CN114788822A - 野黄芩素在制备治疗胰腺癌药物中的应用 - Google Patents
野黄芩素在制备治疗胰腺癌药物中的应用 Download PDFInfo
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- CN114788822A CN114788822A CN202210583952.5A CN202210583952A CN114788822A CN 114788822 A CN114788822 A CN 114788822A CN 202210583952 A CN202210583952 A CN 202210583952A CN 114788822 A CN114788822 A CN 114788822A
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- Prior art keywords
- acid
- scutellarein
- pancreatic cancer
- panc
- treatment
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Abstract
本发明公开了野黄芩素在制备治疗胰腺癌药物中的应用。本发明首次将野黄芩素应用于胰腺癌的治疗中，在体外选用胰腺癌细胞系PANC‑1为检测模型，给予野黄芩素处理，结果显示野黄芩素能显著抑制胰腺癌细胞PANC‑1细胞增殖、克隆形成，体内实验选用BALB/c Nude裸鼠接种PANC‑1细胞，腹腔注射野黄芩素处理，结果显示野黄芩素可抑制给药裸鼠移植瘤增长，与对照组相比抑瘤率具有显著性差异。以上结果表明野黄芩素在体内外均对胰腺癌均具有抑制作用，且体内实验给药剂量下未显示明显毒性，提示野黄芩素用于胰腺癌治疗具有较好安全性。因此野黄芩素及其药用盐在胰腺癌治疗和预防方面具有很好的应用前景。
Description
技术领域
本发明属于医药技术领域，具体涉及野黄芩素在制备治疗胰腺癌药物中的应用。
背景技术
胰腺癌具有侵袭性强、早期诊断困难、转移和死亡率高等特点，是死亡率最高的恶性肿瘤。目前临床上胰腺癌治疗手段主要为外科切除以及化学药物治疗。手术根治性切除是胰腺癌最有效的治疗方式，几乎是胰腺癌患者可以获得长期生存的唯一机会，但80%的初诊患者因为局部进展和远端转移, 在就诊时往往已经发展至中晚期失去根治性手术的机会，仅10%～20%的患者确诊时可以接受手术治疗。然而却不能从根本上改善胰腺癌患者的临床预后，作为全身性疾病，形态学的切除并不能从生物学上根治胰腺癌。即使能够手术切除,胰腺癌患者的中位生存时间也不足2年。
化疗不仅作为提高中晚期胰腺癌患者生活质量以及改善预后的重要手段，同而且在胰腺癌术前及术后治疗中起着重要作用。胰腺癌由于其特殊的生物学行为，胰腺癌药物研发和治疗进展一直落后于其他消化道肿瘤。胰腺癌间质组织丰富，大量纤维结缔组织形成的肿瘤微环境是化疗药物作用的壁垒，导致胰腺癌组织局部药物浓度底，化疗敏感性较差，进而使得胰腺癌化疗具有很大的局限性。
