CN118203668A - 一种协同抗胰腺肿瘤的药物组合物及应用 - Google Patents
一种协同抗胰腺肿瘤的药物组合物及应用 Download PDFInfo
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Abstract
本发明涉及联合用药技术领域,尤其涉及一种协同抗胰腺肿瘤的药物组合物及应用。本发明提供了一种协同抗胰腺肿瘤的药物组合物,所述药物组合物包括活性成分和药学上可接受的辅料,其中,所述活性成分包括IR/IGF1R抑制剂和CCK受体抑制剂。本发明提供的药物组合物,活性成分包括IR/IGF1R抑制剂和CCK受体抑制剂,两种抑制剂联合应用,可以协同降低胰腺肿瘤细胞的增殖,对胰腺肿瘤细胞有明显的抑制作用。
Description
技术领域
本发明涉及联合用药技术领域,尤其涉及一种协同抗胰腺肿瘤的药物组合物及应用。
背景技术
胰腺肿瘤是常见的消化系统恶性肿瘤,预后险恶。胰腺肿瘤在疾病早期阶段没有特异症状,所以被发现时多数患者已到疾病晚期,加之胰腺肿瘤细胞对放化疗不敏感,患者生存中位期小于半年。研究发现,胰腺肿瘤细胞能分泌某些生长因子并表达相应的受体,通过自分泌机制实现自我支持。这样的自分泌因子包括胰岛素样生长因子-1(IGF-1)、表皮生长因子(EGF)和转化生长因子(TGF);对应的受体则包括IGF-1的受体IGF1R和EGF/TGF的受体EGFR、HER2等。胰腺肿瘤细胞自分泌的IGF-1与旁分泌的胰岛素在结构上相似,而胰岛素受体(insμlin receptor,IR)与IGF-1受体(IGF1R)在结构上也相似。因此,胰岛素和IGF-1既激活自己的受体也激活对方的受体。IR/IGF1R被激活后,信号沿两条通路下传:一条通路由RAS-RAF-MEK-ERK等酶组成,另一条由RAS/IRS1-PI3K-AKT等酶组成。两条通路激活后均可刺激胰腺肿瘤细胞的生长、移行、糖酵解并通过表达血管内皮生长因子(VEGF)促进血管生成。针对胰腺肿瘤自分泌机制研发的受体抑制剂有很多,有些已在临床试用,但效果却不十分理想。
胰腺肿瘤细胞较位于其它脏器的肿瘤细胞有更强的生存和迁徙能力,究其原因,胰腺肿瘤细胞除享有自分泌支持外,还享有来自胰岛素的旁分泌支持和来自胃肠激素如胆囊收缩素/促胰酶素(cholecystokinin,CCK)的内分泌支持。CCK是一种多肽激素,由位于十二指肠、近端空肠粘膜中的I型内分泌细胞分泌。CCK通过位于胆囊、胃幽门、胰腺、小肠和脑中特定区域的CCK受体发挥了如抑制胃排空、胆囊收缩、胰腺生长、调节胰酶的分泌、调节饱腹感和控制食欲等作用。除此以外,CCK还能促进胰腺的生长并参与胰腺肿瘤的发生发展。因此,CCK及其受体是胰腺肿瘤治疗的潜在靶点。人正常的CCK靶细胞主要表达CCK 2型受体(CCK2R),而人胰腺肿瘤细胞则过度表达CCK2R。CCK2R属G蛋白偶联类受体(G protein-coμpled receptor,GPCR),激活后刺激多个信号传导系统。CCK2R的分子生物学机制尚未被完全阐明,所以,虽有多个CCK2R抑制剂出现,其抑制效果并不十分理想。近期发现,GPCR与IR/IGF1R两受体系统之间存在着信号偶联,但具体到CCK2R与IR/IGF1R的偶联状况则还不清楚。
发明内容
针对以上技术问题,本发明提供一种协同抗胰腺肿瘤的药物组合物,该组合物的活性成分包括R/IGF1R抑制剂和CCK受体抑制剂,两种抑制剂联合应用,可以协同降低胰腺肿瘤细胞的增殖,对胰腺肿瘤细胞有明显的抑制作用。
为解决上述技术问题,本发明实施例采用了如下技术方案:
第一方面,本发明实施例提供一种协同抗胰腺肿瘤的药物组合物,所述药物组合物包括活性成分和药学上可接受的辅料,其中,所述活性成分包括IR/IGF1R抑制剂和CCK受体抑制剂。
