CN106821965A - 一种维甲酸多药共递送纳米粒溶液及其制备和应用 - Google Patents
一种维甲酸多药共递送纳米粒溶液及其制备和应用 Download PDFInfo
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Abstract
本发明涉及一种维甲酸多药共递送纳米粒溶液及其作为肿瘤治疗药物的应用。以维甲酸、组蛋白去乙酰化酶抑制剂、哌立福辛、乳化剂、基质、助溶剂为原料，通过溶剂稀释法一步合成维甲酸多药共递送纳米粒。配方中的基质、乳化剂、助溶剂为辅料，起到稳定纳米粒及调节粒径的作用；组蛋白去乙酰化酶抑制剂、哌立福辛作为辅助药物，用于逆转肿瘤细胞对维甲酸类药物的耐受；维甲酸作为主药，诱导肿瘤细胞分化与凋亡。各个成分相辅相成，协同发挥作用。本发明药物搭配合理，作用机制明确，制备工艺简单，具有肿瘤被动靶向性，有望应用于肿瘤治疗领域。
Description
技术领域
本发明涉及一种维甲酸多药共递送纳米粒及其作为肿瘤治疗药物的应用。
背景技术
1988年，我国学者成功应用全反式维甲酸(ATRA)对急性早幼粒细胞性白血病进行分化治疗，使急性早幼粒细胞白血病的缓解率由传统化疗的46％左右提升至95％左右。由此可见，分化治疗可能是根治恶性肿瘤的一个突破口。然而，目前在临床上，维甲酸仅用于治疗急性早幼粒细胞白血病，而并未用于其它恶性肿瘤的分化治疗。虽然在细胞水平，维甲酸及其衍生物的确能诱导一些实体瘤细胞分化与凋亡，但是维甲酸对这些肿瘤细胞的诱导分化作用十分有限，并且，很多肿瘤细胞，包括急性粒细胞白血病细胞也对维甲酸出现了不同程度的耐药。如果这种耐药问题得以解决，就为维甲酸应用于其它恶性肿瘤的分化治疗攻破了第一道屏障。
早期研究发现，组蛋白去乙酰化酶抑制剂对急性粒细胞白血病的维甲酸耐受具有逆转作用；近期研究表明，全反式维甲酸与组蛋白去乙酰化酶抑制剂联合应用也对其他肿瘤细胞，例如成神经细胞瘤细胞产生抑制生长的作用。13-顺式维甲酸与组蛋白去乙酰化酶抑制剂联合应用治疗实体瘤已有一期临床报道，并取得了很好的疗效。2014年，Cancer Research上的一篇文章从另一个角度揭示了维甲酸对很多其他恶性肿瘤疗效甚微的原因：星形细胞上调基因1(AEG-1)的过表达通过多种途径阻断了维甲酸的信号通路。AEG-1在胰腺癌、肺癌、骨肉瘤、胃癌等多种实体瘤组织中过表达，极有可能是阻碍维甲酸对这些肿瘤组织诱导分化的重要环节。
维甲酸、组蛋白去乙酰化酶抑制剂以及AEG-1抑制剂联用，构成以维甲酸为核心，多种药物辅助增效的多药体系，将有可能大幅提高实体瘤对维甲酸的敏感性，从而为维甲酸诱导实体瘤分化凋亡的临床应用奠定了基础。如果利用纳米材料对肿瘤组织的被动靶向性，将此维甲酸多药体系制成纳米粒，其疗效可能进一步提高。
发明内容
针对目前实体瘤对维甲酸耐受等问题，本发明提供了一种维甲酸多药共递送纳米粒的配方及制备方法，并将其应用于恶性肿瘤的治疗。
该配方搭配合理，各药物间协同作用机制明确，制备方法简便易行，所得纳米材料具有较高的稳定性及很好的抗肿瘤活性，是一种良好的抗肿瘤药物制剂。
本发明是通过以下技术方案来实现：
1.一种维甲酸多药共递送纳米粒溶液，除水溶剂外，此纳米粒溶液还包含以下溶质成分，溶质成分的质量组成为：维甲酸或其异构体1％-20％；组蛋白去乙酰化酶抑制剂0.5％-25％；哌立福辛0.5％-25％；基质0％-90％，乳化剂0％-90％，助溶剂0％-10％。
2.技术方案1所述的纳米粒，其制备方法由以下步骤组成：
(1)将维甲酸、组蛋白去乙酰化酶抑制剂、哌立福辛、乳化剂、基质、助溶剂溶于适量有机溶剂；
(2)将步骤(1)所制得的溶液在高速搅拌下加至水中，制得纳米粒；
(3)将步骤(2)所制得的纳米粒以透析、超滤、蒸发、冷冻干燥或喷雾干燥的方法除去有机溶剂、部分或全部水；得纳米粒或纳米粒水溶液；
(4)纳米粒或纳米粒水溶液放入水中，调成所需维甲酸多药共递送纳米粒溶液。