临床上治疗胰腺癌的一线药物为吉西他滨，已上市的胰腺癌靶向药物还有针对靶点EGFR的厄洛替尼、针对靶点mTOR的依维莫司等。在现有的化疗药物应用方面中，由于临床化疗药物单独应用有效率低、患者生存率改善有限、耐药性频发，因此以化疗药物为基础的联合化疗策略是胰腺癌治疗的主要策略。然而目前联合化疗方案虽然可在一定程度上提升胰腺癌疗效，但是仍然存在毒副作用明显，患者耐受性差等缺点，患者整体预后不佳。在新型药物治疗，如肿瘤靶向药物和肿瘤免疫药物治疗是肝胆胰肿瘤治疗领域的热点，仑伐替尼与帕博利珠单抗联合用药为肝癌治疗带来了颠覆性进展，但胰腺癌作为冷肿瘤其对肿瘤免疫治疗应答率低。此外，在分子分型和靶向药物研发方面，也难以通过分子分型指导胰腺癌个体化治疗。基于以上胰腺癌临床和治疗现状，目前针对胰腺癌尚无满意的药物治疗方案，提示了胰腺癌治疗新策略和新药物研发的迫切性和必要性，特别是高效低毒的新型胰腺癌治疗药物研发具有重要意义。
中药半枝莲为唇形科植物半枝莲Scutellaria barbata D.Don的干燥全草。黄酮类成分是半枝莲的有效药理成分，半枝莲中黄酮类成分种类多达50多种，分别为黄酮、二氢黄酮和黄酮苷类。2010版《中国药典》规定半枝莲中黄酮类成分含量不得低于1.50%。作为半枝莲中重要的黄酮类成分，野黄芩素不但具有多种生物学活性，且在其活性范围内具有较好的安全性。目前野黄芩素在胰腺癌方面的活性未见报道，且野黄芩素在胰腺癌治疗方面并无相关文献及专利公开。
发明内容
本发明的目的是提供野黄芩素在制备治疗胰腺癌药物中的应用。
本发明的目的是这样实现的，所述应用是野黄芩素或其药用盐作为唯一活性成分或活性成分之一在制备治疗胰腺癌药物中的应用。
野黄芩素的结构式如式（I）所示：
本发明的有益效果为：
本发明首次将野黄芩素应用于胰腺癌的治疗中，本发明在体外选用胰腺癌细胞系PANC-1为检测模型，给予野黄芩素处理，结果显示野黄芩素能显著抑制胰腺癌细胞PANC-1细胞增殖、克隆形成；体内实验选用BALB/c Nude裸鼠接种PANC-1细胞，腹腔注射野黄芩素处理，结果显示野黄芩素可抑制给药裸鼠移植瘤增长，与对照组相比抑瘤率具有显著性差异。综上可知，野黄芩素在体内外均对胰腺癌均具有抑制作用，且体内实验给药剂量下未显示明显毒性，说明野黄芩素用于胰腺癌治疗具有较好安全性。因此野黄芩素及其药用盐在胰腺癌治疗和预防方面具有很好的应用前景。
附图说明
图1为野黄芩素对胰腺癌细胞PANC-1的增殖的影响图；
图2为野黄芩素对胰腺癌细胞PANC-1的克隆的影响图，其中图A为野黄芩素对胰腺癌细胞PANC-1的克隆的形成的影响图，图B为野黄芩素对胰腺癌细胞PANC-1的克隆数量的影响的统计图；
图3为野黄芩素对胰腺癌细胞 PANC-1的迁移的影响图,其中，图A为细胞融合变化图，图B为细胞融合距离统计图；
图4为野黄芩素急性毒性实验结果，其中，图A为小鼠体重检测结果，图B为小鼠肾脏系数变化图，图C为小鼠肺脏系数变化图，图D为小鼠肝脏系数变化图，图E为小鼠肝脏系数变化图；
图5为50mg/kg野黄芩素对裸鼠胰腺癌移植瘤增长的影响图：图A为荷瘤裸鼠给予50mg/kg野黄芩素后的大小变化图，图B为裸鼠体重监测结果图，D为移植瘤瘤体大小变化图，E为移植瘤瘤体重量变化图，F为移植瘤瘤体体积变化图，G为50mg/kg野黄芩素的抑瘤效果图；
图6为野黄芩素的化学结构示意图。
具体实施方式
下面结合附图和实施例对本发明作进一步的详细说明，但不以任何方式对本发明加以限制，基于本发明教导所作的任何变换或改进，均落入本发明的保护范围。
