CN106727733B - 一种鲜冬虫夏草抗肿瘤化疗的联合药物及其应用 - Google Patents
一种鲜冬虫夏草抗肿瘤化疗的联合药物及其应用 Download PDFInfo
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Abstract
本发明公开了一种冬虫夏草抗肿瘤化疗的联合药物，包括鲜冬虫夏草提取物，顺铂，其中所述鲜冬虫夏草提取物是以鲜冬虫夏草为原料，以水为提取溶剂，采用闪式提取和超滤获得。更具体地为冬虫夏草提取物对肿瘤化疗辅助治疗具有减毒增效作用、能够增强化疗药物对肺癌细胞生长的抑制作用、对化疗药物引起的肝肾组织损伤具有保护作用。本发明提供的鲜冬虫夏草提取物对肿瘤化疗辅助治疗具有显著地减毒协同增效作用，并且首次发现对化疗药物引起的肝肾组织损伤具有保护作用，为其下一步研究新用途和研究药物作用机制提供科学依据和重要信息。
Description
技术领域
本发明涉及一种药物联合应用领域，具体涉及一种鲜冬虫夏草抗肿瘤化疗的联合药物及其应用。
背景技术
恶性肿瘤是目前危害人类生存和健康的主要疾病之一，其治疗手段主要包括手术、化疗和放疗。其中，手术治疗会受到病情的发展程度、病人的体质、有无其它疾病等条件的限制，通过手术等物理方式切除肿瘤，只能治标而并不能治本。而放疗作为治疗恶性肿瘤的一个重要手段，虽能产生很好的效果，但是会产生放射性皮炎、放射性食管炎以及食欲下降、恶心、呕吐、腹痛、腹泻或免疫力下降等诸多毒副作用。化学治疗是目前恶性肿瘤综合治疗中较为有效而又普遍使用的方法之一，但单纯化疗常引起免疫抑制和其他诸多不良反应和毒副作用，导致恶性反复感染，预后不良而加速患者的死亡等不良反应。如顺铂类化疗药物作为第一代抗肿瘤铂类药物对生殖***癌症、头颈癌和骨肉瘤等有非常好的治疗效果，在临床化疗或联合化疗治疗恶性肿瘤药物中所占比例为70％～80％，另外，对肺癌、胃癌、间皮瘤等实体肿瘤的临床治疗也能起到一定的作用，但是单独使用顺铂类药物会引起一定的副作用，例如严重的胃肠道反应、肾毒性、耳毒性、神经毒性，长期单独使用也会导致越来越严重的耐药性。因此，研发高效低毒，易于推广的可用于化疗增效减毒双重作用的天然中药成为临床亟待解决的问题。
冬虫夏草为麦角菌科真菌冬虫夏草菌Cordyceps sinensis(Berk.)Sacc.寄生在蝙蝠蛾科昆虫幼虫上的子座及幼虫尸体的复合体，是我国特产的名贵中药，含有核苷、多糖、蛋白、氨基酸等多种活性成分，传统中医认为具有补肺益肾、止血化痰等功效。已有大量研究表明，冬虫夏草具有抗疲劳、耐缺氧能力、抗病毒，对肝、肺、肾、心血管、免疫、神经等均有一定的调节作用，对黑色素瘤、胃癌、肺癌、甲状腺癌、乳腺癌等多种肿瘤细胞的增殖均有抑制作用。然而，现有文献报道都以阴干、烘干或者晒干冬虫夏草或者以冬虫夏草菌丝体发酵液、虫草花等为研究材料，且多采用煮沸、高温超声或回流提取获得提取物，这些处理方法可能会造成部分活性物质结构的变化，导致冬虫夏草的药理活性受到影响。目前很少有冬虫夏草联合化学药物抗肺部肿瘤的相关报道。如文献《冬虫夏草水煎剂联合顺铂对荷瘤小鼠抑瘤作用的实验研究》记载采用常规法高温加热煎煮获得冬虫夏草水煎剂，并联合顺铂研究对结肠癌HCTB荷瘤小鼠的抑瘤作用，结果显示冬虫夏草水煎剂联合顺铂能减轻接种HCTB荷瘤小鼠瘤体质量，而未提及冬虫夏草减轻顺铂的毒性作用。文献《冬虫夏草联合NP方案治疗晚期非小细胞肺癌的临床观察》中报道采用冬虫夏草颗粒(由日本国小林制药(株)中央研究所研究部提供，应为冬虫夏草发酵菌丝体)联合多种化疗药物包括NP方案中的长春瑞滨、顺铂治疗晚期非小细胞肺癌，该治疗方案联合使用多个化疗药物不仅成本高、而且使用冬虫夏草发酵产物，活性物质也不明确，且发现治疗组有效率、受益率仅为35.5％和58.8％，只是略高于仅服用化疗药物不服用冬虫夏草颗粒的对照组，治疗组生活质量卡氏评分变化也不是很大，此外治疗组还产生了一定毒副反应如出现恶心呕吐、感染。