3.技术方案1所述的维甲酸或其异构体是全反式维甲酸、9-顺式维甲酸、13-顺式维甲酸中的一种或二种以上的任意比例组成的混合物。
4.技术方案1所述的组蛋白去乙酰化酶抑制剂是伏立诺他、西达本胺之中的一种或二种以任意比例组成的混合物。
5.技术方案1所述的基质是聚己内酯、聚己内酯-聚乙二醇嵌段共聚物、聚乳酸、聚羟基乙酸、乳酸-羟基乙酸共聚物中的一种或二种以上的任意比例组成的混合物。
6.技术方案1所述的乳化剂是卵磷脂、豆磷脂、泊洛沙姆188、聚氧乙烯蓖麻油、吐温80中的一种或二种以上的任意比例组成的混合物。
7.技术方案1所述的助溶剂是乙二胺、乙醇胺中的一种或二种以任意比例组成的混合物。
8.技术方案2中，步骤(1)所述有机溶剂是乙醇、丙酮、四氢呋喃中的一种或二种以上的任意比例组成的混合物。
9.技术方案1所述纳米粒溶液作为肿瘤治疗药物的应用。
配方中的基质、乳化剂、助溶剂为辅料，起到稳定纳米粒及调节粒径的作用；组蛋白去乙酰化酶抑制剂、哌立福辛作为辅助药物，用于逆转肿瘤细胞对维甲酸类药物的耐受；维甲酸及其异构体作为主药，诱导肿瘤细胞分化与凋亡。各个成分相辅相成，协同发挥作用。本发明药物搭配合理，作用机制明确，制备工艺简单，具有肿瘤被动靶向性，有望应用于肿瘤治疗领域。
具体实施方式
实施例1
将30.0mg全反式维甲酸、26.4mg伏立诺他、46.2mg哌立福辛、1.00g泊洛沙姆188、7μl乙二胺溶于20ml热乙醇。在高速搅拌下，将上述乙醇溶液缓缓加入80ml水中，旋转蒸发除去乙醇，得分散于水中的纳米粒。
实施例2
将300mg 9-顺式维甲酸、26.4mg伏立诺他、46.2mg哌立福辛、400mg聚己内酯、1.60g吐温80溶于由10ml乙醇及10ml丙酮组成的混合物中。在高速搅拌下，将上述溶液缓缓加入80ml水中，透析除去丙酮及乙醇，得分散于水中的纳米粒。
实施例3
将30mg全反式维甲酸、105.6mg伏立诺他、46.2mg哌立福辛、300mg聚己内酯-聚乙二醇嵌段共聚物溶于由10ml乙醇及10ml丙酮组成的混合物中。在高速搅拌下，将上述溶液缓缓加入80ml水中，先在真空下低温蒸发除去大部分丙酮及乙醇，随后冷冻干燥，得纳米粒粉末。
实施例4
将30mg全反式维甲酸、52.8mg伏立诺他、23.1mg哌立福辛、200mg卵磷脂、100mg泊洛沙姆溶于20ml热乙醇，在高速搅拌下，将上述乙醇溶液缓缓加入80ml水中，真空下低温蒸发除去大部分乙醇，得分散于水中的纳米粒。
实施例5
将30mg全反式维甲酸、39.0mg西达本胺、46.2mg哌立福辛、400mg聚己内酯、1.60g吐温80溶于由10ml乙醇及10ml丙酮组成的混合物中。在高速搅拌下，将上述溶液缓缓加入80ml水中，透析除去丙酮及乙醇，得分散于水中的纳米粒。
实施例6
将300mg全反式维甲酸、16.5mg伏立诺他、28.9mg哌立福辛、300mg聚己内酯、900mg泊洛沙姆溶于由10ml乙醇及10ml丙酮组成的混合物中。在高速搅拌下，将上述溶液缓缓加入80ml水中，透析除去丙酮及乙醇，并重新稀释到100ml，得分散于水中的纳米粒溶液。
另将MDA-MB-231乳腺癌细胞以8000cells/well的密度接种于96孔板中，孵育24h以使细胞贴壁。将上述纳米粒溶液以1640培养基稀释390倍，与细胞共培养48h，同时以不含药物的空白纳米粒作参照，以MTT法计算增殖率。实验结果显示，上述纳米粒能明显抑制MDA-MB-231细胞的增殖，具有较好的抗肿瘤效果。
Claims (10)
1.一种维甲酸多药共递送纳米粒溶液，除水溶剂外，此纳米粒溶液还包含以下溶质成分，溶质成分的质量组成为：维甲酸1％-20％；组蛋白去乙酰化酶抑制剂0.5％-25％；哌立福辛0.5％-25％；基质0％-90％，乳化剂0％-90％，助溶剂0％-10％；
溶质于水溶剂中的质量浓度为0.01-20％。
