Construction Of Stable Perylenediimide Radical Anion Photothermal Materials And Their Immune Combination Therapy

Perylenediimide radical anions have great applications in biology due to their near-infrared absorption and good photothermal properties,as well as excellent thermal and photostability.However,the poor stability of radicals and the preparation of radicals by chemical reduction methods suitable for biological fields require the use of highly toxic chemical reducing agents,resulting in fewer applications of perylenediimide radical anions in biological fields,and the inability of single photothermal therapy to avoid tumor recurrence and metastasis further limits their applications.To address the above problems,this thesis introduces an "electron-absorbing" group at the perylenediimide bay position to enhance the stability of the radical anion,and a functional polymer at the imide position to give it spontaneous radical generation,antigen loading-delivery ability and improved biocompatibility,followed by cancer cell membrane wrapping to provide specific tumor targeting.The combination of photothermal-immunotherapy is highly effective in killing tumors.Firstly,the cyano-group with strong "electron absorption" was introduced at the perylenediimide bay position to verify the radical anion generation ability of cyanogenic perylenediimide by testing its redox potential,and co-assembled with organic amines to obtain stable perylenediimide radical anions.Subsequently,an integrated core-shell macromolecule was constructed to significantly improve the radical stability,and a block copolymer of acrylate with tertiary amine and mannose was introduced at the imide site to form nanoparticles by self-assembly in an aqueous environment through hydrophobic and π-π interactions to produce a stable cyanogenic perylenediimide photothermal reagent.Among them,the polymer chain segment with tertiary amine provides the reduction of cyanogenic perylenediimide nuclei to spontaneously form radical anions to bring photothermal properties,while its acid responsiveness makes it electrically neutral in physiological environment and thus reduces physiological toxicity;the mannose chain segment gives it hydrophilicity,biocompatibility and antigen presentation cell targeting.Therefore,the above design strategy is expected to achieve efficient synergistic anti-cancer treatment by photothermal therapy with cyano-substituted perylenediimide radical anions and immunotherapy with amphiphilic block copolymers loaded with tumor antigens and stimulated immune response.To verify the synergistic anticancer effect of cyano-substituted perylenediimide functional polymers,the immunostimulatory effect of a series of structures of cyanogenic perylenediimide photothermal reagents was evaluated,and the best cyanogenic perylenediimide photothermal reagents were screened for combined photothermal-immunotherapy.The screened optimal structures were prepared as nanoparticles using cancer cell membrane wrapping,and their tumor and antigen presenting cell targeting ability was verified by cell uptake assays.Subsequently,the nanoparticles were co-incubated with cancer cells,killed by photothermal heat and loaded with antigen in situ,and the complexes were extracted and co-incubated with dendritic cells,demonstrating that the complexes significantly promoted the maturation of dendritic cells and stimulated immune responses,which validated the feasibility of the combined photothermal-immunotherapy strategy at the cellular level.In conclusion,this thesis constructs a stable perylenediimide radical anion to achieve combined photothermal and multiple enhanced activation immunotherapy of tumors,which provides a new idea for the biological application of perylenediimide radical anions.