发明内容
为解决现有技术存在的问题，本发明提供一种鲜冬虫夏草抗肿瘤化疗的联合药物及其应用。本发明提供的鲜冬虫夏草不经过晒干、烘干处理，并提供一种高效的提取方法。本发明所涉及的抗肿瘤化疗的联合药物中的鲜冬虫夏草提取物，与顺铂联合用药不仅有增效的作用，同时对肿瘤化疗引起的肝肾组织损伤也具有保护作用，具有较好的开发前景。
本发明的目的通过以下技术方案实现：
一方面，本发明提供了一种冬虫夏草抗肿瘤化疗的联合药物，包括鲜冬虫夏草提取物和顺铂，其中所述鲜冬虫夏草提取物是以鲜冬虫夏草为原料，以水为提取溶剂，采用闪式提取和超滤获得。
在一些实施例中，其中所述鲜冬虫夏草提取物是以新鲜采收的冬虫夏草为原料，以水为提取溶剂，控制温度在20℃～25℃，采用闪式提取，然后离心，收集上清液后超滤，并进行冷冻干燥处理所得。
在一些实施例中，其中所述鲜冬虫夏草提取物的制备方法包括以下步骤：
a、将鲜冬虫夏草剪碎，按鲜冬虫夏草和水的重量体积比加入1:10～12g/mL的水，浸泡3h～5h，控制温度为20℃～25℃；
b、将浸泡后的鲜冬虫夏草置于闪式提取器中提取，然后离心，收集上清液，控制温度为20℃～25℃；
c、将离心后的沉淀再加水，冷冻，再快速冻融，然后重复步骤b，进行闪式提取，离心，收集上清液；
d、将步骤b和步骤c所收集的上清液合并，加水稀释后，过滤，之后进行超滤；
e、将超滤后的保留液进行冷冻干燥，得到鲜冬虫夏草提取物。
在一些实施例中，其中在步骤b中，所述的闪式提取的条件为：闪式提取2次，每次提取时间为80s～120s，转速为8000rpm～10000rpm，电压为120V～160V；所述的离心的条件为：离心时间为15min，离心的转速为10000rpm～12000rpm。
在一些实施例中，其中在步骤c中，所述的沉淀和稀释用水的重量体积比为1:10～12g/mL；所述的冷冻温度为-20℃，冷冻时间为4h。
在一些实施例中，其中在步骤d中，所述上清液与水的体积比为1:4；所述的过滤的介质，是0.45μm的微膜；所述超滤的条件为：使用截留分子量大于5KDa的超滤膜，设定温度为25℃，时间为15min，压力为0.08KPa。
在一些实施例中，其中所述鲜冬虫夏草提取物的制备方法包括下述步骤：
a、将鲜冬虫夏草洗净沥干，剪碎至长度为0.2cm内，按鲜冬虫夏草与水的重量体积比加入1:10～1:12的水，浸泡3h～5h，控制温度为20℃～25℃；
b、将浸泡后的鲜冬虫夏草置于闪式提取器中，闪式提取2次，每次提取时间为80s～120s，转速为8000rpm～10000rpm，电压为120V～160V，然后离心15min，离心的转速为10000rpm～12000rpm，取上清液，控制温度为20℃～25℃；
c、将离心后的沉淀，按沉淀与水的重量体积比再加入1:10～1:12的水，置于-20℃的环境下冷冻4h，再快速冻融，然后重复步骤b，进行闪式提取，离心，收集上清液；
d、将步骤b和步骤c所收集的上清液合并，加水稀释4倍，使用0.45μm微膜过滤，之后使用截留分子量大于5KDa的超滤膜，设定温度为25℃，时间为15min，压力为0.08KPa进行超滤；
e、将超滤后的保留液进行冷冻干燥，得到鲜冬虫夏草提取物。
另一方面，本发明提供了一种本发明所述的联合药物在制备肿瘤化疗药物中的应用。
在一些实施例中，其中所述肿瘤化疗药物对肺癌Lewis细胞具有抑制作用。
在一些实施例中，其中所述肿瘤化疗药物对肿瘤化疗引起的肝肾组织损伤具有保护作用。
本发明所述的联合药物不限于其最终给予患者服用时的状态，可以为口服液或者胶囊剂型、片剂等形式。
本发明的积极效果：
1.鲜冬虫夏草药理活性研究尚处于空白领域，本发明采用闪式提取器在控制低温条件下提取鲜冬虫夏草中的大分子化学成分，很好的发挥了其药用功效。