本发明野黄芩素的应用为野黄芩素或其药用盐作为唯一活性成分或活性成分之一在制备治疗胰腺癌药物中的应用。
所述野黄芩素的结构如式（I）所示：
野黄芩素的临床给药剂量为5.54 mg/kg-22.16 mg/kg。
本发明进一步提供了一种治疗胰腺癌的药物组合物，以治疗有效量的野黄芩素或其药用盐为活性成分，加上药学上可接受的辅料或载体制备而成。
所述的药用盐指药学上可接受的盐，为化合物野黄芩素与有机酸，或无机酸，或无机碱、有机碱所形成的盐，所述无机酸为：盐酸、磷酸、硫酸、硝酸，所述有机酸为：甲酸、乙酸、丙酸、丁酸、己酸、庚酸、草酸、马来酸、酒石酸、柠檬酸、乙二酸、己二酸、天冬氨酸、苯磺酸、樟脑酸、樟脑磺酸、二葡糖酸、琥珀酸、环戊烷丙酸、十二烷基硫酸、乙磺酸、葡庚糖酸、甘油磷酸、半硫酸、延胡索酸、2-羟基乙磺酸、乳酸、甲磺酸、烟酸、2-萘磺酸、扑酸、果胶酯酸、3-苯基丙酸、苦味酸、新戊酸，所述无机碱、有机碱为：氢氧化钠、三羟甲基氨基甲烷、N-甲基-葡萄糖胺。
药学上可接受的载体包括但不限于卵磷脂、维生素E、聚乙二醇、丙二醇、丙三醇、吐温或其他药物制剂用的表明活性剂、氧化铝、硬脂酸铝、离子交换材料、缓冲物质如磷酸盐、山梨酸、聚乙烯吡咯酮、纤维素物质、聚乙烯醇、羧甲基纤维素钠、羊毛脂、环糊精等可用于促进本发明所述化合物、其药用盐或前药药物传递的载体。
药学上可接受的辅料包括但不限于：崩解剂如羧甲基淀粉钠、交联羧甲基纤维素钠、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、海藻酸钠等，粘合剂如聚维酮K30、微晶纤维素、褐藻酸钠等，填充剂如无水乳糖、淀粉、葡萄糖、乳糖珠粒等，润滑剂如十二烷基硫酸镁、硬脂酸镁等，以及其他赋形剂、增溶剂、香味剂、着色剂等。
所述药物组合物可通过肠道或者非肠道途径给药，给药剂型可以为而不限于为注射剂、粉针剂、粉剂、颗粒剂、胶囊、片剂或植入剂。
实施例1 野黄芩素在体内外环境对胰腺癌的影响
1、野黄芩素在体外对胰腺癌PANC-1细胞的增殖抑制作用
实验方法：（1）将对数生长期的PANC-1细胞接种于24孔培养
板中，每孔接种1×104个细胞，置于二氧化碳细胞培养箱中培养。
（2）细胞贴壁后，每孔分别加入0、12.5、25、50、100、200μM野黄芩素处理，每一给药浓度设7个处理孔，用于不同时间点收集细胞计数。
（3）给药后于0、1、2、3、4、5、6、7天取各处理组细胞计数，每次计数重复三次，实验独立重复三次。
（4）采用SPSS对数据进行统计学分析，采用GraphPad Prism 9作图。
实验结果：从图1可知，与对照组相比较，野黄芩素处理组PANC-1细胞的增殖能力明显下降，且野黄芩素对PANC-1细增殖抑制活性呈剂量依赖性，在低剂量12.5和25 μM剂量下即可观察到增殖抑制，50 μM及更高剂量下细胞增殖抑制活性显著，提示野黄芩素对胰腺癌具有抑制活性。
、野黄芩素在体外对胰腺癌PANC-1细胞克隆形成抑制作用
实验方法：（1）将对数生长期的PANC-1细胞接种于6孔培养板
中，每孔接种1000个，于二氧化碳细胞培养箱中培养。
（2）待细胞贴壁后，每孔分别加入0、1.57、3.13、6.25、12.5、25 μM浓度的野黄芩素处理细胞。
（3）处理24 h后，去除含药培养基，更换2 mL普通完全培养基继续培养。
