Multifunctional Polymer Micelles For Tumor Chemotherapy, Photothermal, And Photodynamics, And Applications Thereof

The combination of photodynamic therapy,photothermal therapy and chemotherapy in multifunctional nanovesicles has emerged as a promising strategy to improve cancer therapeutic efficacy.More and more researches demonstrate that multifunctional nano-delivery system exert distinctly unique advantages on the multimodal synergistic therapy.Objectives:In order to overcome the shortcomings of non-specific binding,in vivo instability,toxic and side effects of traditional chemotherapy,and to break the limitations of photothermal therapy in the treatment of metastatic tumor cells,in this study,multifunctional targeted polymer micelles were used to contribute to the naissance of multimodal synergistic therapy by three monotherapies(including chemotherapy with systemic therapeutic effects,PTT or PDT with low invasiveness and high precision).Aiming to improve the lethality of antineoplastic agents to malignant tumor cells,and achieve the remarkable superadditive(namely "1+1>2"))synergistic effects.Methods:The new pH and reduction dual responsive polymeric micelles(PMs)based on amphiphilic copolymer PCL-ss-PEG-ss-PCL,in which chemotherapeutic drug(DOX),photosensitizer(ICG)and/or oxygen-generating agent(MnO2)were co-encapsulated,and the bio-active molecules were modified,were prepared by the thin-film hydration and ultrasonic dispersion method.Then,we investigated its physicochemical characteristics,stability and tumor-targeting ability of the multifunctional PMs,and studied its potential in targeting and synergistic chemo-photothermal/photodynamic-photothermal cancer therapy.Results:We fabricated a new pH/reduction/temperature multi-responsive and folate decorated polymeric micelles(Folate targeted ICG-DOX-loaded polymeric micelles,FA Co-PMs).and hyaluronic acid and transmembrane peptide modified oxygen-producing polymeric micelles(HA-TAT-ICG-MnO2-loaded polymeric micelles,HTIM-PMs).Those polymeric micelles exhibited nano-sized structure(～100 nm)with good monodispersity,high encapsulation efficiency,excellent light-thermal conversion efficiency,and triggered drug release in response to irradiation,acidic pH or reduction environment.In vitro cellular uptake study indicated FA Co-PMs and HTIM-PMs achieved significant targeting effect to tumor cells via receptor-mediated endocytosis,and laser-induced hyperthermia further enhanced drug accumulation into cancer cells.With the presence of acidic environment and H2O2,MnO2 could be rapidly reduced to oxygen and Mn2+,improving the therapeutic effect of PDT and PTT-PDT synthetic therapy.In vivo imaging,fluorescence imaging and immunohistochemical characterization confirmed that the polymeric micelles delivery system significantly improved the lethality to tumor and enhanced apoptosis and necrosis of tumor cells with 808 nm laser irradiation.Moreover,the results of H&E staining and the changes of body weight showed that this delivery system had good biocompatibility.Conclusion:The present study suggested that the versatile co-delivery polymeric micelles have strong advantages of tumor targeting,near-infrared imaging,acidity/reduction/temperature triggered drug release,and excellent combination cancer therapeutic effects.Therefore,the designed polymeric micelles were promising strategies for antitumor drug delivery and clinical application.