与现有技术相比,本发明实施例中药物组合物,通过利用IR/IGF1R抑制剂和CCK受体抑制剂为药物组合物的活性成分,可以降低胰腺肿瘤细胞的增殖,对胰腺肿瘤细胞有明显的抑制作用。
在本发明中,活性成分除了IR/IGF1R抑制剂和CCK受体抑制剂外,还可以加入EGFR受体抑制剂和/或HER2受体抑制剂。
优选的,所述活性成分为IR/IGF1R抑制剂和CCK受体抑制剂。
在本发明中,IR/IGFIR抑制剂抑制胰岛素受体(IR)和IGF-1受体(IGF1R)的激活,CCK受体抑制剂抑制抑制CCK2型受体(CCK2R)的激活,两者联合使用,可以协同降低胰腺肿瘤细胞的增殖,对胰腺肿瘤细胞进行抑制。
优选的,所述IR/IGF1R抑制剂包括表没食子儿茶素没食子酸酯、五没食子酰葡萄糖。
在本发明中,没食子儿茶素没食子酸酯(EGCE)是茶多酚中最有效的活性成分,属于儿茶素。五没食子酰葡萄糖(PGG)是一种天然的可水解没食子单宁,富含于各种植物和草药中。它具有广泛的生物活性,特别是抗癌活性和众多的分子靶点。EGCG可以抑制肿瘤细胞的侵袭和转移;调整肿瘤引发物的代谢过程;调控致癌物代谢酶类;抑制致癌基因和DNA的共价结合;抑制肿瘤细胞增殖过程;抑制亚硝化过程;显著的抗氧化、清除自由基,抗致突变作用,增强免疫系统功能,抑制肝脂和胆固醇的增长,抑制肿瘤的生长。
优选的,所述CCK受体抑制剂为YF476。在本发明中,YF476又叫Sograzepide,中文名为:N-[(3R)-1-(3,3-二甲基-2-氧代丁基)-2,3-二氢-2-氧代-5-(2-吡啶基)-1H-1,4-苯并二氮杂卓-3-基]-N’-[3-(甲基氨基)苯基]脲,是一种胃泌素/胆囊收缩素2受体拮抗剂。在本发明的CCK受体抑制剂中,不仅仅可以为YF476,只要能够抑制CCK2R激活的抑制剂均可以实现本发明的目的。
优选的,所述IR/IGF1R抑制剂和CCK受体抑制剂的质量比为40-60:1。更进一步的,所述IR/IGF1R抑制剂和CCK受体抑制剂的质量比为50:1。所述药物组合物为口服制剂或注射制剂。所述口服制剂包括胶囊剂、片剂或颗粒剂。
在本发明中,药物组合物可以是常规的制剂工艺制成的药物学上可接受的任意常规口服制剂或注射制剂,口服制剂如胶囊剂、片剂、颗粒剂或液剂,为使上述口服制剂能够实现,需在制备的过程中加入药学上可接受的辅料,所述药物学上可接受的辅料为填充剂、崩解剂、润滑剂、助悬剂、粘合剂或甜味剂等。
填充剂包括淀粉、乳糖、微晶纤维素或蔗糖中的至少一种;崩解剂包括淀粉、羧甲基淀粉钠、预胶化淀粉、低取代羟丙纤维素或交联羧甲基纤维素钠中的至少一种;润滑剂包括硬脂酸镁或二氧化硅、十二烷基硫酸钠中的至少一种;助悬剂包括聚乙烯吡咯烷酮、蔗糖或羟丙基甲基纤维素中的至少一种;粘合剂包括羟丙基甲基纤维素、淀粉浆或聚乙烯吡咯烷酮中的至少一种;甜味剂为糖精钠、甘草次酸、蔗糖、阿斯帕坦或甜蜜素中的至少一种。
为使上述注射制剂能够实现,需在制备的过程中加入药学上可接受的辅料,包括注射用水、注射用氯化钠溶液。
本发明以胰腺肿瘤中的MiaPaCa-2细胞作为研究对象,通过将IR/IGF1R抑制剂和CCK受体抑制剂进行联合用药,对MiaPaCa-2细胞进行体外抗癌活性测试。结果表明,IR/IGF1R抑制剂和CCK受体抑制剂相比单独使用IR/IGF1R抑制剂或CCK受体抑制剂,能明显抑制MiaPaCa-2细胞的增殖。
第二方面,本发明还提供了上述药物组合物在制备抗癌细胞药物中的应用。优选的,所述癌细胞包括胰腺癌细胞。
跟现有技术相比,本发明的技术方案具有如下有益效果之一:
本发明提供的药物组合物,活性成分包括IR/IGF1R抑制剂和CCK受体抑制剂,两种抑制剂联合应用,可以协同降低胰腺肿瘤细胞的增殖,对胰腺肿瘤细胞有明显的抑制作用。
