“舟楫之剂”——“桔梗-甘草”药对增强肺癌治疗药物靶向输运分布作用及机制研究

Lung cancer has the characteristic of high incidence and motality. To date, drug for treatment on lung cancer has unsatisfactory effect for the defect on multidrug resistance and deficiency on drug targeting carrier. Radix Platycodonis, recorded in classical book of traditional Chinese medicine, has the effect of “open lung and load the drug up” and act as the agent for water transport if combined with Radix liquiritiae. Lung cancer has the characteristic of high incidence and motality. To date, drug for treatment on lung cancer has unsatisfactory effect for the defect on multidrug resistance and deficiency on drug targeting carrier. Radix Platycodonis, recorded in classical book of traditional Chinese medicine, has the effect of “open lung and load the drug up” and act as the agent for water transport if combined with Radix liquiritiae. According to our former work, distribution of paclitaxel increased in lung in the pharmacokinetics expriments about application of the combination“Radix Platycodonis -Radix liquiritiae”with paclitaxel injection. So, it eluciated that “Radix Platycodonis -Radix liquiritiae” could act a role in transporting more drug to lung if paclitaxel injection used in treatment for lung cancer with “Radix Platycodonis -Radix liquiritiae” together and “Radix Platycodonis -Radix liquiritiae”could have the targeting effect for transporting drug to lung. Therefore, our project choosed xiaoaiping oral liquid, paclitaxel injection and hydroxycamptothecin as the research object and study the difference on pharmacokinetics, drug distribution using microdialysis sampling technique and the mass spectrometric analysis, and effect between the combination or not and.made correlation analysis. Furthermore, to explore the scientific reference for the application of the“Radix Platycodonis -Radix liquiritiae” as the agent for water transport, it madd further analysis on the protein and mRNA level of transport protein P-gp、MRP、LRP and affinity between pathogenic tissue and drug, even effect on the PH of the pathogenic tissue microenvironment.

由于缺乏理想的药物靶向运输载体，使得肿瘤药物在癌症患者术后康复治疗中无法达到药尽其效。发病率极高的肺癌靶向药物及输送载体成为当今研究热点。关于靶向运输在古代医家张元素的《医学启源》已有记载，如：“桔梗归肺经，具‘开提肺气载药上浮’作用，与甘草同行，可作舟楫之剂”，而且课题组前期实验显示紫杉醇注射液与“桔梗-甘草”合用可增加其在肺部的分布。因此，为了明确“桔梗-甘草”的肺靶向输送的“舟楫”作用，本课题拟以消癌平口服液、紫杉醇注射液、羟基喜树碱注射液为模型药物，通过对模型药物单独使用及与“桔梗-甘草”联合使用的药代动力学、体内分布及药效进行关联性分析；并结合“桔梗-甘草”对外排转运蛋白P-gp、MRP、LRP表达、对肺癌病变组织与药物亲和力、肺癌病变微环境pH的影响，探寻“桔梗-甘草”的肺靶向输送作用及增效作用机制，阐述“桔梗-甘草同行为舟楫之剂”的科学内涵，为临床肺癌药物治疗方案提供理论依据

由于缺乏理想的药物靶向运输载体，使得肿瘤药物在癌症患者术后康复治疗中无法达到药尽其效，提升药物在病灶的分布和浓度是对肿瘤靶部位有效治疗的抗肿瘤药物研究突破方向。“桔梗具‘开提肺气载药上浮’作用，与甘草同行，可作舟楫之剂”。“桔梗-甘草”引经作用配伍抗肺癌药物是否有提升化疗药物在病靶部位分布的作用是本课题的研究方向。为了明确“桔梗-甘草”的肺靶向输送的“舟楫”作用，本课题以消癌平口服液、紫杉醇注射液、羟基喜树碱注射液为模型药物，通过对模型药物单独使用及与“桔梗-甘草”联合后的药代动力学、体内分布及药效进行研究；并结合“桔梗-甘草”对外排转运蛋白P-gp、MRP、LRP表达、对肺癌病变组织与药物亲和力的影响，探寻“桔梗-甘草”的肺靶向输送作用及增效作用机制。结果表明，“桔梗-甘草”联合消癌平可显著改变消癌平中活性成分Tenacissoside H、Tenacissoside G和17β-tenacigeninB的药代动力学参数，促进消癌平活性成分Tenacissoside H和Tenacissoside G的吸收，但却减少了17β-tenacigeninB的吸收。“桔梗-甘草”联合羟基喜树碱和紫杉醇对其吸收无显著影响，但明显改变了二者在组织中的分布，增加了药物在肝、肺和心脏和肿瘤部位的分布。研究进一步结合动物模型探讨了桔梗甘草联合药物前后的抗癌作用差异，发现桔梗甘草联合后明显提升了化疗药物的抑瘤作用，提升了机体红细胞、血红蛋白以及血小板水平，显著抑制了IL-10，提升了IL-2、TNF-α或IFN-γ水平，提升了药物在病变部位的亲和力，抗癌作用与病变部位浓度密切相关。同时基于动物模型和体外耐药细胞模型探讨了桔梗甘草联合化疗药物提升化疗药物疗效的潜在作用机制，表明其与桔梗甘草逆转耐药蛋白LRP、P-gp和 MRP1有关。本项目证实了“‘桔梗-甘草’引药上行，为舟楫之剂”作用的客观存在，探讨了桔梗-甘草与肺癌治疗药物联合应用的增效减毒的作用，可为临床肺癌治疗给药方案设计提供理论依据。