Cell Membranes In Situ Construct Bioresponsive Networks To Inhibit Tumor Migration

Cancer is now the second leading cause of death in the world.For cancer,traditional treatment methods,such as chemotherapy,often fail to achieve a good effect,and will also bring large side effects,poor prognosis,poor quality of life of patients,cancer is easy to relapse and other shortcomings.Cancer metastasis is the cause of death in 90%of cancer patients,so it is an urgent task to find a safe and effective drug to inhibit tumor cell metastasis.In recent years,epithelial-mesenchymal transformation（EMT）has been widely studied as a mechanism of tumor metastasis.The increase of mesenchymal markers and the disappearance of epithelial features are associated with the early stage of metastasis in various solid tumors.EMT is a crucial process for tumor cells to increase motility and migration.Binding of CD44 to the receptor-ligand of hyaluronic acid has been shown to induce epithelial-mesenchymal transformation.CD44,as a single-chain glycoprotein,is associated with cell adhesion and migration,homing and activation of lymphocytes,regulation of extracellular matrix,and abnormal behavior of tumor cells.The expression of CD44 was positively correlated with the mesenchymal phenotype of cells.When CD44 expression was down-regulated,the number of cells undergoing EMT was also decreased.The receptor-ligand binding of CD44 and hyaluronic acid can change the conformation of CD44,thus triggering a series of downstream signal responses and enhancing cell proliferation and metastasis ability.CD44-mediated iron endocytosis can regulate epigenetic inheritance and promote EMT process.However,high molecular weight hyaluronic acid can isolate iron ions in the cell by interacting with CD44,regulate iron-dependent epigenetic plasticity,and prevent cell EMT process.In this study,we synthesized an enzyme responsive polymer nanodrug,which have a ability of targeting CD44 receptor-hyaluronic acid-phosphorylated dopamine（HDP,HA-Dopa-H₂PO₄）.The hyaluronic acid skeleton specifically targets the CD44receptor of tumor cells.The enzyme response part can interact with alkaline phosphatase in tumor microenvironment to achieve the purpose of dephosphorylation.Therefore,the two phenolic hydroxyl groups of catechol are exposed,which can coordinate and cross-link with iron ions to block cell iron supply,inhibit tumor cell migration,and prevent tumor EMT process.In this paper,the structure analysis and morphology observation of nano-drug HDP were carried out,the ability of enzyme response and the crosslinking with iron were studied.Its cytotoxicity,inhibition of tumor cell migration and biological mechanism were studied.The results showed that HDP had good biocompatibility and no obvious cytotoxicity.Compared with other control molecules,HDP has better anti-tumor cell metastasis ability and inhibits tumor EMT process.Combined with chemotherapeutic drugs,HDP achieved higher efficacy and demonstrated its potential as an adjuvant for chemotherapeutic drugs.To sum up,this project designed and synthesized the nanodrug HDP,which can specifically target CD44 receptor.It dephosphorylates in the tumor microenvironment and cross-links with iron in the environment to form a cell-enveloping polymer network,which inhibits the migration and EMT process of tumor cells.At the same time,HDP provides a new idea for the development of chemotherapy adjuvant due to its excellent biocompatibility.