CN114605278A - T3或其可药用盐在制备脑胶质瘤放化疗药物方面的应用 - Google Patents
T3或其可药用盐在制备脑胶质瘤放化疗药物方面的应用 Download PDFInfo
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Abstract
本发明提出一种T3或其可药用盐,本发明的T3或其可药用盐在制备脑胶质瘤放化疗药物方面的应用,可以提高胶质瘤的治疗效率,降低复发率。本发明是对TH信号通路参与mGSCs特性维持机制的重要补充,对T3影响GBM放化疗抵抗调控机制的进一步完善,为增强GBM放化疗敏感性提供新的靶点,为GBM临床治疗提供理论基础。
Description
技术领域
本发明涉及一种T3或其可药用盐在制备脑胶质瘤放化疗药物方面的应用。
背景技术
胶质母细胞瘤(glioblastoma,GBM)是颅内最常见的原发性肿瘤,脑胶质瘤占颅脑肿瘤的40%~50%,是最常见的原发性颅内肿瘤,年发病率为3~8人/10万人口。如同其他肿瘤一样,胶质瘤也是由于先天的遗传高危因素和环境的致癌因素相互作用所导致。一些已知的遗传疾病,例如神经纤维瘤病(I型)以及结核性硬化疾病等,为脑胶质瘤的遗传易感因素。
脑胶质瘤所导致的症状和体征,主要取决其占位效应以及所影响的脑区功能。胶质瘤由于其在空间的“占位”效应,例如,颅内高压或对颅神经的压迫,可以使患者产生头痛、恶心及呕吐、癫痫、视物模糊等症状。此外,由于其对脑部功能区的影响,还可以使患者产生其他的症状。比如,视神经胶质瘤可以导致患者视觉的丧失;脊髓胶质瘤可以使患者产生肢体的疼痛、麻木以及肌力弱等症状;中央区胶质瘤可以引起患者运动与感觉的障碍;语言区胶质瘤可以引起患者语言表达和理解的困难。胶质瘤由于恶性程度不同,其所产生症状的速度也不同。例如,低级别胶质瘤患者的病史往往在几个月甚至一年,而高级别胶质瘤患者的病史往往在几个星期至几个月。根据患者的病史、症状以及体征,可以初步推断出病变的部位以及恶性程度。
目前的治疗方法包括手术、放疗、化疗及其结合等综合治疗方案。但是胶质瘤很难根治,往往会复发。因此,亟待研发一种新的药物,以提高胶质瘤的治疗效率,降低复发率。
发明内容
针对现有技术中的上述问题,本发明提出了一种T3或其可药用盐在制备脑胶质瘤放化疗药物方面的应用,可以提高胶质瘤的治疗效率,降低复发率。
T3又名三碘甲状腺原氨酸,是一种含碘的酪氨酸,它是以碘和酪氨酸为原料在甲状腺腺细胞内合成,具有非常重要的医学价值;T4又名四碘甲状腺原氨酸,它们是一组含碘的酪氨酸,它是以碘和酪氨酸为原料在甲状腺腺细胞内合成。
当甲状腺受到TSH的作用,释放甲状腺激素时,腺上皮细胞先通过吞饮作用把滤泡腔内的甲状球蛋白吞入腺细胞,在溶酶体蛋白水解酶的作用下,使甲状球蛋白分解,解脱下来的T4和T3因能抗拒脱碘酶的作用,分子又小,可以透过毛细血管进入血液循环。甲状球蛋白分子上的T4数量远远超过T3,所以分泌的激素中T4约占总量的90%,T3分泌量较少,但其活性大,是T4的5倍。T4每日分泌总量约96μg,T3约30μg。T4释放入血后,一部分与血浆蛋白结合,另一部分则呈游离状态在血中运输,两者之间可以互相转变,维持T4、T3在血液中的动态平衡,因为只有游离型,才能进入细胞发挥作用。T3释放入血后,因为与血浆蛋白的亲和力小,主要以游离型存在。每天约有50%的T4脱碘转变为T3,故T3的作用不容忽视。
第一方面,本发明提出一种T3或其可药用盐,所述T3的结构式为:
第二方面,本发明提出了所述的T3或其可药用盐在制备脑胶质瘤放化疗药物方面的应用。
作为本发明的具体实施方式,所述药物以T3或其可药用盐作为活性成分,所述活性成分的重量百分含量为1%~99%,例如1%,20%,40%,60%,80%,99%及其任意组合的范围。
作为本发明的具体实施方式,所述药物还包括药学上可接受的载体。
作为本发明的具体实施方式,所述载体至少选自填充剂、粘合剂、润湿剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润湿剂、香味剂或甜味剂中的一种。