（4）细胞培养14天后，去除各孔培养基，用PBS润洗，后加入4%多聚甲醛固定液，静置30 min。
（5）移除固定液，用PBS润洗后加入0.5%结晶紫染色液，静置15min。弃染液，缓慢冲洗去除多余染料。
（6）晾干并拍照，并使用Image J分析每孔形成的克隆数、采用SPSS对数据进行统计学分析，采用GraphPad Prism 9作图。
实验结果：图2显示，野黄芩素可有效地抑制胰腺癌PANC-1克
隆形成，且在较低剂量下即可发挥抑制作用，在12.5 μM的浓度下几乎无法形成克隆，进一步证明野黄芩素对胰腺癌具有增殖抑制活性，且一定程度上提示野黄芩素可抑制胰腺癌侵袭性。
、野黄芩素在体外对胰腺癌PANC-1细胞的迁移抑制作用
实验方法：（1）将划痕插件（规格：2孔）置于6孔培养皿中，
标准划痕宽度为500 μM，配制1.25×105个/mL的PANC-1细胞混悬液，插件每孔接种100 μL PANC-1细胞混悬液，于二氧化碳细胞培养箱中培养过夜。
（2）待细胞贴壁后，用0、12.5、25、50、100、200 μM的野黄芩素处理细胞。
（3）处理24h后，移除划痕插件，PBS润洗一次去除漂浮细胞，加入2mL完全培养基继续培养，并于0、24、48 h在显微镜下观察划痕融合情况。
（4）拍照并采用Image J定量划痕宽度，GraphPad Prism 9作图并采用SPSS软件进行统计分析。
实验结果：图3显示，在24 h时间点，对照组PANC-1细胞划
痕完全融合，而野黄芩素处理组细胞划痕融合受到明显抑制，在48 h时间点，100μM和200 μM野黄芩素处理的PANC-1细胞划痕仍不能完全融合，提示野黄芩素可明显抑制胰腺癌细胞的迁移，说明其具有抑制胰腺癌转移的活性。
、野黄芩素的急性毒性检测
实验步骤：
（1）实验动物分组：四周龄ICR雄性小鼠（18±2 g），适应性喂养3天后，随机分组，每组5只。
溶剂对照组：90%生理盐水+4%吐温80+6%DMSO
野黄芩素50 mg/kg组（低剂量组）：精密称取野黄芩素粉末+90%生理盐水+4%吐温80+6% DMSO制成浓度为5 mg/mL的工作液。
野黄芩素100 mg/kg组（中剂量组）：精密称取野黄芩素粉末+90%生理盐水+4%吐温80+6% DMSO制成浓度为10 mg/mL的工作液。
野黄芩素200 mg/kg组（高剂量组）：精密称取野黄芩素粉末+90%生理盐水+4%吐温80+6% DMSO制成浓度为20 mg/mL的工作液。
按照对应剂量给予野黄芩素腹腔注射，1次/天，连续给药7天。
（2）每天观察小鼠体征（观察指标：肤色、毛色、呼吸、眼口鼻分泌物、活动及存活情况）及检测小鼠体重。实验结束处死动物后，解剖检查各组小鼠心、肺、肝、肾等器官；生理盐水清洗脏器，按组别称量，并进行数据分析，脏器指数=脏器湿重（mg）/体质量（g）。
实验结果:图4显示，（1）给药后各组小鼠各项体征指标和行为
均正常，无小鼠死亡。（2）各组小鼠7天体重情况正常（图4A），对照组及野黄芩素低、中、高给药组小鼠体重均无明显降低趋势。（3）解剖后肉眼未见心、肝、脾、肺、肾、胃等重要脏器的异常改变（图4B-E），与对照组相比，野黄芩素样品低、中、高剂量组各脏器指数未见明显改变，提示野黄芩素对小鼠主要器官无明显毒性。按照给药剂量换算标准，野黄芩素用于人治疗时的安全剂量5.54 mg/kg-22.16 mg/kg。
