活性氧自由基的增加达到一定水平(毒性阈值)时，它可能压倒细胞的抗氧化能力并引发细胞死亡。在生理条件下，正常细胞通过控制活性氧自由基产生(促氧化剂)和消除(抗氧化能力)之间的平衡，维持氧化还原稳态与低水平的活性氧自由基。正常细胞可以通过调动“储备”的抗氧化能力，可以耐受一定水平的外源性活性氧自由基应激，以防止活性氧自由基水平达到细胞死亡阈值。而在癌细胞中，由代谢异常和致癌信号传导引起的活性氧自由基维持在一个较高的水平，并且通过抗氧化能力的上调和氧化还原动力学的转变，将活性氧自由基水平维持在毒性阈值以下。因此，癌细胞将更多地依赖于抗氧化系统，并且更容易受到外源性物质诱导的氧化应激影响。使用外源性调节剂改变癌细胞中的活性氧自由基的应激，可能使活性氧自由基升高至毒性阈值水平以上，从而导致细胞死亡。这为设计以使用活性氧自由基介导机制，选择性杀死癌细胞的治疗策略提供了生物化学基础。
通常有两种方法可以提高癌细胞中活性氧自由基的水平。一种方法是引入促进活性氧自由基生成的试剂，另一种方法是破坏细胞的抗氧化系统。虽然活性氧自由基产生剂在单独使用的情况下是有效的，但是联合破坏抗氧化系统的药剂，可能更容易将癌细胞中的活性氧自由基升高至细胞毒性水平，而正常细胞仍处于适应性增殖振荡状态。
发明内容
为克服现有技术中存在的上述缺陷，本发明期望通过提高肿瘤细胞活性氧自由基和消耗肿瘤细胞内还原剂的双重机制来提高肿瘤细胞内活性氧自由基的水平，进而高效地杀死癌细胞。相关研究报道指出肉桂醛、漆黄素、吉马酮等能够提高细胞内的活性氧自由基水平，从而激发细胞的凋亡通路。大蒜素能够通过硫醇—二硫化物交换反应途径消耗细胞内的还原型谷胱甘肽上调活性氧自由基。在本发明中，提出制备一种协同提高活性氧自由基的双药(复合)纳米载药颗粒，通过协同提高肿瘤细胞内活性氧自由基水平，进而实现高效低毒的肿瘤治疗。
本发明提供了一种双药纳米制剂(新型的利用活性氧自由基实施抗肿瘤的纳米药剂)，所述纳米制剂包括高分子材料、大蒜素、活性氧自由基产生剂。
其中，所述高分子材料包括脂质体、聚乙二醇-聚乳酸乙醇酸、聚己内酯、白蛋白等中的一种或几种；优选地，为聚乙二醇-聚乳酸乙醇酸。
其中，所述活性氧自由基产生剂可以促进肿瘤细胞内生成更多的活性氧自由基，包括肉桂醛、漆黄素、吉马酮、香菇多糖、异土木香内酯、青蒿琥酯等中的一种或多种；优选地，为肉桂醛。
其中，所述大蒜素抑制肿瘤细胞内的抗氧化系统功能。
大蒜素是指从大蒜的鳞茎中提取的一种有机硫化合物，为二烯丙基三硫醚(dially trisulfied)。
其中，所述大蒜素、活性氧自由基产生剂两者协同可诱导肿瘤细胞内活性氧自由基水平升高。
其中，所述纳米药剂包括以下重量份的物质：高分子材料40-98份、活性氧自由基产生剂1-59份、大蒜素1-59份。
优选地，所述纳米药剂包括以下重量份的物质：高分子材料40-60份、活性氧自由基产生剂20-40份、大蒜素2-20份。
进一步优选地，所述纳米药剂包括以下重量份的物质：高分子材料59份、活性氧自由基产生剂39份、大蒜素2份。
其中，所述纳米制剂还可以包括肿瘤靶向分子，所述肿瘤靶向分子包括叶酸、RGD肽、透明质酸、双磷酸盐，但不限于此。
按所述纳米药剂各组分总重量为100份计算，所述纳米药剂中肿瘤靶向分子的重量份数为0-2份；优选地，为0-1份。
本发明还提供了一种双药纳米制剂的制备方法，利用高分子材料包裹大蒜素、活性氧自由基产生剂制备双药纳米制剂。
其中，所述高分子材料包括脂质体、聚乙二醇-聚乳酸乙醇酸、聚己内酯、白蛋白等中的一种或几种；优选地，为聚乙二醇-聚乳酸乙醇酸。
其中，所述大蒜素、活性氧自由基产生剂两者协同可诱导肿瘤细胞内活性氧自由基水平升高。
其中，所述活性氧自由基产生剂可以促进肿瘤细胞内生成更多的活性氧自由基，包括肉桂醛、漆黄素、吉马酮、香菇多糖、异土木香内酯、青蒿琥酯等中的一种或多种；优选地，为肉桂醛。