附图说明
图1为本发明实验1-MTT实验的结果示意图;
图2为本发明实验2-抑制剂-裸鼠实验的结果示意图。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合具体实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用于解释本发明,并不用于限定本发明。
为了探究IR/IGFIR抑制剂和CCK抑制剂联合使用对胰腺肿瘤细胞的抑制上具有协同作用,进行以下实验。
在本发明的实验、实施例和试验例中:EGCG来自于索莱宝的E8120;YF476来自于MCE的HY-14850。
实验1
MTT实验
取对数生长期的野生型MiaPaCa-2细胞用0.25%胰酶消化,制成细胞悬液,接种于96孔板,每孔约5000个细胞,在37℃,5%CO2饱和湿度的培养箱中培养24h,平均分为四组,分别为空白对照组、EGCG组(E组)、YF476组(Y组)和联合用药组(E+Y组),每组24孔。用不含血清的DMEM培养基配制EGCG和YF476溶液,使其终浓度分别为50μmol/L和1nmol/L,弃掉细胞上清液。在E组的孔中加入50μmol/L的EGCG药液,在Y组的孔中加入1nmol/L的YF476药液,在E+Y组的孔中加入EGCG和YF476的混合药液,混合药液中EGCG的浓度为50μmol/L,YF476的浓度为1nmol/L。E组、Y组和E+Y组加入药液的体积均为100μL,空白对照组中不加入药液。分别孵育24和48小时后,每孔加入10μL噻唑蓝(MTT)溶液(5mg/ml,即0.5%MTT),继续培养4h,弃掉上清液,随后每孔加入150μL二甲基亚砜,置摇床上低速振荡10min,使结晶物充分溶解。最后在酶联免疫检测仪OD490nm处测量各孔的吸光值。结果如表1和图1所示。
表1 24、48小时后空白对照、E组、Y组和E+Y组细胞增殖率和抑制率
空白对照组 | E组 | Y组 | E+Y组 | |
24小时后细胞增殖率(%) | 100 | 67.01 | 75.24 | 56.01 |
24小时后细胞抑制率(%) | 0 | 32.99 | 24.76 | 43.99 |
48小时后细胞增殖率(%) | 100 | 52.62 | 72.57 | 40.61 |
48小时后细胞抑制率(%) | 0 | 47.38 | 27.43 | 59.39 |
通过表1和图1(左)可以看出,单独使用50μM EGCG能抑制MiaPaCa-2细胞的增殖(p<0.05),单独使用0.1nM YF476能抑制MiaPaCa-2细胞的增殖(p<0.05),当两者联合应用时,细胞增殖被明显抑制,且抑制作用具有叠加效果(p<0.05),通过图1(右)可以看出,两者作用48小时时,同样对MiaPaCa-2细胞增殖具有抑制作用。
实验2
抑制剂-裸鼠实验
皮下注射构建人胰腺癌动物模型:40只裸鼠在屏障系统中适应性喂养一周,MiaPaCa-2细胞调整为1.5×107个细胞/mL在小鼠右侧腋窝上注射,待瘤长成后随机分成4组,每组10只,分别设为对照组(CT组)、EGCG组(E组)、YF476组(Y组)和联合用药组(E+Y组);自由摄食水,CT组腹腔注射生理盐水,E组腹腔注射EGCG(25μg/g/day),Y组腹腔注射YF476(500ng/g/day),联合用药组(E+Y)腹腔注射EGCG(25μg/g)+YF476(500ng/g/d)。每日注射量为100μL。平均每三天记录一次肿瘤长径和短径及小鼠体重,饲养六周后,处死小鼠,摘除移植瘤,称重,测量瘤体积,并取4×4×4mm组织一处,标记后用多聚甲醛固定,其余瘤组织置于-80℃保存。
