CN112741849A - 一种肿瘤免疫辅助治疗药物及其应用 - Google Patents
一种肿瘤免疫辅助治疗药物及其应用 Download PDFInfo
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- CN112741849A CN112741849A CN202110176135.3A CN202110176135A CN112741849A CN 112741849 A CN112741849 A CN 112741849A CN 202110176135 A CN202110176135 A CN 202110176135A CN 112741849 A CN112741849 A CN 112741849A
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- tumor
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- echinacea purpurea
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Abstract
本发明公开了一种肿瘤免疫辅助治疗药物及其应用，属于生物医药领域。本发明利用紫锥菊提取物作为肿瘤免疫辅助治疗药物，在放化疗过程中，既可抑制肿瘤生长，增强化药抑制效果，还能够减轻毒副作用，具有显著的增效减毒作用；并通过建立荷瘤小鼠模型评价其对荷瘤小鼠肿瘤的抑制效果。结果表明，紫锥菊可抑制肿瘤生长，提高机体免疫，增强化药抑瘤效果，且降低了化药对肝脏的毒副作用，产生良好的减毒增效作用，具有非常好的应用前景。
Description
技术领域
本发明属于生物医药领域，特别涉及一种肿瘤免疫辅助治疗药物及其应用。
背景技术
近年来，恶性肿瘤的发病率和死亡率呈快速上升趋势，严重威胁人类健康。手术治疗、化疗和放射治疗是恶性肿瘤综合治疗的常用方法，但多数恶性肿瘤生存率很低，在抑制肿瘤的同时也带来了更多的不良反应。对人体正常细胞造成相当程度的损伤，引起肝肾毒性、消化障碍、免疫功能下降、骨髓抑制以及发热等多种炎症反应等等。因此迫切需要寻找到既能控制恶性肿瘤生长、又能减少不良反应的药物。
中医中药在预防与治疗肿瘤方面发挥了重要的作用。中医理论中，肿瘤属于“脾虚、痰、淤、毒”，由机体正气虚弱，外邪入侵、脾运化失调导致淤阻、积聚。因此古代方剂及现代中成药中常用扶正固本、健脾益气、清热解毒、活血化瘀功效中药来防控肿瘤。如黄芪、党参、半枝莲、莪术等传统中药。这些中药具有多靶点、低毒高效、防治兼备的独特优势，在临床肿瘤防治中具有不可低估的价值。
发明内容
目前关于紫锥菊的研究以及应用甚少，本发明所涉及的肿瘤免疫辅助治疗药物主要包括紫锥菊水提取物，具有益气扶正、清热解毒的功效，可提高免疫增强肿瘤治疗效果、降低化药毒副作用。
本发明的第一个目的是提供紫锥菊在制备用于减轻放化疗毒性作用的肿瘤免疫辅助治疗药物中的应用。
在本发明的一种实施方式中，所述应用过程包括：将紫锥菊全草切成小段，纯净水浸泡，加热煮沸，滤出药汁抽滤；滤渣再加入纯净水，药渣煎煮，滤出药汁抽滤，合并两次煎煮液，滤过，取上清液，浓缩，干燥。
本发明的第二个目的是提供用于减轻放化疗毒性作用的肿瘤免疫辅助治疗药物，所述药物的制备包括过程：