2.本发明是首次发现鲜冬虫夏草冷水提取物与顺铂联合用药对肺部肿瘤化疗具有显著的协同增效和减毒的作用。
3.本发明首次发现鲜冬虫夏草冷水提取物与顺铂联合对肿瘤化疗引起的肝肾组织损伤具有保护作用。
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以解释本发明，并不用于限定本发明。
鲜冬虫夏草来源：宜昌山城水都冬虫夏草有限公司新鲜采收。
超声仪器来源及参数：KQ-500DB数控超声清洗机(昆山市超声仪器有限公司)，功率：500W；超声频率：40KHz。
离心设备来源：272R-3超大容量冷冻离心机(湖南湘离仪器厂)
一、制备实施例
实施例1
取鲜冬虫夏草10g，洗净后剪碎至长度为0.2cm内，加入100mL去离子水浸泡3h，控制温度在20℃～25℃。将浸泡后的鲜冬虫夏草置于闪式提取器中，控制温度在20℃～25℃，电压为120V，转速为8000rpm，时间为80s。10000rpm离心15min，收集上清液。将残渣置于-20℃环境中冷冻4h，再快速冻融。之后加入100mL去离子水，再置于闪式提取器中提取，离心，收集上清液。合并两次的上清液。将上清液加去离子水稀释4倍后，经0.45μm微膜过滤，之后使用超滤膜进行超滤，截留分子量大于5KDa的成分，设定温度为25℃，时间为15min，压力为0.08KPa。最后将超滤之后的保留液进行冷冻干燥，得到鲜冬虫夏草提取物1.62g，提取率为16.2％。
实施例2
取鲜冬虫夏草10g，洗净后剪碎至长度为0.2cm内，加入120mL去离子水浸泡5h，控制温度在20℃～25℃。将浸泡后的鲜冬虫夏草置于闪式提取器中，控制温度在20℃～25℃，电压为160V，转速为10000rpm，时间为120s。12000rpm离心15min，收集上清液。将残渣置于-20℃环境中冷冻4h再快速冻融。之后加入120mL去离子水再置于闪式提取器中提取，离心，收集上清液。合并两次的上清液。将上清液加去离子水稀释4倍后，经0.45μm微膜过滤，之后使用超滤膜进行超滤，截留分子量大于5KDa的成分，设定温度为25℃，时间为15min，压力为0.08KPa。最后将超滤之后的保留液进行冷冻干燥，得到鲜冬虫夏草提取物1.55g，提取率为15.5％。
实施例3
取鲜冬虫夏草10g，洗净后剪碎至长度为0.2cm内，冷冻干燥，控制温度在20℃～25℃下进行超微粉碎，再加入100mL去离子水90℃水浴中提取1.5h，过滤。残渣再加入100mL去离子水90℃水浴提取一次，过滤后合并提取液。经0.45μm微膜过滤，保留滤液，进行冷冻干燥，得到鲜冬虫夏草提取物1.60g，提取率为16.0％。
二、测试实施例
试验1、鲜冬虫夏草提取物在抗肿瘤减毒增效作用研究中的应用
1.实验材料
实验动物来自湖南斯莱克的SPF级C57BL/6雌性小鼠，体重范围为18g～20g。动物购进后，先在检疫室观察一周，然后移入SPF级实验室饲养。
取实施例1的鲜冬虫夏草冷提取物和实施例3的鲜冬虫夏草热提取物，加去离子水溶解，分别制成浓度为20mg/mL、80mg/mL的药物浓度。冬虫夏草提取物采用灌胃给药，小鼠灌胃体积为10mL/kg，按照低剂量为200mg/kg，高剂量800mg/kg，每天给药一次；顺铂采用腹腔注射给药，腹腔注射体积为1mL/kg，给药剂量为2mg/kg，隔天给药。
2.实验设计
(1)细胞培养
将小鼠Lewis肺癌细胞培养于含有10％新鲜胎牛血清的DMEM培养基中，在37℃、体积分数为5％CO2、饱和湿度的培养箱中连读培养。至对数生长期时，用质量分数为0.25％胰酶常规消化，将细胞调整为1×106个/mL的悬液。
(2)动物分组、肺癌小鼠模型的建立及给药