其中，所述大蒜素抑制肿瘤细胞内的抗氧化系统功能。
进一步地，还可以通过化学反应将肿瘤靶向分子修饰到所述高分子材料表面。
其中，所述肿瘤靶向分子包括叶酸、RGD肽、透明质酸、双磷酸盐，但不限于此。
其中，所述制备纳米制剂的方法包括纳米共沉淀法、单乳法、双乳法、化学链接法等中的一种或多种；优选地，为纳米共沉淀法。
其中，所述纳米制剂的制备方法以纳米共沉淀法为例，具体如下：
(1)按照原料组分的重量配比，分别量取20-40份活性氧自由基产生剂，2-20份大蒜素，40-60份高分子材料(载药材料)。
(2)将步骤(1)中量取的药物(活性氧自由基产生剂和大蒜素)和载药材料溶于1毫升的有机溶剂中，形成溶液。
(3)在搅拌的条件下，将步骤(2)的溶液缓慢滴入一定体积的磷酸盐缓冲液中，其中磷酸盐缓冲液和有机溶剂的体积比为3:1，形成液体。
(4)通过高速离心的方式去除步骤(3)液体中的有机溶剂，再用磷酸盐缓冲液洗涤5次。
本发明的创新点在于，利用纳米技术将两种可诱导肿瘤细胞内活性氧自由基水平升高的天然药物制备成双药(复合)纳米药剂，其中一种药物活性氧自由基产生剂促进肿瘤细胞内生成更多的活性氧自由基，另一种药物大蒜素抑制肿瘤细胞内的抗氧化系统功能；该纳米药剂可以通过提高肿瘤细胞活性氧自由基和消耗肿瘤细胞内还原剂的双重机制来提高肿瘤细胞内活性氧自由基的水平，进而高效地杀死癌细胞。
本发明还提供了由上述方法制备得到的双药纳米药剂。
本发明还提供了一种药物组合物，所述药物组合物包括双药纳米药剂及载体。
所述载体为脂质体、聚乙二醇-聚乳酸乙醇酸、聚己内酯、白蛋白等中的一种或几种构建出的纳米颗粒。
本发明还提供了所述双药纳米药剂、或药物组合物在制备抗肿瘤药物中的应用。
所述双药纳米药剂、或药物组合物用于诱导肿瘤细胞内活性氧自由基水平升高。
所述肿瘤包括但不限于乳腺癌、肺癌、肝癌、前列腺癌等。
本发明的有益效果在于：本发明制备的具有协同提高活性氧自由基的双药纳米载药颗粒，通过协同提高肿瘤细胞内活性氧自由基水平，进而实现高效低毒的肿瘤治疗。在双药纳米药剂颗粒中，肉桂醛与大蒜素均保持了一个较为缓慢的释放速率，在室温下该双药纳米药剂稳定性好。通过在治疗载体表面修饰肿瘤靶向分子，可以进一步提高纳米药剂的治疗效果。
附图说明
图1是本发明提出的一种抗乳腺癌的双药纳米载药颗粒的制备示意图。
图2是本发明的肉桂醛与大蒜素的双药纳米颗粒在制备好后拍摄的透射电子显微镜影像照片。
图3与图4是本发明的肉桂醛与大蒜素的双药纳米颗粒中肉桂醛与大蒜素在室温条件下的体外的释放曲线。
图5是本发明的肉桂醛与大蒜素的双药纳米颗粒在室温条件下的体外稳定性测试。
图6是本发明的肉桂醛与大蒜素的双药联合对乳腺癌细胞的体外协同抑瘤效果的评价。
图7是本发明的肉桂醛与大蒜素的双药纳米颗粒对乳腺癌细胞的体外协同抑瘤效果的评价。
具体实施方式
下面结合具体实施例，对本发明内容作进一步的说明。但是下文中的具体实施方法不应当被理解为对本发明的限制。
实施例1：
本发明进一步的优选方案，其是按照重量配比的组分为：由39份肉桂醛、2份大蒜素和59份载药材料混合组成。步骤一，按照原料组分的重量配比，分别量取39份肉桂醛、2份大蒜素和59份载药材料，载药材料为聚乙二醇-聚乳酸乙醇酸。步骤二，将步骤一中量取的肉桂醛、大蒜素和载药材料溶于1毫升的有机溶剂中。步骤三，将步骤二中获得的溶有肉桂醛、大蒜素和载药材料的有机溶剂，在搅拌的条件下缓慢滴入一定体积的磷酸盐缓冲液中，其中磷酸盐缓冲液和有机溶剂的体积比为3:1。步骤四，将步骤三中获得的液体，通过高速离心的方式去除有机溶剂，再用磷酸盐缓冲液洗涤5次。
以下结合附图对本发明中的肉桂醛与大蒜素的双药纳米药剂颗粒制备实施例进行进一步的说明。结合附图1，制备本发明提出的一种抗肿瘤的双药纳米药剂颗粒成品所采用的肉桂醛、大蒜素和载药材料等全部原料均为市售医药原料，具体规格如下：