结果如图2所示,通过图2(A)可以看出,单独注射EGCG(E组)组小鼠肿瘤重量较对照组(CT组)小鼠的肿瘤明显降低(p<0.05),单独注射YF476组(Y组)小鼠肿瘤重量较对照组(CT组)小鼠的肿瘤明显降低,但差异无统计学意义,而联合用药组(E+Y组)较注射EGCG组(E组)小鼠肿瘤重量明显降低(p<0.05),较注射YF476组(Y组)小鼠肿瘤重量明显降低(p<0.01),表明联合治疗较单独用药对肿瘤的抑制作用更明显,具有很好的联合抑制效果。图2(B)显示的是四组小鼠的肿瘤体积,联合给予EGCG和YF476较单独用药对肿瘤体积具有明显的抑制效果(p<0.01)。
实施例1
本实施例提供了一种协同抗胰腺肿瘤的药物组合物,包含50kgEGCG,1kgYF476,800kg微晶纤维素,充分混匀后,罐装制成胶囊。
实施例2
本实施例提供了一种协同抗胰腺肿瘤的药物组合物,包含52kgEGCG,1kgYF476,700kg乳糖,混合均匀后,加入500kg淀粉制成淀粉浆,进行喷雾制粒。再加入150kg硬脂酸镁和100kg聚乙烯吡咯烷酮,混合均匀后,压片制成片剂。
实施例3
本实施例提供了一种协同抗胰腺肿瘤的药物组合物,包含45kgEGCG,1kgYF476,350kg淀粉,200kg羧甲基纤维素,真空干燥,混合均匀,过100目筛,制成颗粒剂。
实施例4
本实施例提供了一种协同抗胰腺肿瘤的药物组合物,包含50kgEGCG,1kgYF476,溶于1000kg注射用水后混匀,制成注射液。
实施例5
本实施例提供了一种协同抗胰腺肿瘤的药物组合物,包含60kgEGCG,1kgYF476,溶于1000kg注射用水后混匀,制成注射液。
实施例6
本实施例提供了一种协同抗胰腺肿瘤的药物组合物,包含40kgEGCG,1kgYF476,溶于1000kg注射用水后混匀,制成注射液。
实施例7
本实施例提供了一种协同抗胰腺肿瘤的药物组合物,包含50kgPGG,1kgYF476,溶于1000kg注射用水后混匀,制成注射液。
实施例8
本实施例提供了一种协同抗胰腺肿瘤的药物组合物,包含55kgEGCG,1kgYF476,溶于1000kg注射用水后混匀,制成注射液。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换或改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种协同抗胰腺肿瘤的药物组合物,所述药物组合物包括活性成分和药学上可接受的辅料,其特征在于,其中,所述活性成分包括IR/IGF1R抑制剂和CCK受体抑制剂。
2.根据权利要求1所述的药物组合物,其特征在于,所述活性成分为IR/IGF1R抑制剂和CCK受体抑制剂。
3.根据权利要求1或2所述的药物组合物,其特征在于,所述IR/IGF1R抑制剂选自表没食子儿茶素没食子酸酯、五没食子酰葡萄糖中的一种或多种。
4.根据权利要求1或2所述的药物组合物,其特征在于,所述CCK受体抑制剂为YF476。
5.根据权利要求1所述的药物组合物,其特征在于,所述IR/IGF1R抑制剂和CCK受体抑制剂的质量比为40-60:1。
6.根据权利要求1所述的药物组合物,其特征在于,所述IR/IGF1R抑制剂和CCK受体抑制剂的质量比为50:1。
7.根据权利要求1-6任一项所述的药物组合物,其特征在于,所述药物组合物为口服制剂或注射制剂。
8.根据权利要求7所述的药物组合物,其特征在于,所述口服制剂包括胶囊剂、片剂或颗粒剂。
9.一种权利要求1-8任一项所述药物组合物在制备抗癌细胞药物中的应用。
10.根据权利要求9所述的应用,其特征在于,所述癌细胞包括胰腺癌细胞。
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