Nir-Ⅱ Fluorescent Conjugated Polymer-based Photothermal/Photodynamic And CO Multimodal Therapy Of Tumors

Phototherapy mainly includes photothermal therapy（PTT）and photodynamic therapy（PDT）.PTT has the advantages of high precision,high specificity,and non-invasiveness,but the heat shock protein secreted by tumor cells limits its therapeuic effect;PDT has the advantages of high selectivity,negligible drug resistance and non-invasiveness,however,the short lifespan and small scope of action of reactive oxygen species（ROS）generated by photosensitizers and the hypoxic characteristics of tumor tissue lead to poor therapeuic efficacy.As a new type of topical therapy,gas therapy（GT）has the advantages of fast gas molecule penetration,low side effects to normal tissues,and no drug resistance.Therefore,the synergistic use of PTT,PDT,and GT for multimodal treatment of tumors can greatly improve the therapeuic effect.In this dissertation,the conjugated polymer nanoparticles（TTQ-Mn CO NPs）and conjugated polymer brushes（PBF-g-CO-PEG）were prepared to realize NIR-II fluorescence imaging-guided synergistic therapy of NIR-II PTT/CO and PDT/CO,respectively.The specific research contents of this dissertation are as follows:（1）NIR-II light-triggered NIR-II fluorescence imaging-guided NIR-II PTT/CO gas synergistic therapy:In this chapter,based on the previous research works of our group,the NIR-II photothermal and fluorescence performance of TTQ-1T and TTQ-2TC-4T was firstly tested and compared;and then TTQ-2TC-4T with excellent photothermal performance and NIR-II fluorescence signal was selected.Subsequently,the NIR-II laser（1064 nm）-triggered NIR-II PTT/CO synergistic therapeuic nanoparticles（TTQ-Mn CO NPs）were successfully fabricated.TTQ-Mn CO NPs exhibit excellent biocompatibility,particle stability,and photostability.The results of in vitro experiments showed that under 1064 nm laser irradiation,the NIR-II photothermal conversion efficiency of TTQ-Mn CO NPs was as high as 44.43%,indicating the excellent NIR-II PTT effect of TTQ-Mn CO NPs,which could effectively stimulate CO release to achieve GT effect as well.The results of in vivo testing in the MCF-7 tumor-bearing mice showed that TTQ-Mn CO NPs had bright NIR-II fluorescence under 808nm laser irradiation,enabling tumor imaging with a high signal-to-noise ratio（SBR=7.99）.In addition,compared with single NIR-II PTT（tumor inhibition rate of 82.23%）,NIR-II PTT/CO gas synergistic therapy displayed a more obvious anti-tumor effect（tumor inhibition rate as high as94.83%）.（2）NIR-II light-triggered NIR-II fluorescence imaging-guided PDT/CO synergistic therapy based on conjugated polymer brushes:In this work,we covalently bound a CO donor（CORM-401）onto the side chain of a water-soluble dendrimer conjugated polymer brush（PBF-AM3）.Subsequantly,a conjugated polymer brush PBF-g-CO-PEG with desirable NIR-II fluorescence imaging-guided PDT/CO synergistic therapeutic effect was prepared.PBF-g-CO-PEG exhibits bright NIR-II fluorescence,excellent water dispersibility and biocompatibility as well as a high CORM-401 loading rate（2.01%）.Under 740 nm laser irradiation,PBF-g-CO-PEG can efficiently generate singlet oxygen（¹O₂）,which can induce apoptosis in cancer cells.In addition,the PDT process can also stimulate CORM-401 to release CO without affecting the production of ¹O₂.In vitro cell experiments demonstrated that PBF-g-CO-PEG had excellent cytocompatibility and ideal PDT/CO synergistic therapeuic effect under 740 nm laser irradiation.The in vivo experimental results of the 4T1 tumor-bearing mice show that PBF-g-CO-PEG can achieve high signal-to-noise ratio of tumor under 808nm laser irradiation and PDT/CO gas synergistic therapeutic therapy under 740 nm laser irradiation,which can effectively inhibit tumor growth.In conclusion,PBF-g-CO-PEG has great potential for imaging-guided precision cancer therapy.