根据动物体重进行随机分为A、B、C、D、E、F共6个组，分别代表模型组、顺铂组(2mg/kg)、顺铂(2mg/kg)+鲜冬虫夏草热提取物低剂量组(200mg/kg)、顺铂(2mg/kg)+鲜冬虫夏草热提取物高剂量组(800mg/kg)、顺铂(2mg/kg)+鲜冬虫夏草冷提取物低剂量组(200mg/kg)、顺铂(2mg/kg)+鲜冬虫夏草冷提取物高剂量(800mg/kg)，每组15只动物，共90只。
实验开始前7天，C、D、E、F组小鼠每天灌胃给予相应剂量的鲜冬虫夏草提取物，A组和B组每天灌胃给予等量去离子水。第8天，A、B、C、D、E、F 6个组小鼠都在左肢腋下皮下接种Lewis肺癌细胞1×106/只，同时C、D、E、F组小鼠灌胃给于相应剂量的鲜冬虫夏草提取物，A、B组小鼠灌胃给于等量去离子水。第9天后，B组小鼠只腹腔注射2mg/kg顺铂溶液，隔天给药；C组小鼠：配制200mg/kg的鲜冬虫夏草热提取物灌胃给药，连续20天，同时配制2mg/kg顺铂溶液腹腔注射，隔天给药；D组小鼠：配制800mg/kg的鲜冬虫夏草热提取物灌胃给药，连续20天，同时配制2mg/kg顺铂溶液腹腔注射，隔天给药；E组小鼠：配制200mg/kg的鲜冬虫夏草冷提取物灌胃给药，连续20天，同时配制2mg/kg顺铂溶液腹腔注射，隔天给药；F组小鼠：配制800mg/kg的鲜冬虫夏草冷提取物灌胃给药，连续20天，同时配制2mg/kg顺铂溶液腹腔注射，隔天给药；A组小鼠每天灌胃给予等量生理盐水。
第28天给药24h后，称量各组小鼠体重后摘眼球取血，放置4h后离心，分离血清，按照ELISA试剂盒说明书步骤进行操作，测定谷草转氨酶(ASTL)、谷丙转氨酶(ALTL)、尿素氮(UREAL)、血肌酐(CREA2)。脱颈椎处死小鼠，剥离瘤块并称取瘤质量、脏器质量，计算抑瘤率、脏器系数。其中，抑瘤率计算公式为：抑瘤率/％＝(对照组平均瘤质量－给药组平均瘤质量)/对照组平均瘤质量×100％，脏器系数计算公式为：
所有实验数据经标准化处理后，用SPSS16进行统计学分析，进行单因素方差分析，并计算p值。
3.结果
(1)增效结果
鲜冬虫夏草提取物对Lewis肺癌细胞生长的影响及对顺铂增效作用如表1所示：
表1鲜冬虫夏草提取物对Lewis肺癌细胞生长的影响及对顺铂增效作用
| 组别 | 剂量/mg·kg<sup>-1</sup> | 肿瘤重量(g) | 抑瘤率(％) |
| A.模型给药组 | - | 3.27±0.42<sup>**</sup> | - |
| B.顺铂给药组 | 2 | 1.77±0.22 | 45.9 |
| C.(实施例3+顺铂)给药组 | 200+2 | 2.09±0.43 | 36.1 |
| D.(实施例3+顺铂)给药组 | 800+2 | 1.58±0.26 | 45.7 |
| E.(实施例1+顺铂)给药组 | 200+2 | 1.19±0.20* | 63.6 |
| F.(实施例1+顺铂)给药组 | 800+2 | 1.08±0.28* | 67.0 |
注：与顺铂组相比较：*p＜0.05，**p＜0.01；“-”表示无。
由表1数据可知，与顺铂给药组相比，实施例1(鲜冬虫夏草冷提取物)联合顺铂给药组能降低肿瘤的重量，并且显示出显著性差异(*p＜0.05)，抑瘤率高达67％，说明鲜冬虫夏草冷提取物能增强顺铂的疗效，并且与顺铂组相比较，具有统计学差异。然而，实施例3(鲜冬虫夏草热提取物)联合顺铂给药组相比顺铂组不仅没有降低肿瘤的质量，且抑瘤率有一定程度的降低，表明鲜冬虫夏草热提取物联合顺铂给药相比顺铂组不能降低肺癌小鼠的肿瘤重量，鲜冬虫夏草热取提物对辅助***化疗没有达到增效作用。
(2)减毒结果
鲜冬虫夏草联合顺铂给药对肺癌小鼠的脏器系数的影响如表2所示：
表2鲜冬虫夏草联合顺铂给药对肺癌小鼠的脏器系数的影响
注：与顺铂组相比较：*p＜0.05，**p＜0.01；“-”表示无。
