中性粒细胞（NEs）-血小板（BP）-循环肿瘤细胞（CTC）的复合体、CTC团簇以及NEs胞外诱捕网（NET）在肿瘤转移关键环节中发挥了重要作用。本项目在研究完成NEs递药系统靶向实体瘤的基础上，根据NEs和乏氧诱导因子HIF-1α参与肿瘤转移多个关键环节的特性，应用NEs作为HIF-1α抑制剂的载体，特异性干预肿瘤转移多个关键环节，提高肿瘤转移治疗效果。通过直观及系统研究HIF-1α抑制剂干预复合体的乏氧微环境及击散CTC团簇的作用，对复合体渗出血管形成转移灶的影响、CTC团簇与肿瘤转移关系、NET-转移肿瘤细胞微环境乏氧特性、对转移肿瘤细胞在远端组织形成转移灶影响等，阐明HIF-1α干预肿瘤转移各环节的作用及作用机制等关键科学问题，为肿瘤转移的防治提供新思路，为基于HIF-1α靶点的新型抗肿瘤转移药物的发现及其递送系统的研发提供依据，并开辟药物递送系统用于研究生物学现象或过程的新方向。

Metastatic tumors are a major source of mortality for most cancers. Interaction of circulating tumour cells (CTCs) with neutrophils (NEs) and platelets, circulating tumour cell clusters (CTC-clusters), and neutrophil extracellular traps (NETs) play important roles in multiple stages of metastasis. We have recently demonstrated that NEs-mediated delivery of drugs efficiently suppressed the recurrent growth of solid tumors with significantly improved survival rate. In the light of this evidence and that NEs and HIF-1α are involved in multiple key stages in metastasis progression, we utilize NEs as HIF-1α inhibitor carriers and navigators to improve the therapeutic effect of metastatic cancer by specifically targeting multiple key stages in tumor metastasis. The goal of this proposal is: 1) to directly and systematically investigate the role of HIF-1α inhibitor in intervening hypoxic tumor microenvironment formed by NEs-platelet-CTCs complex and breaking off CTC-clusters, 2) to evaluate the extravasation effect of CTCs into the metastatic foci, 3)to identify the relationship between circulating tumor cell clusters and tumor metastasis, 4) to validate microenvironmental hypoxia formed by NETs-metastatic tumor cells and the effect of HIF-1α inhibitor in formation of distant metastases, and 5) to elucidate the intervention effect and mechanism of HIF-1α inhibitor in various stages of tumor metastasis. Our proposal will provide new insights into the prevention and treatment of metastatic cancer, and scientific basis for the discovery and development of novel anti-metastatic drugs and their delivery system targeting HIF-1α, opening up a promising new avenue of utilizing drug delivery system in the research of biological phenomena and processes.