作为本发明的具体实施方式,所述填充剂至少选自淀粉、蔗糖和乳糖中的一种;和/或,所述粘合剂至少选自纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮中的一种;和/或,所述润湿剂为甘油;和/或,所述崩解剂至少选自琼脂和碳酸钙中的一种;和/或,所述吸收促进剂为季铵化合物;和/或,表面活性剂为十六烷醇;和/或,所述吸附载体至少选自高岭土和蒙脱石中的一种;和/或,所述润滑剂至少选自滑石粉、硬脂酸钙和聚乙二醇中的一种。
作为本发明的具体实施方式,所述的药物的剂型包括粉剂、注射液、胶囊、片剂和口服液。
第三方面,本发明提出了一种药物组合物,包括治疗有效量的权利要求1所述的T3或其可药用盐,以一种药学上可接受的载体或赋形剂。
第四方面,本发明提出了所述的药物组合物在制备胶质瘤放化疗药物中的应用。
本发明所述药物的使用剂量可随特定的给药方式、病症的严重程度等而相应调整。如表1所示,一般情况下,剂量水平在每天约0.01-200mg/kg体重,可有效用于上述疾病。对于特殊的病人的特定计量水平将取决于许多因素,包括年龄、健康状况、性别、饮食、给药时间、给药途径、排泄速度、药物组合和收到治疗的特定疾病及严重程度。
表1 左甲状腺素钠片的每日剂量
本发明的T3或其可药用盐在制备脑胶质瘤放化疗药物方面的应用,可以提高胶质瘤的治疗效率,降低复发率。申请人研究发现,诱导甲状腺功能减退可延长胶质瘤患者生存时间,其原因可能与T3影响放疗敏感性有关。与之相应的,诱导患者甲状腺功能亢进可增加肿瘤风险。T3选择性促进mGSCs的增殖,而mGSCs的特点之一是放化疗抵抗性强;另外,经放化疗处理的mGSCs加入T3后细胞致死率降低,是因为T3可能参与了GBM的放化疗抵抗。
具体实施方式
下面结合具体实施例对本发明作进一步说明,但并不构成对本发明的任何限制。
实施例1
实施例1提出了一种脑胶质瘤放化疗药物,所述药物为胶囊,其中T3的重量百分比为50%,其中,T350mg,乳糖5mg,蔗糖5mg,琼脂10mg,淀粉25mg,高岭土5mg。
实施例2
实施例2提出了一种脑胶质瘤放化疗药物,所述药物为片剂,每片100mg,T3药用盐的重量百分比为1%,其中,T3药用盐1mg,淀粉90mg,琼脂5mg,蒙脱石4mg。
实施例3
实施例3提出了一种脑胶质瘤放化疗药物,所述药物为颗粒剂,其中T3的重量百分比为99%,其中,T3为99mg,藻酸盐1mg。
通过以下研究阐释本发明药物中T3或其可药用盐的作用机理:
第一部分明确THRA在mGSCs特性维持中的作用
a)干扰THRA表达,检测mGSCs增殖、凋亡和干性变化;
b)验证THRA对GSCs亚型转化的调控作用,体外实验观察对放化疗抵抗的作用;c)干扰THRA表达后,体内实验观察mGSCs的成瘤能力和小鼠生存期。
第二部分CUT&Tag结合RNA-seq筛选并验证T3介导的下游潜在靶点
a)通过CUT&Tag方法结合RNA-seq(利用敲减DIO1和敲减THRA的间质型胶质瘤干细胞)分析筛选下游潜在靶点和通路;
b)干扰筛选出的目标靶点后,检测mGSCs的增殖能力、凋亡和干性变化;
c)明确目标靶点对GSCs亚型转化的调控,体外实验观察对放化疗抵抗的作用;
d)观察目标靶点对GSCs的成瘤能力和小鼠生存期的影响。
第三部分明确T3代谢通路关键靶点及相关信号通路的临床相关性
a)在mGSCs中,分别干扰T3相关代谢通路关键靶点(DIO1,THRA和目的靶点),通过体内和体外实验明确各靶点对下游通路的调控作用;
b)分析临床病人血清中T3和T4的表达与放化疗抵抗及预后的关系;
c)检测GBM患者肿瘤组织中关键靶点的表达,分析放化疗抵抗和预后的关系以及与下游潜在靶点和通路的关系。
第四部分通过靶点抑制剂明确T3下游代谢通路参与放化疗抵抗
a)体外实验验证THRA抑制剂以及下游靶点抑制剂可以增强mGSCs的放化疗敏感性;
b)借助裸鼠颅内原位成瘤模型,验证THRA抑制剂和下游靶点抑制剂可以增强mGSCs的放化疗敏感性;
c)提出GBM患者放化疗疗效的预测和干预方案。
研究方法
第一部分明确THRA在mGSCs特性维持的作用
a)利用慢病毒构建稳定敲减THRA的干细胞株,通过检测luciferase生物发光的强度确定细胞增殖的变化;采用流式细胞术检测干细胞凋亡情况;采用成球实验,通过观察干细胞球的大小以及数目检测细胞的干性;
