K237-KDR介导隐形纳米粒"节拍式化疗"诱导肿瘤血管"正常化"的作用和机制研究

Normalization of tumor vasculature is a newly revealed paramount mechanism of clinical antiangiogenic drugs for cancer therapy. Metronomic chemotherapy is a novel antiangiogenic strategy developed over the past 10 years, but whether or not metronomic chemotherapy has the nature of normalizing tumor vasculature has not been documented yet. In this study, K237-PTX-NP, paclitaxel loaded stealth nanoparticles decorated with K237 peptide that can target KDR receptors highly expressed in the tumor vascular endothelial cells, are chosen as the model for metronomic chemotherapy. For the first time, the potential of utilizing metronomic chemotherapy to normalize tumor vessel will be explored through monitoring the dynamic changes of various characteristic parameters of tumor vessel and microenvironment, dissecting the effect of normalizing tumor vessel and the underlying molecular mechanism, and evaluating the enhanced antitumor efficacy of conventional cytotoxic chemotherapy during the "normalization window". Our investigation will provide new theoretical ideas and guidance in the development of metronomic chemotherapy, tumor vessel normalization, and tumor vessel targeted nanoparticulate drug delivery system.

肿瘤血管"正常化"是抗血管生成药物治疗肿瘤应用中具有重要意义的全新作用机制，"节拍式化疗"作为一种新型肿瘤抗血管生成治疗策略是否也具有诱导肿瘤血管"正常化"的作用，尚未见相关研究报道。本项目以靶向肿瘤血管内皮细胞特异性高表达的KDR受体的K237多肽修饰的紫杉醇（PTX）隐形纳米粒（K237-PTX-NP）为给药系统模型，首次开展靶向纳米给药系统"节拍式化疗"诱导肿瘤血管"正常化"的探索性研究，考察各主要肿瘤血管"正常化"特征参数和肿瘤组织微环境参数在"节拍式化疗"中的动力学变化，探讨"节拍式化疗"诱导肿瘤血管"正常化"的作用和分子机制，评价在肿瘤血管"正常化窗口"期间协同细胞毒性化疗增强抗肿瘤作用的效应。本研究将为"节拍式化疗"和肿瘤血管"正常化"的基础和临床研究的发展、以及靶向肿瘤血管纳米给药系统的发展提供新的理论思路和指导作用。

肿瘤血管正常化是一种有望增强普通化疗疗效的方法。迄今为止，主动靶向纳米药物节拍式化疗是否具有诱导肿瘤血管正常化的作用尚有待探索。本研究中我们主要的创新点包括：1.率先构建F56多肽修饰的载有紫杉醇的纳米粒（F56-PTX-NP），发现F56-PTX-NP具有MDA-MB-231肿瘤血管内皮细胞表面VEGFR1受体特异性结合能力；2.发现F56-PTX-NP“节拍式化疗”可准确靶向肿瘤血管内皮细胞、“修剪”肿瘤血管，并诱导内皮细胞分泌TSP-1。3.揭示F56-PTX-NP“节拍式化疗”诱导肿瘤血管“正常化”的作用，包括显著增加周皮细胞和基底膜对肿瘤血管内皮细胞的覆盖、增加肿瘤组织氧分压（pO2）、降低肿瘤间质压力、增加肿瘤血流灌注、增加化疗药物（阿霉素）的递送和抗肿瘤疗效，其“正常化窗口”（normalization window）显著长于已报道中其他抗血管生成方法诱导的“正常化窗口”时间。本研究首次揭示了（靶向纳米给药系统）“节拍式化疗”诱导肿瘤血管“正常化”的作用并阐明其分子机制，为“节拍式化疗”和肿瘤血管“正常化”基础研究和临床转化的发展提供了新的理论思路和指导作用。