将紫锥菊全草切成小段，纯净水浸泡，加热煮沸，滤出药汁抽滤；滤渣再加入纯净水，药渣煎煮，滤出药汁抽滤，合并两次煎煮液，滤过，取上清液，浓缩，干燥。
在本发明的一种实施方式中，所述肿瘤免疫辅助治疗药物的剂型包括胶囊剂、颗粒剂、片剂、丸剂、散剂或口服液剂型。
在本发明的一种实施方式中，所述肿瘤免疫辅助治疗药物还包括如下任意一种或多种组分：
(1)填料或增溶剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸等；
(2)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖、阿拉伯胶等；
(3)保湿剂，例如，甘油等；
(4)崩解剂、例如琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些符合硅酸盐和碳酸钠等；
(5)缓溶剂，例如石蜡等；
(6)吸收加速剂，例如季铵化合物等；
(7)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯等；
(8)吸附剂，例如，高岭土等；
(9)润滑剂，例如，滑石、硬脂酸钙、固体聚乙二醇、十二烷基硫酸钠等，或其混合物；
以及，(10)胶囊剂、片剂、丸剂中还可包含缓冲剂。
在本发明的一种实施方式中，所述肿瘤免疫辅助治疗药物还包括药物可接受的载体。所述药物可接受的载体包括但不限于：甘露醇、山梨醇、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、盐酸半胱氨酸、巯基乙酸、蛋氨酸、维生素C、EDTA二钠、EDTA钙钠、一价碱金属的碳酸盐、醋酸盐、磷酸盐或者水溶液、盐酸、醋酸、硫酸、磷酸、氨基酸、氯化钠、氯化钾、乳酸钠、木糖醇、麦芽糖、葡萄糖、果糖、右旋糖苷、淀粉、蔗糖、甘露糖醇、硅衍生物、纤维素及其衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、吐温80、琼脂、碳酸钙、碳酸氢钙、表明活性剂、聚乙二醇、环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、硬脂酸镁。
在本发明的一种实施方式中，所述紫锥菊的处理过程具体包括：
将紫锥菊全草切成2～3cm长的小段，加入8～10倍重量的纯净水，浸泡20～40min，加热煮沸1～3h，滤出药汁抽滤。再加6～8倍量水，药渣煎煮1～3h，滤出药汁抽滤，合并两次煎煮液，滤过，取上清液，浓缩，即得紫锥菊水提取液，干燥后，获得固体产品。
本发明的第三个目的是提供一种肿瘤治疗药物组合物，包括免疫辅助组分和抗肿瘤活性组分；
其中，免疫辅助组分通过如下方法制备得到：将紫锥菊全草切成小段，纯净水浸泡，加热煮沸，滤出药汁抽滤；滤渣再加入纯净水，药渣煎煮，滤出药汁抽滤，合并两次煎煮液，滤过，取上清液，浓缩，干燥。
在本发明的一种实施方式中，所述抗肿瘤活性组分包括：氟尿嘧啶、顺铂、紫杉醇、阿霉素、环磷酰胺、丝裂霉素等。
在本发明的一种实施方式中，免疫辅助组分与抗肿瘤活性组分的质量比为2～50：1。
在本发明的一种实施方式中，所述肿瘤治疗药物组合物的剂型包括胶囊剂、颗粒剂、片剂、丸剂、散剂或口服液剂型。
在本发明的一种实施方式中，所述肿瘤治疗药物组合物还包括如下任意一种或多种成分：赋形剂、稀释剂、增溶剂、粘合剂、保湿剂、崩解剂、缓溶剂、润湿剂、吸附剂、润滑剂、缓释剂。