b)在稳定敲减THRA的mGSCs中借助免疫荧光和激光共聚焦显微镜,观察间质型干细胞标志分子:CD44和YKL-40,前神经亚型标志分子:SOX2,Oligo2,同时检测S100β和Tuj-1细胞分化指标,明确THRA对间质型干细胞亚型转化的作用;放化疗不同处理后,检测细胞的凋亡情况,明确对放化疗抵抗的作用;
c)利用稳定敲减THRA的mGSCs,构建裸鼠颅内原位肿瘤模型,每只小鼠颅内注射1×105个细胞,借助小动物活体成像方法观察肿瘤的进展,同时观察荷瘤小鼠的生存期。
第二部分CUT&Tag结合RNA-seq筛选并验证T3介导的下游潜在靶点和通路
a)借助最前沿用于探寻下游转录因子的方法即CUT&Tag技术,在加入T3与否的条件下,捕获THRA并得到与之结合的相关转录因子,从而明确T3与THRA结合后,进一步激活的下游靶点;利用敲减DIO1和敲减THRA的mGSCs,通过RNA-seq分析筛选下游潜在靶点和通路;
b)构建稳定敲减下游靶点的mGSCs,通过检测luciferase生物发光的强度确定细胞增殖的变化;采用流式细胞术检测干细胞凋亡情况;采用成球实验,通过观察干细胞球的大小以及数目测定细胞的干性;
c)借助免疫荧光和激光共聚焦显微镜,观察间质型干细胞标志分子:CD44和YKL-40,前神经亚型标志分子:SOX2,Oligo2,同时检测S100β和Tuj-1细胞分化指标,明确下游靶点对间质型干细胞亚型转化的作用;通过检测放化疗处理后细胞凋亡情况,明确对放化疗抵抗的作用;
d)利用稳定敲减下游靶点的mGSCs,构建裸鼠颅内原位肿瘤模型,每只小鼠颅内注射1×105个细胞,借助小动物活体成像方法,定期观察肿瘤的进展,同时观察荷瘤小鼠的生存期。
DIO1调控T3水平,进而T3与THRA结合后激活TH信号通路,再进一步调控下游靶点影响脂肪酸代谢,从而维持mGSCs特性(增值、干性及亚型转化)参与GBM放化疗抵抗。
第三部分明确T3代谢通路关键靶点及相关信号通路的临床相关性
a)在稳定敲减DIO1或THRA的细胞系中,通过Western blot、免疫荧光等方法验证对下游通路的影响;同时构建裸鼠颅内原位肿瘤模型,借助小动物活体成像方法观察肿瘤的进展;通过免疫组化、Westernblot和免疫荧光验证DIO1和THRA对下游靶点和通路的影响;在稳定敲减DIO1的mGSCs中回复T3的表达水平,通过体外实验进一步验证DIO1通过T3激活下游靶点和通路;
b)在mGSCs中,通过慢病毒转染方法分别敲减T3代谢通路下游靶点;经放化疗处理后,观察细胞的增殖、干性、亚型转化和凋亡情况;在裸鼠颅内原位成瘤模型中,观察敲减下游靶点的小鼠对放化疗的反应,从而明确T3下游代谢通路参与放化疗抵抗;
c)收集200例临床GBM患者血清,利用ELISA试剂盒检测血清中T3和T4的表达,分析其与患者预后的关系,验证T3对GBM进展的促进作用;将进行放化疗的GBM患者分为敏感组和不敏感组,比较两组患者血清中T3的表达水平,从临床样本中分析并验证T3与GBM放化疗抵抗性的关系;
d)收集放化疗敏感和不敏感GBM患者肿瘤组织标本,免疫组化检测T3代谢通路关键靶点的表达情况,同时使用ELISA试剂盒检测肿瘤内T3的表达量,验证DIO1与T3的相关关系,分析DIO1表达和T3水平与放化疗抵抗性的关系;分析DIO1表达与下游潜在靶点和通路的关系,分析关键靶点与肿瘤分级、临床预后和放化疗抵抗的关系。
第四部分通过靶点抑制剂明确T3下游代谢通路参与放化疗抵抗
a)在mGSCs中,分别加入THRA的特异性抑制剂决奈达隆(Dronedarone)和下游靶点分子的抑制剂,检测在放化疗作用下细胞的增殖、凋亡、干性及亚型转化情况;筛选THRA和下游靶点分子的抑制剂,借助GeneCards数据库,筛选2个已获批临床应用的药物靶点,为临床应用提供有效的证据支持;
b)借助裸鼠颅内原位成瘤模型,将mGSCs立体定向注射到裸鼠颅内固定部位,分为对照组、THRA特异性抑制剂组、下游靶点抑制剂组,然后分别行放疗和化疗处理,观察小鼠对放疗或化疗的抵抗情况;
c)针对临床GBM患者,我们根据研究结果可以对其放化疗疗效进行预测并进一步验证,从而为临床放化疗疗效的预测及干预方案的提出提供理论依据。
