Construction Of Metal-phenolic Network-based Nanodrugs And Their Anticancer Applications

Cancer is one of the major threatens to human health,and tens of millions of cancer patients occur around the world every year.Nowadays,the mainly used anticancer strategies include surgery,chemotherapy,radiotherapy,and photodynamic therapy.Among them,chemotherapy is still one of the most widely used cancer therapeutic methods.However,the multidrug resistance of cancer,the low tumor accumulation of anticancer drugs,and the serious side effects result in the unsatisfactory therapeutic outcomes of chemotherapy.To solve the above problems,some novel anticancer methods have been developed and shown broad application prospects.As a new anticancer strategy,chemodynamic therapy(CDT)can convert the overexpressed hydrogen peroxide molecules in the tumor microenvironment into highly toxic hydroxyl radicals through Fenton or Fenton-like reaction,so as to effectively ablate the tumor tissues.Moreover,CDT can avoid the toxicity to normal tissues(because the content of hydrogen peroxide in the tumor area is higher than that in normal tissues,which makes CDT tumor-selective)and low efficiency(because CDT does not need external stimulation and oxygen)encountered by some traditional anticancer methods(e.g.,chemotherapy and photodynamic therapy).In this thesis,we prepared a series of metal-phenolic networks(MPNs)-based nanodrugs(through the combination of MPNs and some traditional nanocarriers that have been proved to have good biocompatibility)for cancer combination therapy and achieved superior anticancer outcomes.For the first system,doxorubicin(DOX)-based nanodrugs(termed DDTF)were constructed by loading DOX into dendrimer(Den)molecules and coating MPNs on the surface.The synthesized DDTF nanodrug could achieve efficient nuclear delivery of DOX for chemotherapy and MPN-induced CDT.The DOX-induced apoptosis and CDT-induced ferroptosis could finally lead to highly efficient anticancer outcomes.The DDTF nanodrugs could also reverse the multidrug resistance of cancer cells and show an efficient therapeutic effect in multidrug-resistant cancer cells and tumor models.For the second and third systems,we used MPNs to stabilize human serum albumin(HSA)to construct drug delivery nanosystems for the codelivery of small-molecule drugs and toxic proteins.In the second system,we loaded a hypoxia-responsive prodrug tirapazamine(TPZ)and glucose oxidase(GOx)in this system(termed HGTFT).GOx could consume oxygen and glucose and realize cancer starvation therapy,and TPZ could be converted into toxic TPZ radical in the hypoxic environment for cancer chemotherapy.In addition,the GOx-catalyzed reaction could produce hydrogen peroxide,which could enhance the MPN-mediated CDT.Furthermore,we proved that the HGTFT nanodrug could efficiently target the tumor area after intravenous administration and realize the starvation therapy,hypoxia enhanced chemotherapy,and CDT of tumors.For the third system,we loaded a cytolytic peptide melittin(Mel)and the immune adjuvant R848 into the nanodrug composed of HSA and MPNs(termed HRMTF).Mel could penetrate the cell membrane,induce the release of tumor-specific danger-associated molecular patterns,and realize immunogenic cell death(ICD).Combining the Mel-caused ICD with the MPN-induced CDT and R848-induced immunostimulation,the HRMTF could effectively kill cancer cells and stimulate the anticancer immune responses.In animal experiments,we verified that the HRMTF could arouse the anticancer immune responses and eradicate the primary and distant tumors in vivo.Collectively,we constructed a series of MPN-based nanodrugs to realize the combination of CDT and other anticancer therapeutic modalities(e.g.,chemotherapy,starvation therapy,and immunotherapy).This thesis confirmed the feasibility and effectiveness of the MPN-based nanodrugs from the aspects of the construction of the MPN-based nanodrugs,the interaction process between the drugs and cancer cells,the process of the Fenton reaction-triggered CDT,the tumor targeting of the drugs in vivo,and the stimulation of immune system.We expect that this thesis will provide new solutions to the common issues in the field of cancer therapy,such as multidrug resistance of cancer cells,low Fenton reaction efficiency,unsatisfactory tumor targeting efficiency,and severe side effects of nanodrugs.