、野黄芩素对胰腺癌裸鼠移植瘤的肿瘤增殖的抑制作用
实验方法：（1）肿瘤模型构建：BALB/cNude雌性裸鼠（16±2g）适应性喂养5天后，观察动物状态，无异常则进行实验。PANC-1胰腺癌细胞培养至对数生长期，胰酶消化收集细胞，以新鲜PBS溶液进行重悬，调整细胞浓度为8×107个/mL，将细胞悬液与预冷Matrix gel混合，每只注射200 μL接种至裸鼠右上肢皮下，每只裸鼠接种8×106个细胞。接种后观察裸鼠生长状态及成瘤情况，待其肿瘤体积约80 mm3时，模型构建成功，开始给予野黄芩素处理。
（2）分组给药:
溶剂对照组：90% 生理盐水+4% 吐温80+6% DMSO;
野黄芩素50 mg/kg组：精密称取野黄芩素粉末+9 %生理盐水+4% 吐温80+6% DMSO配制为浓度为5 mg/mL的工作液。
荷瘤裸鼠随机分组，即溶剂对照组、野黄芩素给药组（50 mg/kg），每组5只。荷瘤裸鼠分别腹腔注射对照溶剂和野黄芩素溶液，每48 h给药一次，给药周期为14天。
检测指标：给药期间监测裸鼠体征、体重、瘤体大小；实验结束时，对各组裸鼠拍照记录，处死动物后剥离瘤组织，称量瘤体重量，按照瘤体大小排列并拍照记录。
计算抑瘤率和脾脏系数：抑瘤率（%）=（对照组平均瘤重－野黄芩素样品组平均瘤重）/野黄芩素样品组平均瘤重×100；脾脏系数=W脾脏（mg）/W体重（g）。
实验结果：图5显示，与对照组相比，50mg/kg野黄芩素给药处理，可明显抑制胰腺癌裸鼠移植瘤的肿瘤增殖，且荷瘤鼠的体重监测（图5B）和脏器系数（图5C）实验结果显示未表现出明显毒性，以上结果表明野黄芩素在体内具有较好的抑制胰腺癌的活性，且安全性高，适于临床应用(按照给药剂量换算标准，野黄芩素用于人治疗时的有效剂量为5.54 mg/kg)。
实施例2 野黄芩素的制备
取干燥半枝莲饮片10 kg，粉碎后用95%乙醇在室温下冷浸三次，合并提取液，减压浓缩除去有机溶剂后得到半枝莲浸膏723 g，将半枝莲浸膏用石油醚、二氯甲烷、乙酸乙酯进行萃取，分别得到石油醚部位（238.8 g）、二氯甲烷部位（32.5 g）、乙酸乙酯（144.9 g）部位、水相部位（146.1 g），乙酸乙酯部位采用硅胶柱层析法以进一步分离，以氯仿-甲醇（100:1-2:1）梯度洗脱，收集合并氯仿：甲醇（20:1）部分进一步分离，浓缩，然后各馏分经多次正相硅胶柱、反向C18柱以及重结晶纯化得到单体化合物野黄芩素。
化合物野黄芩素：黄色粉末，ESI-MS m/z 287 [M+H]+；分子式为C15H10O6，波谱数据如下： 1H-NMR (400 MHz，DMSO-d 6) δ 6.57 (s, 1H), 6.73 (s，1H), 6.93 (d，J = 8.7Hz, 2H), 7.91 (d，J = 8.7 Hz, 2H), 8.74 (br s,1H), 10.35 (br s, 2H), 12.79 (s,1H)。
实施例3
按实施例2的方法先制得化合物野黄芩素，再采用有机酸（酒石酸，柠檬酸，甲酸，乙二酸等）或无机酸（盐酸，硫酸，磷酸等）制成盐，按常规加注射用水，精滤，灌封灭菌制成注射液。
实施例4
