Biomimic Self-assembly To Construct The Artificial Fibronectin And Its Antitumor Properties

Cancer,also known as malignancy,is one of the refractory diseases.Cancer is the result of abnormal proliferation of somatic cells deficient of normal regulation.The high cancer mortality rate is due to the rapid tumor metastasis.Tumor metastasis is a complex process,which was related with extracellular matrix?ECM?.ECM can communicate with the tumor cells and induce the tumor cells to secret the tumor malignant factors.Fibronectins?FN?is one of the components of the ECM,which can connect the fibronectin-fibrin of the cells to the ECM.The fibronectin can be secreted by the tumor cells,subsequently,it can bind to the integrin and transform into the natural FN.Actually,the formation of the natural FN is due to the self-assembly on cell surfaces through the ligand-receptor interactions.Herein,inspired by the formation of the natural FN,we designed and prepared the artificial FN to modulate the tumor microenvironment.The FN formed as the physical barrier to repair the degraded the tumor ECM,which can be used for the inhibition of the tumor metastasis.The self-assembled nanoparticles are widely used in therapeutics,diagnostics,and bioimaging due to their good biocompatibility and safety.We designed and synthesized a series of peptide BP-KFFVLK-DGR-FFVLK-CREKA?FNMP?which can be used to construct artificial fibronectin?FN?.The FNMP includes four motifs:i)BP is a fluorescent molecule,which can induce the peptide self-assembly into the nanoparticles through the hydrophobicity and?-?interactions,ii)KLVFF peptide can induce the nanoparticles into nanofibers through hydrogen interactions,iii)the targeting peptide RGD can binding into the integrin of the tumor cell,iv)the CREKA peptide can targeting into the fibrin-fibronectin binding site.The FNMP can self-assemble into NPs,which were injected into the tumor bearing mice.The FNMP was enriched in the tumor site in form of NPs due to the passive and active targeting mechanism.Subsequently,the FNMP NPs transformed into NFs in situ to construct the artificial FN induced by RGD-integrin interactions as physical barrier to inhibit the tumor invasion and metastasis.First,we synthesized the fluorescent molecule BPCOOH,which was coupled with the polypeptide,as a strong hydrophobic core.Secondly,we synthesized the peptide nanomaterials through the soild-phase peptide synthesis methods,the structural transformation of the peptide from nanoparticles to nanofibers induced by Ca²⁺was confirmed through the transmission electron microscope?TEM?,The formation of the?-sheet structure was verified by the circular dichroism?CD?and Fourier transform infrared spectroscopy?FTIR?.Moreover,the structural transformation on the surface of the tumor cells which incubated with the FNMP and C-FNMP nanoparticles was observed by laser confocal electron microscopy?CLSM?and scanning electron microscopy?SEM?.Wound healing and tranwell migration and invasion assays were performed to confirm the biological effect,the results showed that the nanomaterials of FNMP can effectively inhibit the tumor invasion and metastasis.Lastly,the fluorescence imaging in vivo and ex vivo indicated that the nanoparticles of FNMP can enhanced retention time.The quantity of the lung modules and the result of the H&E staining showed that the FNMP can effectively inhibit the tumor metastasis compared to the C-FNMP and PBS.The constructed artificial fibronectin in situ can not only repair the degraded extracellular matrix,but also enhances the ability to block the tumor metastasis.The bio-mimic strategy for in vivo transformation of nanostructures,which may be utilized to modulate the tumor microenvironment for tumor therapy.