2.如权利要求1所述溶液，其特征在于：溶质成分的质量组成为：维甲酸1％-20％；组蛋白去乙酰化酶抑制剂0.5％-25％；哌立福辛0.5％-25％；基质0％-90％，乳化剂0％-90％，助溶剂0％-10％；溶质于水溶剂中的质量浓度为0.01-20％。
3.如权利要求1或2所述溶液，其特征在于：维甲酸是指全反式维甲酸、9-顺式维甲酸、13-顺式维甲酸中的一种或二种以上的任意比例组成的混合物。
4.如权利要求1或2所述溶液，其特征在于：组蛋白去乙酰化酶抑制剂是伏立诺他、西达本胺中的一种或二种以任意比例组成的混合物。
5.如权利要求1或2所述溶液，其特征在于：基质是聚己内酯、聚己内酯-聚乙二醇嵌段共聚物、聚乳酸、聚羟基乙酸、乳酸-羟基乙酸共聚物中的一种或二种以上的任意比例组成的混合物。
6.如权利要求1或2所述溶液，其特征在于：乳化剂是卵磷脂、豆磷脂、泊洛沙姆188、聚氧乙烯蓖麻油、吐温80中的一种或二种以上的任意比例组成的混合物。
7.如权利要求1或2所述溶液，其特征在于：助溶剂是乙二胺、乙醇胺中的一种或二种的任意比例组成的混合物。
8.一种权利要求1-7任一所述的纳米粒溶液的制备方法，由以下步骤组成：
(1)将维甲酸、组蛋白去乙酰化酶抑制剂、哌立福辛、乳化剂、基质、助溶剂溶于有机溶剂；
(2)将步骤(1)所制得的溶液在高速搅拌下加至水中，制得纳米粒；
(3)将步骤(2)所制得的纳米粒以透析、超滤、蒸发、冷冻干燥或喷雾干燥的方法除去有机溶剂、部分或全部水；得纳米粒或纳米粒水溶液；
(4)纳米粒或纳米粒水溶液放入水中，调成所需维甲酸多药共递送纳米粒溶液。
9.如权利要求8所述制备方法，其特征在于：步骤(1)所述有机溶剂是乙醇、丙酮、四氢呋喃之一或任意几种以任意比例组成的混合物。
10.一种权利要求1-7任一所述纳米粒溶液作为肿瘤治疗药物的应用。
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US10287353B2 (en) | 2016-05-11 | 2019-05-14 | Huya Bioscience International, Llc | Combination therapies of HDAC inhibitors and PD-1 inhibitors |
| US10385130B2 (en) | 2016-05-11 | 2019-08-20 | Huya Bioscience International, Llc | Combination therapies of HDAC inhibitors and PD-1 inhibitors |
| US10385131B2 (en) | 2016-05-11 | 2019-08-20 | Huya Bioscience International, Llc | Combination therapies of HDAC inhibitors and PD-L1 inhibitors |
| US11535670B2 (en) | 2016-05-11 | 2022-12-27 | Huyabio International, Llc | Combination therapies of HDAC inhibitors and PD-L1 inhibitors |
| CN112294810A (zh) * | 2019-07-29 | 2021-02-02 | 深圳微芯生物科技股份有限公司 | 含有西达本胺和表面活性剂的药物组合物 |
| WO2021018318A1 (zh) * | 2019-07-29 | 2021-02-04 | 深圳微芯生物科技股份有限公司 | 含有西达本胺和表面活性剂的药物组合物 |
| CN112294810B (zh) * | 2019-07-29 | 2024-03-01 | 深圳微芯生物科技股份有限公司 | 含有西达本胺和表面活性剂的药物组合物 |
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