Construction And Biological Application Of Novel Perylene Diimide Based Photothermal Materials

Photothermal therapy（PTT）is a new treatment technique,which has the advantages of low invasibility,low toxicity and high spatiotemporal selectivity.PTT has a great prospect in the treatment of cancer,bacterial infection,thrombosis and other diseases.Designing and constructing photothermal materials with low toxicity and high photothermal conversion efficiency is the key to improve PTT.Perylene diimide（PDI）dyes have excellent light,heat and chemical stability,high molar extinction coefficient and adjustable photophysical properties.Therefore,PDI based photothermal materials have been widely studied.At present,PDI based photothermal materials are often constructed by extendingπ-conjugated structure or modifying strong electron-donating groups to form D-A configuration,which promotes the absorption redshift and the improvement of photothermal properties.However,the construction of PDI photothermal materials still faces the following problems:（1）The strategy to improve the photothermal conversion efficiency is single and the improvement is limited,and it is difficult to achieve a large red-shifted absorption and a significant improvement in the photothermal conversion efficiency;（2）The therapeutic function is single,and the single photothermal effect is difficult to achieve complete inhibition of tumors or bacteria,and there are also side effects such as damage to surrounding normal tissues.Against these issues,it is still necessary to develop new molecules and new strategies to further improve photothermal properties,and integrate multiple functions to comprehensively improve the effectiveness of PTT.Therefore,in this work,based on D-A configuration of PDI molecules,a variety of photothermal treatment enhancement strategies were designed.By constructing J-aggregated carrier-free photothermal nanomaterials,topological photothermal nanocomplexes with long conjugated structures,and cationic radical based photothermal materials,anti-tumor therapy enhanced by chemotherapy enhanced PTT and immunotherapy synergistic PTT and antibacterial therapy enhanced by physical photothermal treatment were successfully realized,respectively.The research content of this paper mainly includes the following aspects:1.A low-toxicity,carrier-free photothermal nanomaterials（ZPQ NPs）for enhancing chemical-photothermal cancer therapy was constructed by co-assembly of natural flavonols with dimethylamine-substituted D-A type PDI.Flavonols,especially quercetin,induce the J-aggregation of PDI,resulting in a variety of enhanced photophysical properties,including 60 nm redshifted absorption,a 4.5-fold increase in fluorescence intensity at high concentrations,and an increase in photothermal conversion efficiency to 40.1%under 808 nm laser radiation.In addition,ZPQ NPs also showed enhanced cellular uptake and intracellular reactive oxygen species clearance.Under the guidance of in vivo fluorescence imaging,chemotherapy combined with PTT can effectively kill cancer cells,completely ablate the tumor,and reduce the inflammatory response after PTT.2.In order to further improve the efficacy of PTT,a strategy for changing the tumor immunosuppressive microenvironment was developed to achieve immunotherapy synergistic PTT.A novel topological macromolecule（FTDI）composed of TDI based photothermal molecule as nucleus and fluorinated cationic polymer as shell were constructed by enhancing D-A and extending conjugation construction.FTDI has 808 nm absorption and high photothermal conversion efficiency with 54%.To achieve functionalization,nanocomplexes（FTDI@RNA@AGM）formed by loading MYC-si RNA and amphoteric-charged agmatine prodrug.Cell experiments showed that the nanocomplex had high cell uptake and strong lysosome escape ability,and could achieve efficient transfection of si RNA,thus enhancing the knockdown efficiency of oncogenic gene MYC,reducing the expression level of ornithine decarboxylase（ODC）.The above way could result in reducing the polyamine level in cancer cells and inhibiting the proliferation and survival ability of cancer cells.In vivo experiments showed that the decrease of polyamine level could increase the vitality of immune cells,lead to the high expression of CD8⁺T cells and M1 macrophages,and successfully down-regulate the expression of immunosuppressive cells（M2 macrophages,regulatory T cells and myeloid-derived suppressor cells）.The above results showed that the nanocomplex promoted the transformation of the immune microenvironment from"cold"tumor to"hot"tumor,and combined with PTT achieved effective inhibition of tumor,the inhibition rate was up to 96%or more.3.In order to further explore the application potential of PDI dyes with near infrared two-region（NIR-II）PTT,a class of cationic radical photothermal molecules were successfully constructed and applied to antibacterial therapy.D-A type PDI molecules with more electron-donating substitutions are easily oxidized to stable cationic radicals,and thus exhibits NIR-II absorption.In order to expand its biological application,stable cationic radical(B3NPDI/2CB[7]^·+)was obtained by assembly water-soluble B3NPDI with cucurbit[7]uril（CB[7]）and oxidized.B3NPDI/2CB[7]^·+has a photothermal conversion efficiency of up to 68%and good photothermal stability.In addition,B3NPDI/2CB[7]^·+has a high affinity and targeting to bacterial cell membranes due to its cationic structure,and thus has certain antibacterial activity.Subsequently,under the irradiation of 1064 nm laser,combined with the photothermal effect,Bacillus subtilis could be effectively inhibited,and the antibacterial efficiency reached more than 99%.In summary,this paper provides a new design idea and a new PTT application strategy for the construction of efficient and multi-functional photothermal materials.