1.肉桂醛：分子式为C9H8O，分子量为132.16，纯度为98％。
2.大蒜素；分子式为C6H10S3，分子量为178.34，纯度为98％。
3.载药材料：聚乙二醇-聚乳酸乙醇酸经过核磁验证。
4.溶剂：
(1)乙腈，HPLC级。
(2)蒸馏水，色谱纯。
本发明经过反复的验证，均取得了满意的效果。现以肉桂醛、大蒜素和聚乙二醇-聚乳酸乙醇酸混合制得的双药纳米载药颗粒为例：
透射电子显微镜影像照片显示。含有肉桂醛与大蒜素的双药纳米药剂颗粒为较为规则的圆形，表面光滑，粒径均一，均为180纳米左右的颗粒(图2)。在双药纳米药剂颗粒中，肉桂醛与大蒜素均保持了一个较为缓慢的释放速率(图3和图4)。此外，含有肉桂醛与大蒜素的双药纳米药剂颗粒在缓释溶液和10％的胎牛血清中保持很好的稳定性，在很长的一段时间内，该双药纳米药剂颗粒的粒径都没有明显的改变(图5)。
体外实验中，采用MTT的方法测定药物对乳腺癌细胞的杀灭效果，实验分为两组，分别为肉桂醛单药组，肉桂醛和大蒜素联合组，其中大蒜素的药物浓度是75微摩，肉桂醛的浓度在0-200微摩；图6显示肉桂醛和大蒜素的联合组的治疗效果明显优于肉桂醛单药组，并通过该实验确定肉桂醛的最佳药物浓度为50微摩。
进一步，利用聚乙二醇-聚乳酸乙醇酸包裹单药或联合药物制成纳米药剂，并测试纳米药剂的乳腺癌细胞杀灭效果，实验分为4组：对照组(PBS缓冲液)、单独包裹肉桂醛组(50微摩)、单独包裹大蒜素组(75微摩)、肉桂醛(50微摩)与大蒜素(75微摩)双药联合组。实验结果表明肉桂醛(50微摩)与大蒜素(75微摩)双药联合治疗组的癌细胞杀灭效果优于单药组的治疗效果。
本发明的保护内容不局限于以上实施例。在不背离发明构思的精神和范围下，本领域技术人员能够想到的变化和优点都被包括在本发明中，并且以所附的权利要求书为保护范围。

Claims (12)

1.一种双药纳米制剂，其特征在于，所述纳米制剂包括高分子材料、大蒜素、活性氧自由基产生剂。
2.如权利要求1所述的纳米制剂，其特征在于，所述高分子材料包括脂质体、聚乙二醇-聚乳酸乙醇酸、聚己内酯、白蛋白中的一种或几种。
3.如权利要求1所述的纳米制剂，其特征在于，所述活性氧自由基产生剂包括肉桂醛、漆黄素、吉马酮、香菇多糖、异土木香内酯、青蒿琥酯中的一种或多种。
4.如权利要求1所述的纳米制剂，其特征在于，所述纳米药剂包括以下重量份的物质：高分子材料40-98份、活性氧自由基产生剂1-59份、大蒜素1-59份。
5.如权利要求1所述的纳米制剂，其特征在于，所述纳米制剂还包括肿瘤靶向分子，所述肿瘤靶向分子包括叶酸、RGD肽、透明质酸、双磷酸盐。
6.如权利要求1所述的纳米制剂，其特征在于，利用所述高分子材料包裹大蒜素、活性氧自由基产生剂，制备双药纳米制剂。
7.一种双药纳米制剂的制备方法，其特征在于，利用高分子材料包裹大蒜素、活性氧自由基产生剂制备双药纳米制剂。
8.根据权利要求7所述的方法，其特征在于，所述高分子材料包括脂质体、聚乙二醇-聚乳酸乙醇酸、聚己内酯、白蛋白中的一种或几种；和/或，所述活性氧自由基产生剂包括肉桂醛、漆黄素、吉马酮、香菇多糖、异土木香内酯、青蒿琥酯中的一种或几种。
9.根据权利要求7或8所述方法制备得到的双药纳米制剂。
10.一种药物组合物，其特征在于，包括如权利要求1-6、9之任一项所述的双药纳米制剂及载体。
11.根据权利要求1-6、9之任一项所述的双药纳米制剂、或根据权利要求10所述的药物组合物在制备抗肿瘤药物中的应用。
12.根据权利要求11所述的应用，其特征在于，所述肿瘤包括乳腺癌、肺癌、肝癌、前列腺癌。
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