由表2可知，实施例1(鲜冬虫夏草冷提取物)与顺铂联合用药后能明显改善顺铂导致的肺癌小鼠脏器萎缩的状况，其中实施例1(鲜冬虫夏草冷提取物)的减毒作用比实施例3(鲜冬虫夏草热提取物)更明显，尤其对脾脏和胸腺作用更明显。表明鲜冬虫夏草冷提取物可对抗化疗药物顺铂所致的免疫抑制，促进机体免疫功能的恢复，从而可提高机体的抗肿瘤作用。
(3)生化指标测定结果
鲜冬虫夏草联合顺铂给药对肺癌小鼠生化指标的影响如表3所示：
表3鲜冬虫夏草联合顺铂给药对肺癌小鼠生化指标的影响
注：与顺铂组相比较：*p＜0.05，**p＜0.01；
由表3数据可知，与顺铂给药组对比，实施例1(鲜冬虫夏草冷提取物)与联合顺铂给药，ASTL、ALTL、UREAL、CREA2含量显著降低(ALTL、UREAL、CREA2含量的*p＜0.05)，说明本发明所述的鲜冬虫夏草提取物联合顺铂可以保护抗肿瘤活性药物引起的肝肾损伤；而实施例3(鲜冬虫夏草热提取物)+顺铂给药组，ASTL、ALTL、UREAL、CREA2含量无显著差异，说明鲜冬虫夏草热提取物对保护抗肿瘤活性药物引起的肝肾损伤的效果不是很明显。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。本发明所引用的所有出版物或专利都将作为本发明的参考文献。
Claims (3)
1.一种冬虫夏草抗lewis肺癌的药物组合物，由鲜冬虫夏草提取物和顺铂组成，其中所述鲜冬虫夏草提取物的制备方法包括以下步骤：
a、将鲜冬虫夏草洗净沥干，剪碎至长度为0.2cm内，按鲜冬虫夏草与水的重量体积比加入1:10～1:12的水，浸泡3h～5h，控制温度为20℃～25℃；
b、将浸泡后的鲜冬虫夏草置于闪式提取器中，闪式提取2次，每次提取时间为80s～120s，转速为8000rpm～10000rpm，电压为120V～160V，然后离心15min，离心的转速为10000rpm～12000rpm，取上清液，控制温度为20℃～25℃；
c、将离心后的沉淀，按沉淀与水的重量体积比再加入1:10～1:12的水，置于-20℃的环境下冷冻4h，再快速冻融，然后重复步骤b，进行闪式提取，离心，收集上清液；
d、将步骤b和步骤c所收集的上清液合并，加水稀释4倍，使用0.45μm微膜过滤，之后使用截留分子量大于5KDa的超滤膜，设定温度为25℃，时间为15min，压力为0.08KPa进行超滤；
e、将超滤后的保留液进行冷冻干燥，得到鲜冬虫夏草提取物。
2.一种权利要求1所述的药物组合物在制备抗lewis肺癌药物中的应用。
3.根据权利要求2所述的应用，所述药物组合物对肿瘤化疗引起的肝肾组织损伤具有保护作用。
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| CN102526127A (zh) * | 2012-03-28 | 2012-07-04 | 辽宁大学 | 蛹虫草中有效成分的闪式提取方法 |
| CN103214533A (zh) * | 2013-04-19 | 2013-07-24 | 湖南农业大学 | 一种膜分离技术连续制备虫草素和虫草多糖的方法 |
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| CN103214533A (zh) * | 2013-04-19 | 2013-07-24 | 湖南农业大学 | 一种膜分离技术连续制备虫草素和虫草多糖的方法 |
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| 冬虫夏草合用顺铂诱导非小细胞肺癌凋亡的研究;徐晋等;《南京中医药大学学报》;20081130;第24卷(第06期);第398-400页 * |
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