血管正常化对化疗药物在实体肿瘤内转运的影响及调控机制

Numerous pre-clinical and clinical studies have proved that anti-angiogenic drugs might briefly normalize the tumor vessels, as well as improving the therapeutic effects of certain chemotherapy drugs. "Vascular normalization theory" has gained more and more support on elucidating the synergistic effect of drug combinations, and has shown broad application prospects in the development of clinical combination therapy. However, few studies in depth have been focused on the effects of the time window of vascular normalization on pharmacokinetic behaviors of chemotherapeutic drugs in solid tumors and the regulatory mechanisms, most of which were simply confined to the accumulation of chemotherapeutic drugs in tumors. On the base of the previous studies on cellular pharmacokinetics in the project team, this project has planned to establish real-time visualized pharmacokinetic techniques and analytical methods in mice with colon cancer with modern imaging technology on monitoring the behaviors of entering the solid tumor tissues, transport from proximal to distal of the blood vessels, and behaviors of entering single cell or subcellular organelle of chemotherapeutic drugs. Meanwhile, the time window boundaries of vascular normalization of different drugs will be specified, and variation and regulation mechanisms of pharmacokinetic behaviors of chemotherapeutic drugs will be illustrated in solid tumors within and outside the time window by bridging with the tumor microenvironment. Additionally, the PK-PD model will be constructed of the treatment regimens of vessel normalization combined with chemotherapeutic drugs, thus providing a scientific basis for developing more rational clinical combination regimens.

诸多临床前和临床研究证实抗血管生成药物可短暂地使肿瘤血管恢复并接近正常化，且可改善某些化疗药物的治疗效果。“血管正常化理论”在解释联合用药的协同作用上得到国际越来越广泛的认可，在制定临床联合治疗方案中有广阔的应用前景。然而，血管正常化的时间窗对化疗药物在实体肿瘤内药动行为的影响及调控机制尚未见深入研究，多局限于简单的肿瘤内化疗药物累积的测定。基于项目组前期细胞药代动力学的研究基础，本项目拟在结肠癌小鼠模型上，结合现代成像技术并集成创新，建立化疗药物进入实体瘤组织、由血管近端向远端转运、进入单细胞/亚细胞的实时可视化的药代研究技术与分析方法；明确不同治疗药物血管正常化的时间窗界限，通过与微环境的桥接研究，阐明时间窗内、外化疗药在实体瘤内药动学行为的变化规律及其调控机制；最后构建血管正常化联合化疗药治疗方案的PK-PD模型，为临床上制定更为合理的联合用药方案提供科学依据。

诸多临床前和临床研究证实抗血管生成药物可短暂地使肿瘤血管恢复并接近正常化，且可改善某些化疗药物的治疗效果。“血管正常化理论”在解释联合用药的协同作用上得到国际越来越广泛的认可，在制定临床联合治疗方案中有广阔的应用前景。然而，血管正常化的时间窗对化疗药物在实体肿瘤内药动行为的影响及调控机制尚未见深入研究，多局限于简单的肿瘤内化疗药物累积的测定。本项目在结肠癌、肺癌等小鼠模型上，结合现代成像技术并集成创新，建立了实体瘤内化疗药的药代动力学研究技术新体系，获得可描述化疗药在实体瘤内部行为特征的可视化、定量数据，预测影响药物瘤内处置的因素；以公认的具有促血管正常化作用的抗血管生成药物(贝伐单抗)、阿帕替尼为研究对象，通过不同联合给药方案、不同时程的药效和药代动力学研究，明确不同治疗药物血管正常化的时间窗界限，通过与微环境的桥接研究，阐明时间窗内、外化疗药在实体瘤内药动学行为的变化规律及其调控机制；发现中药参麦注射液促血管正常化的作用，通过药动、药效的关联研究，阐明血管正常化调控药动行为的机制，为临床上制定合理的联合用药方案提供科学依据。. 项目按既定目标超额完成任务。在国际药代及药理领域权威期刊以通讯作者和第一作者发表SCI 论文14篇，国内核心期刊1篇；申请专利2项，其中1项获授权；培养毕业博士5名，毕业硕士2名。相关研究成果“细胞药代动力学新理论技术体系的创建及其在新药研发和临床用药中的应用”于2017年获得江苏省科技进步一等奖（排名第2）。