在本发明的一种实施方式中，所述肿瘤治疗药物组合物还包括药物可接受的载体。所述药物可接受的载体包括但不限于：甘露醇、山梨醇、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、盐酸半胱氨酸、巯基乙酸、蛋氨酸、维生素C、EDTA二钠、EDTA钙钠、一价碱金属的碳酸盐、醋酸盐、磷酸盐或者水溶液、盐酸、醋酸、硫酸、磷酸、氨基酸、氯化钠、氯化钾、乳酸钠、木糖醇、麦芽糖、葡萄糖、果糖、右旋糖苷、淀粉、蔗糖、甘露糖醇、硅衍生物、纤维素及其衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、吐温80、琼脂、碳酸钙、碳酸氢钙、表明活性剂、聚乙二醇、环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、硬脂酸镁。
本发明的有益效果：
本发明利用紫锥菊提取物作为肿瘤免疫辅助治疗药物，在放化疗过程中，既可抑制肿瘤生长，增强化药抑制效果，还能够减轻毒副作用，具有显著的增效减毒作用。本发明通过建立荷瘤小鼠模型，给予紫锥菊提取物，评价其对荷瘤小鼠肿瘤的抑制效果。结果表明，紫锥菊可抑制肿瘤生长，提高机体免疫，增强化药抑瘤效果，且降低了化药对肝脏的毒副作用，产生良好的减毒增效作用。
附图说明
图1为不同处理方式的小鼠的体重变化趋势图；其中，空白组(C)，荷瘤动物模型组(M)，紫锥菊组(Ep)，氟尿嘧啶组(P)，紫锥菊与氟尿嘧啶组(Ep+P)；与空白组比较，*P＜0.05，**P＜0.01。
图2为不同处理方式的小鼠的肿瘤体积变化趋势图；其中，荷瘤动物模型组(M)，紫锥菊组(Ep)，氟尿嘧啶组(P)，紫锥菊与氟尿嘧啶组(Ep+P)；与模型组比较，#P＜0.05，##P＜0.01，###P＜0.001。
图3为不同处理方式的小鼠的脏器指数大小结果比对图；其中，空白组(C)、荷瘤动物模型组(M)，紫锥菊组(Ep)，氟尿嘧啶组(P)，紫锥菊与氟尿嘧啶组(Ep+P)；与空白组比较，*P＜0.05；与模型组比较，#P＜0.05，##P＜0.01。
图4为不同处理方式的小鼠的肿瘤指数大小结果比对图；其中，荷瘤动物模型组(M)，紫锥菊组(Ep)，氟尿嘧啶组(P)，紫锥菊与氟尿嘧啶组(Ep+P)；与模型组比较，#P＜0.05，##P＜0.01。
图5为不同处理方式的小鼠的肝功能结果比对图；其中，空白组(C)、荷瘤动物模型组(M)，紫锥菊组(Ep)，氟尿嘧啶组(P)，紫锥菊与氟尿嘧啶组(Ep+P)；与空白组比较，*P＜0.05，***P＜0.001；与模型组比较，###P＜0.001。
具体实施方式
下面结合具体实施方式，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解，在阅读了本发明记载的内容之后，本领域技术人员可以对本发明做各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
实施例1：
紫锥菊全草切成2～3cm长的小段，称取200g，加入8倍紫锥菊重量的纯净水，浸泡40min后，加热煮沸2h，滤出药汁抽滤。药渣中再加入6倍紫锥菊重量的纯净水，煎煮1h，滤出药汁抽滤，合并两次煎煮液，滤过，取上清液，上清液减压浓缩成浸膏，冻干成粉，加入适量辅料，制成片剂。
实施例2：