有益效果:
(1)确定mGSCs中T3结合THRA调控的下游靶点和信号通路
间质型GSCs特性维持受到TH信号通路调控,确定mGSCs中T3结合THRA调控的下游靶点和信号通路是本课题研究的关键。我们首先利用CUT&Tag方法结合的RNA-seq分析筛选下游潜在靶点和通路,干扰筛选出的目标靶点后,检测mGSCs的增殖能力、凋亡和干性变化。然后明确目标靶点对GSCs亚型转化的调控,结合体外实验观察对放化疗抵抗的作用,进一步观察目标靶点对mGSCs成瘤能力和小鼠生存期的影响,从而确定mGSCs中T3结合THRA调控的下游靶点和信号通路。
(2)T3代谢通路下游靶点及信号通路与临床相关性的确定
为探索下游靶点抑制剂在GBM放化疗抵抗中的应用,首先需明确T3代谢通路下游靶点及信号通路与临床相关性,我们首先在mGSCs中分别干扰T3下游代谢通路关键靶点,通过体内和体外实验明确各靶点对下游通路的调控作用;利用临床病人血清分析T3和T4的表达与放化疗抵抗及预后的关系;最后通过检测GBM患者肿瘤组织中DIO1及关键靶点的表达,进一步确定其放化疗抵抗和预后的关系。从而确定T3代谢通路下游靶点及信号通路与临床相关性。
本发明是对TH信号通路参与mGSCs特性维持机制的重要补充,对T3影响GBM放化疗抵抗调控机制的进一步完善,为增强GBM放化疗敏感性提供新的靶点,为GBM临床治疗提供理论基础。
在本发明中的提到的任何数值,如果在任何最低值和任何最高值之间只是有两个单位的间隔,则包括从最低值到最高值的每次增加一个单位的所有值。例如,如果声明一种组分的量,或诸如温度、压力、时间等工艺变量的值为50-90,在本说明书中它的意思是具体列举了51-89、52-88……以及69-71以及70-71等数值。对于非整数的值,可以适当考虑以0.1、0.01、0.001或0.0001为一单位。这仅是一些特殊指明的例子。在本申请中,以相似方式,所列举的最低值和最高值之间的数值的所有可能组合都被认为已经公开。
应当注意的是,以上所述的实施例仅用于解释本发明,并不构成对本发明的任何限制。通过参照典型实施例对本发明进行了描述,但应当理解为其中所用的词语为描述性和解释性词汇,而不是限定性词汇。可以按规定在本发明权利要求的范围内对本发明作出修改,以及在不背离本发明的范围和精神内对本发明进行修订。尽管其中描述的本发明涉及特定的方法、材料和实施例,但是并不意味着本发明限于其中公开的特定例,相反,本发明可扩展至其他所有具有相同功能的方法和应用。
Claims (9)
2.权利要求1所述的T3或其可药用盐在制备脑胶质瘤放化疗药物方面的应用。
3.根据权利要求2所述的T3或其可药用盐在制备脑胶质瘤放化疗药物方面的应用,其特征在于,所述药物以T3或其可药用盐作为活性成分,所述活性成分的重量百分含量为1%~99%。
4.根据权利要求2或3所述的T3或其可药用盐在制备脑胶质瘤放化疗药物方面的应用,其特征在于,所述药物还包括药学上可接受的载体。
5.根据权利要求4所述的T3或其可药用盐在制备脑胶质瘤放化疗药物方面的应用,其特征在于,所述载体至少选自填充剂、粘合剂、润湿剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润湿剂、香味剂或甜味剂中的一种。
6.根据权利要求5所述的T3或其可药用盐在制备脑胶质瘤放化疗药物方面的应用,其特征在于,所述填充剂至少选自淀粉、蔗糖和乳糖中的一种;和/或,所述粘合剂至少选自纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮中的一种;和/或,所述润湿剂为甘油;和/或,所述崩解剂至少选自琼脂和碳酸钙中的一种;和/或,所述吸收促进剂为季铵化合物;和/或,表面活性剂为十六烷醇;和/或,所述吸附载体至少选自高岭土和蒙脱石中的一种;和/或,所述润滑剂至少选自滑石粉、硬脂酸钙和聚乙二醇中的一种。
7.根据权利要求1-6所述的T3或其可药用盐在制备脑胶质瘤放化疗药物方面的应用,其特征在于,所述的药物的剂型包括粉剂、注射液、胶囊、片剂和口服液。