按实施例2的方法先制得化合物野黄芩素，利用有机酸（酒石酸，柠檬酸，甲酸，乙二酸等）或无机酸（盐酸，硫酸，磷酸等）制成盐，将其溶于无菌注射用水中，搅拌使溶，用无菌抽滤漏斗过滤，再无菌精滤，分装于2安瓿中，低温冷冻干燥后无菌熔封得粉针剂。
实施例5
按实施例2的方法先制得化合物野黄芩素，利用有机酸（酒石酸，柠檬酸，甲酸，乙二酸等）或无机酸（盐酸，硫酸，磷酸等）制成盐，与赋形剂重量比为9:1的比例加入赋形剂，制成粉剂。
实施例6
按实施例2的方法先制得化合物野黄芩素，利用有机酸（酒石酸，柠檬酸，甲酸，乙二酸等）或无机酸（盐酸，硫酸，磷酸等）制成盐，按其与赋形剂重量比为1:5-1:10的比例加入赋形剂，制粒压片。
实施例7
按实施例2的方法先制得化合物野黄芩素，按其与赋形剂重量比为3:1的比例加入赋形剂，制成胶囊或颗粒剂或冲剂。
Claims (6)
1.如下结构式（I）所示的化合物野黄芩素或其药用盐，
2.权利要求1所述野黄芩素或其药用盐作为唯一活性成分或活性成分之一在制备治疗胰腺癌药物中的应用。
3.一种治疗胰腺癌的药物组合物，其特征在于，以治疗有效量的野黄芩素或其药用盐为活性成分，加上药学上可接受的辅料或载体制备而成。
4.根据权利要求3所述的药物组合物，其特征在于，所述的药用盐指药学上可接受的盐，为化合物野黄芩素与有机酸，或无机酸，或无机碱、有机碱所形成的盐，所述无机酸为：盐酸、磷酸、硫酸、硝酸，所述有机酸为：甲酸、乙酸、丙酸、丁酸、己酸、庚酸、草酸、马来酸、酒石酸、柠檬酸、乙二酸、己二酸、天冬氨酸、苯磺酸、樟脑酸、樟脑磺酸、二葡糖酸、琥珀酸、环戊烷丙酸、十二烷基硫酸、乙磺酸、葡庚糖酸、甘油磷酸、半硫酸、延胡索酸、2-羟基乙磺酸、乳酸、甲磺酸、烟酸、2-萘磺酸、扑酸、果胶酯酸、3-苯基丙酸、苦味酸、新戊酸，所述无机碱、有机碱为：氢氧化钠、三羟甲基氨基甲烷、N-甲基-葡萄糖胺。
5.根据权利要求3所述的药物组合物，其特征在于，所述药物组合物可通过肠道或者非肠道途径给药，给药剂型为注射剂、粉针剂、粉剂、颗粒剂、胶囊、片剂或植入剂。
6.一种制备野黄芩素的方法，其特征在于，方法具体如下：
将干燥半枝莲饮片粉碎至400目，用95%乙醇浸提3-4次，合并提取液，减压浓缩除去有机溶剂后得到半枝莲浸膏；将浸膏依次用石油醚、二氯甲烷、乙酸乙酯进行萃取，乙酸乙酯部位采用硅胶柱层析，以体积比为100:1-2:1的氯仿-甲醇进行梯度洗脱，收集合并氯仿-甲醇体积比为20:1的洗脱液进一步分离，浓缩，经正相硅胶柱、反向Ｃ18柱以及重结晶纯化得到单体化合物野黄芩素。
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| 余柳莹: "野黄芩苷和吉西他滨单药及联合处理对人胰腺癌PANC-1细胞作用的影响及机制初步探讨" * |
| 张祎等: "半枝莲化学成分的分离与鉴定(II)" * |
| 汪琛媛等: "半枝莲黄酮类化学成分分析" * |
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| CN116947794B (zh) * | 2023-09-20 | 2023-11-28 | 云南中医药大学 | 一种四环环系重排桉烷型倍半萜类化合物及其制备方法和应用、药物组合物及其应用 |
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