紫锥菊全草切成2～3cm长的小段，称取200g，加入9倍紫锥菊重量的纯净水，浸泡30min后，加热煮沸3h，滤出药汁抽滤。药渣中再加入7倍紫锥菊重量的纯净水，煎煮1h，滤出药汁抽滤，合并两次煎煮液，滤过，取上清液，上清液减压浓缩成浸膏，冻干，粉碎成细粉，装胶囊。
实施例3：
紫锥菊全草切成2～3cm长的小段，称取200g，加入10倍紫锥菊重量的纯净水，浸泡30min后，加热煮沸2h，滤出药汁抽滤。药渣中再加入8倍紫锥菊重量的纯净水，煎煮2h，滤出药汁抽滤，合并两次煎煮液，滤过，取上清液，上清液减压浓缩成浸膏，冻干成粉，加入适量辅料，制成片剂。
实施例4：
紫锥菊全草切成2～3cm长的小段，称取200g，加入8倍紫锥菊重量的纯净水，浸泡40min后，加热煮沸1h，滤出药汁抽滤。药渣中再加入6倍紫锥菊重量的纯净水，煎煮1h，滤出药汁抽滤，合并两次煎煮液，滤过，取上清液，上清液减压浓缩成浸膏，冻干成粉，加入适量辅料，制成片剂。
实施例5：
紫锥菊全草切成2～3cm长的小段，称取200g，加入9倍紫锥菊重量的纯净水，浸泡30min后，加热煮沸3h，滤出药汁抽滤。药渣中再加入8倍紫锥菊重量的纯净水，煎煮1h，滤出药汁抽滤，合并两次煎煮液，滤过，取上清液，上清液减压浓缩成浸膏，冻干，粉碎成细粉，装胶囊。
实施例6：
紫锥菊全草切成2～3cm长的小段，称取200g，加入10倍紫锥菊重量的纯净水，浸泡20min后，加热煮沸2h，滤出药汁抽滤。药渣中再加入7倍紫锥菊重量的纯净水，煎煮1h，滤出药汁抽滤，合并两次煎煮液，滤过，取上清液，上清液减压浓缩成浸膏，冻干成粉，加入适量辅料，制成片剂。
实施例7：
1.材料：
(1)细胞株：小鼠Hepa1-6肝癌细胞由中科院上海生命科学研究所提供。
(2)试剂：DMEM-H培养基，胎牛血清，抗生素均购自美国Gibco公司；磷酸盐缓冲液(PBS)，0.25％胰酶-0.02％乙二胺四乙酸(EDTA)均购自美国Thermo公司；
(3)药物：注射用氟尿嘧啶(山西普德药业有限公司)，紫锥菊购自山东青州市康达中药材种植专业合作社，以实施例3中的紫锥菊提取物作为试验药物。
(4)仪器与环境：超净工作台，CO2恒温培养箱，生物倒置显微镜，离心机，真空冷冻干燥机(ScientZ)，江南大学实验动物中心动物屏障。
(5)实验动物：30只SPF级C57BL/6小鼠，体重20-22g，雄性，由上海灵畅生物科技有限公司提供。实验动物许可证号：SYXK(苏)2016-0045。
2.实验方法：
(1)细胞培养：复苏Hepa1-6肝癌细胞，CO2恒温培养箱中培养，观察细胞形态，待细胞状态良好并长到90％后，对细胞进行传代。
(2)细胞接种：收集培养的细胞，用无菌生理盐水调整细胞密度为2×107个/mL，取0.1mL细胞悬液，以2×106个Hepa1-6细胞接种至小鼠左侧腋窝皮下，留针1min，之后定期每日观察小鼠状态。且每日观察肿瘤生长情况，使用游标卡尺测量肿瘤体积。
(3)实验动物给药：小鼠给予标准饲料喂养，适应一周后，随机分为五组，分别为空白组(正常小鼠，C)、荷瘤动物模型组(M)、紫锥菊组(Ep)、氟尿嘧啶组(P)、紫锥菊与氟尿嘧啶组(Ep+P)。小鼠除空白组外，其余四组均按照上述细胞接种方法接种Hepa1-6肝癌细胞。第二天后分别按动物分组方式每日给药，持续三周给予一定量的紫锥菊提取物。
(4)给药方式：氟尿嘧啶组每日按10mg/kg/d腹腔注射，注射量0.1mL/10g。紫锥菊组每日按2g/kg/d灌胃，灌胃量0.1mL/10g。紫锥菊与氟尿嘧啶组(Ep+P)的给药方式：紫锥菊灌胃剂量同紫锥菊组，氟尿嘧啶腹腔注射剂量同氟尿嘧啶组。