8.一种药物组合物,其特征在于,包括治疗有效量的权利要求1所述的T3或其可药用盐,以一种药学上可接受的载体或赋形剂。
9.权利要求8所述的药物组合物在制备胶质瘤放化疗药物中的应用。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2010148007A2 (en) * | 2009-06-17 | 2010-12-23 | Ordway Research Institute, Inc. | Nanoparticle and polymer formulations for thyroid hormone, analogs, antagonists, and formulations and uses thereof |
CN102858156A (zh) * | 2010-04-28 | 2013-01-02 | 奥斯娜特·阿舒尔-费边 | 用于提供治疗的方法、组合物和试剂盒 |
EP2662079A1 (en) * | 2012-05-10 | 2013-11-13 | Ordway Research Institute, Inc. | Uses of formulations of thyroid hormone antagonists and nanoparticulate forms thereof to increase chemosensivity and radiosensitivity in tumor or cancer cells |
WO2018207171A1 (en) * | 2017-05-08 | 2018-11-15 | Musli Thyropeutics Ltd. | Bimodal modified release compositions for cancer treatment |
WO2021174195A2 (en) * | 2020-02-29 | 2021-09-02 | The University Of Vermon | Use of thyromimetics for the treatment of cancer |
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010148007A2 (en) * | 2009-06-17 | 2010-12-23 | Ordway Research Institute, Inc. | Nanoparticle and polymer formulations for thyroid hormone, analogs, antagonists, and formulations and uses thereof |
CN102858156A (zh) * | 2010-04-28 | 2013-01-02 | 奥斯娜特·阿舒尔-费边 | 用于提供治疗的方法、组合物和试剂盒 |
EP2662079A1 (en) * | 2012-05-10 | 2013-11-13 | Ordway Research Institute, Inc. | Uses of formulations of thyroid hormone antagonists and nanoparticulate forms thereof to increase chemosensivity and radiosensitivity in tumor or cancer cells |
WO2018207171A1 (en) * | 2017-05-08 | 2018-11-15 | Musli Thyropeutics Ltd. | Bimodal modified release compositions for cancer treatment |
WO2021174195A2 (en) * | 2020-02-29 | 2021-09-02 | The University Of Vermon | Use of thyromimetics for the treatment of cancer |
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