Fabrication Of Light-responsive Polymer Composite Nanodrug Carriers And Their Anti-tumor Effects

Nanodrug carrier is a nano-level drug delivery system,which has the advantages of longer blood circulation time,easy modification,and enhanced permeability and retention(EPR),so it is widely used in anti-tumor therapy.To further enhance the therapeutic effect and reduce side effects,responsive nanodrug carriers have been developed.Under the action of specific stimuli(such as p H,glutathione,enzymes,temperature,magnetic field and light,etc.),the responsive nanodrug carrier can achieve precision anti-tumor therapy and reduce side effects effectively.Light-responsive nanodrug carriers with the advantages of simplicity,non-invasiveness,strong specificity and spatiotemporal control have great application prospects in the fields of photodynamic therapy and chemotherapy.However,it is still challenge to design and construct a reasonable and efficient light-responsive nanoplatforms for enhancing anti-tumor effect.In this thesis,through problem-oriented material design concepts,we screened the structural characteristics of nanocarriers and light-responsive materials,constructed four light-responsive polymer composite nanomedicine systems,and systematically studied their applications in fluorescence imaging-guided chemotherapy,photodynamic therapy and synergistic chemo-photodynamic therapy.The main research results are as follows:(1)Near-infrared(NIR)light-responsive ratiometric fluorescent composite nanomicelles for fluorescence imaging-guided chemotherapy.Through the self-assembly of light-responsive amphiphilic fluorescent block copolymers(PEG-b-P(NBA-co-NBANA)),upconversion nanoparticles(UCNPs)and doxorubicin(DOX),we prepared near-infrared light-responsive composite micelles for spatiotemporal controlled theranostics nanoplatform.UCNPs could covert NIR light to UV-light upon NIR light irradiation,which triggered the photoreaction of PEG-b-P(NBA-co-NBANA)to achieve ratiometric fluorescence imaging.In addition,the UCNPs emitted UV-light triggered the DOX release of micelles and then activated anti-tumor effect.Hence,NIR light could regulate ratiometric fluorescence imaging and anti-tumor effect of micelles to achieve the spatial-temporal controllable theranostics.(2)Mitochondria-targeted UCNPs/metal-organic framework composite nanoenzyme for enhanced photodynamic therapy in hypoxic tumor.To improve the hypoxic environment of solid tumors and enhance the effect of photodynamic therapy,we prepared a composite nanomedicine(TPP-UCNPs@MOF-Pt)with surface modified triphenylphosphine(TPP)and platinum nanoparticles(Pt NPs).The in vivo and in vitro experiment proved that Pt NPs on the surface of TPP-UCNPs@MOF-Pt could catalyze H₂O₂ to generate O₂,which effectively improved the hypoxic environment in tumors tissues and then enhanced the photodynamic therapeutic effect.Moreover,TPP-UCNPs@MOF-Pt modified with TPP group could efficiently accumulate in mitochondria.Under 980 nm NIR light irradiation,the reactive oxygen species(ROS)generated by TPP-UCNPs@MOF-Pt can induce rapid depolarization of inner mitochondrial membrane potential and accelerate the apoptosis of tumor cells,further enhancing the photodynamic therapeutic effect on solid tumors.(3)Light-driven ROS-sensitive polymer nanomedicine for synergistic photodynamic therapy and chemotherapy.Compared with single chemotherapy or photodynamic therapy,synergistic therapy has better anti-tumor effects.Hence,we developed a ROS sensitive polymer(PPE-Dex)based nanomedicine(PPE-Dex@DOX/Ce6)with co-loading of the photosensitizer(Ce6)and DOX for synergistic photodynamic therapy and chemotherapy through a hand-driven membrane-extrusion emulsification route.PPE-Dex@DOX/Ce6 nanoparticles generated abundant ROS under 655 nm laser irradiation.ROS can not only be used for photodynamic therapy of tumors,but also triggered the rapid release of DOX by degrading PPE-Dex,then resulting in significant synergistic photodynamic therapy and chemotherapy.In addition,the synergistic effect of photodynamic and chemotherapy mediated by PPE-Dex@DOX/Ce6 nanoparticles was confirmed by the combined index(CI).(4)Spectral-matched polymer/UCNPs composite nanomedicine for enhanced synergistic photodynamic therapy/chemotherapy.To solve the problem of mismatch between the emission spectrum of UCNPs and the absorption spectrum of the photosensitizer,we constructed spectrum-matched composite nanomedicine based on the self-assembly of ROS responsive PEG-b-PPS,UCNPs,Ce6 and DOX for synergistic photodynamic therapy and chemotherapy,and systematically studied the effect of spectrum matching(the emission spectrum of UCNPs and the absorption spectrum of Ce6)on the synergistic photodynamic therapy and chemotherapy.Compared with the spectral-mismatched PUHM@Ce6/DOX,the spectral-matched PUHM@Ce6/DOX could generate higher concentration of ROS.The higher concentration of ROS not only triggered stronger photodynamic therapeutic effect,but also promoted the rapid release of DOX by speeding up the disassembly of PUHM@Ce6/DOX,which thereby enhanced the effect of synergistic photodynamic therapy and chemotherapy.