空白组与模型组每日灌胃生理盐水。观察期间动物常规饲养，自由采食饮水，并记录小鼠体重。
(5)动物处理：末次给药后，动物禁食不禁水12h，摘眼球采血后，颈椎脱臼法处死小鼠，分离肿瘤、肝、脾，精密称质量，计算脏器指数以及肿瘤体积[肿瘤体积(mm3)＝长径×短径2×50％]将取得的血清在4℃、3500r/min条件下，离心15min，检测小鼠血清中肝功能指标，包括总胆红素(TBIL)、谷草转氨酶(AST)。
(6)统计方法：采用SPSS 21.0统计软件进行统计学分析，采用ANOVO单因素方差分析，P<0.05差异有统计学意义。
3.结果分析
(1)记录小鼠体重，具体结果如表1所示，相应各组动物体重随时间变化趋势如图1所示。
表1各组小鼠体重
每隔两天记录小鼠体重，各组动物体重随时间变化趋势如图1所示。结果表明与空白组对比，小鼠接种肿瘤后体重降低，模型组小鼠体重减少的同时，肿瘤逐渐增大，在体重方面与给药组无显著差异。
(2)测定各组动物不同时间的肿瘤大小，如表2所示，相应随时间变化趋势如图2所示。
表2各组小鼠肿瘤大小
通过皮下接种肝癌细胞的方法建立小鼠肝癌模型，并采用临床常用抗肿瘤治疗药物氟尿嘧啶作为化疗药物。
结果表明，模型组小鼠接种肝癌细胞后，肿瘤逐渐增大，给予药物治疗均能有效的抑制肿瘤的生长。其中紫锥菊提取物和氟尿嘧啶合用比单用紫锥菊提取物或氟尿嘧啶组的抑制效果强，产生良好的协同增效作用。
(3)测定各组动物脏器(肝脏、脾脏和肾脏)的指数结果，小鼠牺牲后，称量小鼠肝、脾、肾重量，通过计算比较各组小鼠脏器系数大小，具体结果如表3和图3所示。
脏器指数大小具体是指：脏器中肝脏、脾脏以及肾脏的重量分别与其体重之比值，该系数为毒理实验中常用的指标，本研究通过脏器指数大小用于评价肿瘤对小鼠脏器的毒性作用以及药物对小鼠的干预效果。
表3各组小鼠脏器指数大小
结果表明，各组小鼠肝脏与肾脏指数无显著差异，但给药后脏器质量出现降低的趋势。各组小鼠间脾脏指数具有显著差异，模型组小鼠的脾脏颜色发黑，质量增大，与空白组明显不同，经给药后出现不同程度的回调，其中紫锥菊提取物可显著回调脾脏指数，紫锥菊提取物联合氟尿嘧啶回调效果更为显著，接近于空白组。表明紫锥菊提取物可发挥良好的免疫调节作用，同时增强化药疗效，达到增效减毒的效果。
(4)测定各组动物肿瘤指数结果，小鼠牺牲后，称量小鼠肿瘤重量，通过计算比较各组接种肿瘤的小鼠肿瘤指数大小。具体结果如表4和图4所示。
肿瘤指数大小具体是指：肿瘤的重量与其体重之比值，以此来反映肿瘤的严重程度以及药物对小鼠肿瘤的干预效果。
表4各组小鼠肿瘤指数大小
结果表明，给药可一定程度的减轻肿瘤的生长，紫锥菊提取物联合给药显著抑制肿瘤大小，同时可有效的预防肿瘤的发生与控制肿瘤的发展。
(5)检测各组动物血清肝功能指标，各组小鼠血清肝功能指标总胆红素(TBIL)与谷草转氨酶(AST)采用全自动生化仪进行检测。具体结果见表5和图5。
表5各组小鼠肝功能值
结果显示模型组小鼠的TBIL和AST含量显著升高，经给药后出现不同程度的回调，其中，氟尿嘧啶组对肝功能的影响相对较大，调控作用较弱，紫锥菊提取物联合氟尿嘧啶给药可显著降低对肝脏的影响，减少对机体正常细胞的损伤，发挥减毒增效的作用。
