Construction Of Fibronectin-Coated Metal-Phenolic Network Nanoplatform For Tumor Theranostics

Cancer has become one of the main killers threatening human health.Although traditional treatment methods including chemotherapy,radiotherapy,and surgical resection can cure tumors to some extent,they have some technical bottlenecks such as severe side effects and easy recurrence.Therefore,it is imminent to develop some accurate and efficient treatment strategies.On the one hand,researchers have proposed a variety of new treatment techniques,such as chemodynamic therapy,immunotherapy,and gene therapy.Among them,nanomaterials based on transition metal ions such as Fe and Cu can be used to catalyze the H₂O₂ at the tumor site to produce a large amount of toxic reactive oxygen species,leading to the death of tumor cells by peroxidation,which is called chemodynamic therapy.Blocking T cells or corresponding receptors in the tumor site through PD-1/PD-L1 antibody can implement anti-tumor immunotherapy with high efficacy.In addition,the researchers also have found that chemotherapy or chemodynamic therapy can simultaneously stimulate the immunogenic death of tumor cells.On the other hand,researchers have also put forward efficient treatment strategies that integrate multiple treatments（multimodal treatment）or combine diagnosis and treatment（for real-time monitoring and prognostic evaluation of treatment effects）.The key technology for above strategies is to construct a suitable nanocarrier to efficiently load one or more therapeutic agents and/or contrast agents and effectively deliver them to the lesion site.An ideal nanocarrier can not only efficiently load therapeutic agents and/or contrast agents,and specifically target and enrich the lesions via functionalization,but also be easily synthesized and functionalized for clinical transformation.Among many carrier materials,it is easy for tannic acid（TA）to form a network structure under neutral conditions,and its multiple phenolic hydroxyl functional groups on its surface make it easy to be multi-functionalized（eg.target ligand modification）.Based on these,this study intends to construct chemotherapy drug doxorubicin（DOX）-loaded TA/iron complex（DOX-TAF）,which is then coated with fibronectin（FN）to form DOX-TAF@FN for T1 MR Imaging-guided chemotherapy/chemodynamic/immune combined therapy of melanoma（B16）tumor model.First,a metal phenolic network complex of iron and TA（as main material of nanoplatform）was first constructed via hydroxyl bonding between iron ion and TA,to load chemotherapeutic drugs DOX by a one-step method.Then the formed DOX-TAF was further modified with FN through hydrogen bond between the amino group of FN and the hydroxyl group of TA to generate FN-coated DOX-TAF complex（DOX-TAF@FN）for chemotherapy/chemodynamic/immune combined targeted therapy of B16 tumor model.The presence of FN accords the nanoplatform abilities to extend blood circulation time,reduce immune rejection and precisely target tumor sites.The TA/iron metal phenol network structure endows the drug-loaded nanoplatform with p H-responsive dissociation at the tumor site,accelerating release of DOX,and enhanced chemotherapeutical efficacy,and the dissociated iron ions can simultaneously perform chemodynamic therapy and T₁ MR imaging.The physiochemical characterization results display that the prepared DOX-TAF@FN is uniform,monodisperse in solution,and has high drug loading capacity and p H-responsive drug release profile;at the same time,the metal-phenolic network exhibits a higher dissociation rate of iron ions under acidic conditions than normal physiological environment,and has a great potential for chemodynamic therapy and an excellent relaxation rate.The in vitro results show that after DOX-TAF@FN treated B16 cells,the changes in GSH,ROS and LPO of cells confirm that DOX-TAF@FN has a good chemodynamic therapeutic effect;the expression of CRT in the cells and the release of ATP and HMGB-1 suggest that DOX-TAF@FN can cause the immunogenic death of B16 cells to a high extend.The in vivo results indicate that the expression of CD4 and CD8 in the tumor and spleen verify that the combination of chemotherapy/chemodynamic therapy is able to induce an anti-tumor immune response in mice;and further intratumoral injection of PD-L1 antibody can result in an enhanced immunotherapy effect.In conclusion,the constructed DOX-TAF@FN nanoplatform can achieve T₁ MR imaging-guided targeted chemotherapy/chemodynamic/immune combined therapy at tumor site.The findings from this study provide new ideas for the development of novel,easily synthesized nanoplatforms for imaging-guided therapy with high efficacy.