通过对紫锥菊提取物对肿瘤的抑制作用进行了评价，并与联合化药后的治疗效果进行比较，结果表明紫锥菊提取物与抗肿瘤化药氟尿嘧啶联合使用效果优于单独给药，且降低了化药对机体的毒副作用，提高机体的免疫功能，这一结果证明了紫锥菊提取物可作为肿瘤免疫辅助治疗药物应用于临床。
以上对本发明的实施例所提供的技术方案进行了详细介绍，本文应用了具体个例对本发明实施例的实施方式进行了阐述，仅用来方便说明本发明，并非对本发明作任何形式上的限制，利用本发明所揭示技术内容所做出局部更动或修饰的等效实施例，并且未脱离本发明的技术特征内容，均仍属于本发明技术特征的范围内。
Claims (10)
1.紫锥菊在制备用于减轻放化疗毒性作用的肿瘤免疫辅助治疗药物中的应用。
2.根据权利要求1所述的应用，其特征在于，所述紫锥菊经过如下处理过程：将紫锥菊全草切成小段，纯净水浸泡，加热煮沸，滤出药汁抽滤；滤渣再加入纯净水，药渣煎煮，滤出药汁抽滤，合并两次煎煮液，滤过，取上清液，浓缩，干燥。
3.一种用于减轻放化疗毒性作用的肿瘤免疫辅助治疗药物，其特征在于，包括的紫锥菊提取物；所述紫锥菊提取物的制备过程包括：
将紫锥菊全草切成小段，纯净水浸泡，加热煮沸，滤出药汁抽滤；滤渣再加入纯净水，药渣煎煮，滤出药汁抽滤，合并两次煎煮液，滤过，取上清液，浓缩，干燥。
4.根据权利要求3所述的肿瘤免疫辅助治疗药物，其特征在于，所述肿瘤免疫辅助治疗药物的剂型包括胶囊剂、颗粒剂、片剂、丸剂、散剂或口服液剂型。
5.根据权利要求3所述的肿瘤免疫辅助治疗药物，其特征在于，所述肿瘤免疫辅助治疗药物还包括如下任意一种或多种组分：填料、增溶剂、粘合剂、保湿剂、崩解剂、缓溶剂、吸收加速剂、润湿剂、吸附剂、润滑剂、缓冲剂。
6.根据权利要求3-5任一项所述的肿瘤免疫辅助治疗药物，其特征在于，所述肿瘤免疫辅助治疗药物还包括药物可接受的载体。
7.根据权利要求6所述的肿瘤免疫辅助治疗药物，其特征在于，所述药物可接受的载体选自：甘露醇、山梨醇、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、盐酸半胱氨酸、巯基乙酸、蛋氨酸、维生素C、EDTA二钠、EDTA钙钠、一价碱金属的碳酸盐、醋酸盐、磷酸盐或者水溶液、盐酸、醋酸、硫酸、磷酸、氨基酸、氯化钠、氯化钾、乳酸钠、木糖醇、麦芽糖、葡萄糖、果糖、右旋糖苷、淀粉、蔗糖、甘露糖醇、硅衍生物、纤维素及其衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、吐温80、琼脂、碳酸钙、碳酸氢钙、表明活性剂、聚乙二醇、环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、硬脂酸镁。
8.一种肿瘤治疗药物组合物，其特征在于，包括免疫辅助组分和抗肿瘤活性组分；
其中，免疫辅助组分通过如下方法制备得到：将紫锥菊全草切成小段，纯净水浸泡，加热煮沸，滤出药汁抽滤；滤渣再加入纯净水，药渣煎煮，滤出药汁抽滤，合并两次煎煮液，滤过，取上清液，浓缩，干燥。
9.根据权利要求8所述的肿瘤治疗药物组合物，其特征在于，所述抗肿瘤活性组分包括如下任意一种或多种：氟尿嘧啶、、顺铂、紫杉醇、阿霉素、环磷酰胺、丝裂霉。
10.根据权利要求8所述的肿瘤治疗药物组合物，其特征在于，免疫辅助组分与抗肿瘤活性组分的质量比为2～50：1。
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